TW201904608A

TW201904608A - Method for treating hyperlipemia in diabetic patients by administering PCSK9 inhibitor

Info

Publication number: TW201904608A
Application number: TW107119851A
Authority: TW
Inventors: 波巴諾維克馬嘉布傑斯
Original assignee: 法商賽諾菲生物技術公司
Priority date: 2017-06-09
Filing date: 2018-06-08
Publication date: 2019-02-01
Also published as: IL271212A; AU2018280567A1; MX2019014831A; RU2019144346A3; RU2019144346A; CN110913889A; JP2023123842A; TW202310872A; EP3634469A1; KR20200026826A; CA3066317A1; JP2020522544A

Abstract

Provided are methods for treating high cardiovascular risk patients with hypercholesterolemia and type 1 or type 2 diabetes mellitus receiving insulin therapy. These methods generally comprise administering to a patient a pharmaceutical composition comprising an antibody or antigen binding fragment, thereof, which specifically binds hPCSK9 antibody, in combination with insulin therapy.

Description

藉由投予PCSK9抑制劑治療糖尿病患者高血脂症之方法 Method for treating hyperlipidemia in diabetic patients by administering PCSK9 inhibitor

【相關申請案】[Related applications]

本申請案主張於2017年6月9日提交的美國臨時專利申請號62/517,672、於2017年7月13日提交的美國臨時專利申請號62/532,162和於2018年5月4日提交的歐洲專利申請號18305565.6的優先權的權益。這些相關申請案每個的內容通過引用以其整體由此併入。 This application claims U.S. Provisional Patent Application No. 62 / 517,672, filed on June 9, 2017, U.S. Provisional Patent Application No. 62 / 532,162, filed on July 13, 2017, and Europe, filed on May 4, 2018 Right of Priority for Patent Application No. 18305565.6. The content of each of these related applications is hereby incorporated by reference in its entirety.

本發明係關於與升高的脂質或脂蛋白水準相關的疾病或病症的治療處理的領域。更具體地，本發明係關於PCSK9抑制劑治療患有包括高膽固醇血症在內的高脂血症的糖尿病患者。 The present invention relates to the field of therapeutic treatment of diseases or conditions associated with elevated lipid or lipoprotein levels. More specifically, the present invention relates to the treatment of PCSK9 inhibitors in diabetic patients with hyperlipidemia including hypercholesterolemia.

高脂血症是一般術語，其包括以血液中升高水準的脂質和/或脂蛋白為特徵或與之相關的疾病和病症。高脂血症包括高膽固醇血症、高甘油三酯血症、混合型高脂血症和升高的脂蛋白a(Lp(a))。許多群體中特別普遍的高脂血症形式是高膽固醇血症。 Hyperlipidemia is a general term that includes diseases and conditions characterized or associated with elevated levels of lipids and / or lipoproteins in the blood. Hyperlipidemia includes hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia, and elevated lipoprotein a (Lp (a)). A particularly common form of hyperlipidemia in many groups is hypercholesterolemia.

高膽固醇血症，特別是低密度脂蛋白(LDL)膽固醇(LDL-C)水準的增加，構成動脈粥樣硬化和冠心病(CHD)發展的主要風險(Sharrett et al.,2001,Circulation 104：1108-1113)。低密度脂蛋白膽固醇被確定為膽固醇降低療法的主要目標，並被接受為有效的替代治療終點。大量研究證實，降低LDL-C水準可降低CHD的風險，LDL-C水準與CHD事件之間存在強烈的直接關係；對於LDL-C每降低1mmol/L(~40mg/dL)，心血管疾病(CVD) 死亡率和發病率降低22%。LDL-C的更多減少產生CHD事件的更多減少，並且強化的與標準的他汀類(statin)治療的比較數據表明，LDL-C水準越低，心血管(CV)風險非常高的患者的益處越大。 Hypercholesterolemia, particularly increased levels of low-density lipoprotein (LDL) cholesterol (LDL-C), constitutes a major risk for the development of atherosclerosis and coronary heart disease (CHD) (Sharrett et al., 2001, Circulation 104: 1108-1113). Low-density lipoprotein cholesterol was identified as the main target of cholesterol-lowering therapy and was accepted as an effective alternative treatment endpoint. A large number of studies have confirmed that lowering the level of LDL-C can reduce the risk of CHD, and there is a strong direct relationship between LDL-C level and CHD events; for every 1mmol / L (~ 40mg / dL) reduction in LDL-C, cardiovascular disease ( (CVD) 22% reduction in mortality and morbidity. More reductions in LDL-C produce more reductions in CHD events, and intensive comparisons with standard statin therapy indicate that the lower the LDL-C level, the higher the risk for patients with very high cardiovascular (CV) risk The greater the benefits.

心血管疾病(CVD)是患有1型(T1)或2型(T2)糖尿病(DM)的患者的發病率和死亡率的主要原因，並且胰島素治療的糖尿病患者具有甚至更高的CV風險。此外，在患有動脈粥樣硬化性CVD(ASCVD)的患者中存在共患DM顯著增加了CV事件的風險。一些研究和meta-分析顯示，使用他汀類降低LDL-C導致DM患者中CV事件顯著減少，使用伴隨的依折麥布(ezetimibe)導致與額外的LDL-C降低有關的CV風險進一步降低。然而，即使使用目前可用的治療方法，許多患有DM的患者繼續具有持續的脂質異常，因此暴露於CV事件的殘餘風險。 Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 1 (T1) or type 2 (T2) diabetes (DM), and insulin-treated diabetic patients have an even higher risk of CV. In addition, the presence of comorbid DM in patients with atherosclerotic CVD (ASCVD) significantly increases the risk of CV events. Some studies and meta-analysis have shown that the use of statins to reduce LDL-C results in a significant reduction in CV events in DM patients, and the use of concomitant ezetimibe results in a further reduction in CV risk associated with additional reductions in LDL-C. However, even with currently available treatments, many patients with DM continue to have persistent lipid abnormalities and therefore are exposed to the residual risk of CV events.

目前LDL-C-降低藥物包括前蛋白轉化酶枯草溶菌素/kexin 9型(PCSK9)抑制劑，諸如抗PCSK9抗體。雖然抗PCSK9抗體已經過廣泛的臨床研究，但阿利庫單抗(alirocumab)在糖尿病群體中的功效和安全性尚不完全瞭解。因此，本領域需要鑒定抗PCSK9抗體的治療方案，其為處於高CV風險的接受胰島素治療的糖尿病患者提供治療高膽固醇血症的最佳功效和安全性。 Current LDL-C-lowering drugs include proprotein-converting enzyme subtilisin / kexin type 9 (PCSK9) inhibitors, such as anti-PCSK9 antibodies. Although anti-PCSK9 antibodies have been extensively clinically studied, the efficacy and safety of alirocumab in the diabetic population is not fully understood. Therefore, there is a need in the art to identify anti-PCSK9 antibody treatment regimens that provide the best efficacy and safety for treating hypercholesterolemia in insulin-treated diabetic patients at high CV risk.

本公開提供了用於治療患有糖尿病(DM)接受胰島素治療的患者中的高膽固醇血症的方法。在某些實施例中，該方法包括向患有高膽固醇血症和糖尿病的患者施用一個或多個劑量的特異性結合人類PCSK9的抗體或其抗原結合片段。在某些實施例中，該患者具有高心血管風險。在某些實施例中，該患者除胰島素治療之外還接受伴隨抗糖尿病治療。 The present disclosure provides a method for treating hypercholesterolemia in a patient with diabetes (DM) receiving insulin therapy. In certain embodiments, the method comprises administering to a patient suffering from hypercholesterolemia and diabetes one or more doses of an antibody or antigen-binding fragment thereof that specifically binds human PCSK9. In certain embodiments, the patient has a high cardiovascular risk. In certain embodiments, the patient receives concomitant anti-diabetic therapy in addition to insulin therapy.

根據一方面，該方法包括一種用於治療患有1型糖尿病(T1DM)的患者中的高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300 mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 According to one aspect, the method includes a method for treating hypercholesterolemia in a patient with type 1 diabetes (T1DM), the method comprising: (a) selecting a high cardiovascular risk patient receiving insulin therapy, whose disease Yes (i) T1DM, and (ii) treatment of insufficiently controlled hypercholesterolemia with maximally tolerated statins; and (b) administering to the patient 75 mg, 150 mg, or 300 mg of specific binding human preprotein converting enzyme An antibody or antigen-binding fragment thereof of subtilin / kexin type 9 (PCSK9), wherein the patient is receiving concomitant insulin therapy.

在某些實施例中，每兩週向該患者施用75mg的該抗體或抗原結合片段。在其他實施例中，每兩週向該患者施用150mg的該抗體或抗原結合片段。在其他實施例中，每四週向該患者施用300mg的該抗體或抗原結合片段。 In certain embodiments, the patient is administered 75 mg of the antibody or antigen-binding fragment every two weeks. In other embodiments, the patient is administered 150 mg of the antibody or antigen-binding fragment every two weeks. In other embodiments, the patient is administered 300 mg of the antibody or antigen-binding fragment every four weeks.

在某些實施例中，該抗體或其抗原結合片段包含包含SEQ ID NO：1/6的HCVR/LCVR胺基酸序列對的重鏈和輕鏈CDR。在某些實施例中，該抗體或其抗原結合片段包含SEQ ID NO：2、3和4示出的三個重鏈CDR，和SEQ ID NO：7、8和10示出的三個輕鏈CDR。在某些實施例中，該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的重鏈可變區(HCVR)，和具有SEQ ID NO：6的胺基酸序列的輕鏈可變區(LCVR)。在某些實施例中，該抗體或其抗原結合片段與包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR的抗體或其抗原結合片段競爭結合。在某些實施例中，該抗體或其抗原結合片段與PCSK9的表位結合，該表位與包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR的抗體結合的表位相同。在某些實施例中，該抗體或其抗原結合片段與PCSK9的表位結合，該表位與包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR的抗體的表位重疊。 In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain CDR comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1/6. In certain embodiments, the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs shown in SEQ ID NOs: 2, 3, and 4 and three light chain chains shown in SEQ ID NOs: 7, 8, and 10 CDR. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1 and a light chain having an amino acid sequence of SEQ ID NO: 6 Chain variable region (LCVR). In certain embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof comprising an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 Competitive combination. In certain embodiments, the antibody or antigen-binding fragment thereof binds to an epitope of PCSK9, the epitope is associated with an HCVR comprising an amino acid sequence of SEQ ID NO: 1 and an amino acid having SEQ ID NO: 6 The sequences of the LCVR antibodies bind to the same epitope. In certain embodiments, the antibody or antigen-binding fragment thereof binds to an epitope of PCSK9, the epitope is associated with an HCVR comprising an amino acid sequence of SEQ ID NO: 1 and an amino acid having SEQ ID NO: 6 The sequences of the epitopes of the LCVR antibodies overlap.

在某些實施例中，該抗體或其抗原結合片段包含具有SEQ ID NO：86、87、88、90、91和92的重鏈和輕鏈CDR胺基酸序列。在某些實施例中，該抗體或其抗原結合片段包含具有與SEQ ID NO：85中示出的胺基酸序列具有至少90%、95%或99%同一性的胺基酸序列的HCVR，和具有與SEQ ID NO：89中示出的胺基酸序列具有至少90%、95%或99%同一性的胺基酸序列的LCVR。 In certain embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs: 86, 87, 88, 90, 91, and 92. In certain embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence having at least 90%, 95%, or 99% identity to the amino acid sequence shown in SEQ ID NO: 85, And an LCVR having an amino acid sequence having at least 90%, 95%, or 99% identity to the amino acid sequence shown in SEQ ID NO: 89.

在某些實施例中，該抗體或其抗原結合片段選自以下組成之群組：阿利庫單抗(alirocumab)、依伏庫單抗(evolocumab)、bococizumab、羅德希珠單抗(lodelcizumab)、ralpancizumab和LY3015014。在某些實施例中，該抗體或其抗原結合片段是阿利庫單抗。 In certain embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of: alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab And LY3015014. In certain embodiments, the antibody or antigen-binding fragment thereof is aliculumab.

在某些實施例中，本文所公開的方法進一步包括：(c)如果，例如8週後，該患者中的LDL-C水準低於閾值水準，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果，例如8週後，該患者中的LDL-C水準大於或等於閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。在某些實施例中，該閾值水準是70mg/dL。 In certain embodiments, the methods disclosed herein further comprise: (c) if, for example, after 8 weeks, the patient's LDL-C level is below a threshold level, administering one or more to the patient approximately every two weeks Less than 75 mg of the antibody or antigen-binding fragment thereof, or if, for example, after 8 weeks, the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg are administered approximately every two weeks The antibody or antigen-binding fragment thereof. In some embodiments, the threshold level is 70 mg / dL.

在某些實施例中，本文所公開的方法進一步包括：(c)如果，例如8週後，該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果，例如8週後，該患者中的LDL-C水準大於或等於閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。在某些實施例中，該閾值水準是70mg/dL。 In certain embodiments, the methods disclosed herein further comprise: (c) administering one or more to the patient about every four weeks if, for example, 8 weeks later, the patient's LDL-C level is below a threshold level The following dose of 300 mg of the antibody or antigen-binding fragment thereof, or if, for example, after 8 weeks, the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following dose of 150 mg is administered approximately every two weeks The antibody or antigen-binding fragment thereof. In some embodiments, the threshold level is 70 mg / dL.

在某些實施例中，該抗體或其抗原結合片段係皮下施用。 In certain embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

在某些實施例中，該患者進一步接受伴隨脂質修飾治療(lipid-modifying therapy)(LMT)。在某些實施例中，該LMT選自以下組成之群組：他汀類、膽固醇吸收抑制劑、纖維酸類(fibrate)、菸鹼酸類、ω-3脂肪酸和膽汁酸螯合劑。在某些實施例中，該LMT是他汀類治療。在某些實施例中，該他汀類選自以下組成之群組：阿托伐他汀(atorvastatin)、瑞舒伐他汀(rosuvastatin)、辛伐他汀(simvastatin)、普伐他汀(pravastatin)、洛伐他汀(lovastatin)、氟伐他汀(fluvastatin)、匹伐他汀(pitavastatin)和西立伐他汀(cerivastatin)。在某些實施例中，該他汀類治療是最大耐受劑量他汀類治療。在某些實施例中，該膽固醇吸收抑制劑是依折麥布。在某些實施例中，該患者對他汀類不耐受。 In certain embodiments, the patient further receives lipid-modifying therapy (LMT). In certain embodiments, the LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibrate, a nicotinic acid, an omega-3 fatty acid, and a bile acid chelator. In certain embodiments, the LMT is a statin therapy. In some embodiments, the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin Lovastatin, fluvastatin, pitavastatin and cerivastatin. In certain embodiments, the statin therapy is a maximum tolerated dose of statin therapy. In certain embodiments, the cholesterol absorption inhibitor is ezetimibe. In certain embodiments, the patient is intolerant to statins.

在某些實施例中，該胰島素治療選自以下組成之群組：人胰島素、甘精胰島素、谷賴胰島素、地特(detemir)胰島素、賴脯胰島素、德穀(degludec)胰島素、門冬胰島素和基礎胰島素。在某些實施例中，該患者除胰島素治療之外進一步接受另外的伴隨抗糖尿病治療。在某些實施例中，另外的伴隨抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類(meglitinide)、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油O-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 In certain embodiments, the insulin treatment is selected from the group consisting of: human insulin, insulin glargine, insulin glutamine, detemir insulin, insulin lispro, degludec insulin, insulin aspart And basal insulin. In certain embodiments, the patient receives additional concomitant anti-diabetic therapy in addition to insulin therapy. In certain embodiments, the additional concomitant anti-diabetic treatment is selected from the group consisting of: glucagon-like peptide 1 (GLP-1) therapy, gastrointestinal peptide, glucagon receptor agonist or antagonist , Glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone releasing hormone antagonists or reverse agonists, xenin, xenin analogs, biguanides, sulfonylureas, meglitinide Meglitinide, thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, peroxidases Proliferator-activated receptor (PPAR-) (α, γ, or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) agonist, GPR40 agonist, GPR120 agonist, GPR142 agonist, systemic or low-absorption TGR5 agonist, diabetes immunotherapy, anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, adenosine monophosphate-activated protein kinase (AMPK) stimulant stimulant, inhibitor of 11-β-hydroxysteroid dehydrogenase 1, glucokinase activator, diamidine Inhibitors of glycerol O-fluorenyl transferase (DGAT), modulators of glucose transporter-4, somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

在某些實施例中，該抗體或其抗原結合片段降低該患者的LDL-C水準，例如降低至少30%、35%、40%或45%。在某些實施例中，該抗體或其抗原結合片段降低該患者的非HDL-C水準，例如降低至少25%、30%、35%或40%。在某些實施例中，該抗體或其抗原結合片段降低該患者的載脂蛋白C3(ApoC3)水準(例如，12或24週的治療後，降低至少約6.0%、約6.5%、約7.0%或約7.5%)。在某些實施例中，該抗體或其抗原結合片段減少該患者中的脂蛋白顆粒的數量(例如，12或24週的治療後，減少至少約20%、約30%、約40%或約50%)。在其他實施例中，該抗體或其抗原結合片段減小該患者中的脂蛋白顆粒的尺寸(例如，12或24週的治療後，減小至少約1.5%、約2%、約2.5%或約3%)。 In certain embodiments, the antibody or antigen-binding fragment thereof reduces the patient's LDL-C level, for example, by at least 30%, 35%, 40%, or 45%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient, such as by at least 25%, 30%, 35%, or 40%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the apolipoprotein C3 (ApoC3) level of the patient (e.g., at least about 6.0%, about 6.5%, about 7.0% after 12 or 24 weeks of treatment Or about 7.5%). In certain embodiments, the antibody or antigen-binding fragment thereof reduces the number of lipoprotein particles in the patient (e.g., after 12 or 24 weeks of treatment, a reduction of at least about 20%, about 30%, about 40%, or about 50%). In other embodiments, the antibody or antigen-binding fragment thereof reduces the size of lipoprotein particles in the patient (e.g., after 12 or 24 weeks of treatment, a reduction of at least about 1.5%, about 2%, about 2.5%, or About 3%).

在某些實施例中，該抗體或其抗原結合片段：(a)不影響該患者的血紅蛋白A1c(HbA1c)水準；和/或(b)不影響該患者的空腹血糖(FPG)水準。 In certain embodiments, the antibody or antigen-binding fragment thereof: (a) does not affect the patient's hemoglobin A1c (HbA1c) level; and / or (b) does not affect the patient's fasting blood glucose (FPG) level.

根據另一方面，該方法包括一種用於治療患有1型糖尿病(T1DM)的患者中的高膽固醇血症的方法，該方法包括： (a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果，例如8週後，該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果，例如8週後，該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。 According to another aspect, the method includes a method for treating hypercholesterolemia in a patient with type 1 diabetes (T1DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, Suffering from (i) T1DM, and (ii) treatment of insufficiently controlled hypercholesterolemia with maximally tolerated statins; and (b) administering to the patient 75 mg of bispecific subtilisin that specifically binds human preprotein converting enzyme Antibody or antigen-binding fragment of bacteriocin / kexin type 9 (PCSK9); and (c) if, for example, after 8 weeks, the LDL-C level in the patient is less than 70 mg / dL, the patient is referred to the patient approximately every two weeks Administration of one or more of the following doses of 75 mg of the antibody or antigen-binding fragment thereof, or, if, for example, after 8 weeks, the LDL-C level in the patient is greater than or equal to 70 mg / dL, one or more administrations are performed approximately every two weeks 150 mg of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 And wherein the patient is receiving concomitant insulin therapy.

根據另一方面，該方法包括一種用於治療患有1型糖尿病(T1DM)的患者中的高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)每四週向該患者施用300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果，例如8週後，該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果，例如8週後，該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR，和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。在一個實施例中，該閾值水準是15mg/dL。在另一個實施例中，該閾值水準是25mg/dL。 According to another aspect, the method includes a method for treating hypercholesterolemia in a patient with type 1 diabetes (T1DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, Suffering from (i) T1DM, and (ii) insufficiently controlled hypercholesterolemia treated with the most tolerated statins; and (b) administering to this patient 300 mg of subtilis that specifically binds human preprotein converting enzyme / Kexin 9 (PCSK9) antibodies or antigen-binding fragments thereof; and (c) if, for example, 8 weeks later, the patient's LDL-C level is below a threshold level, the patient is administered one or 300 mg of the antibody or antigen-binding fragment thereof in multiple doses below, or if, for example, after 8 weeks, the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses are administered approximately every two weeks 150 mg of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 1, and an LCVR having an amino acid sequence of SEQ ID NO: 6, and Where the patient received concomitant insulin treatment. In one embodiment, the threshold level is 15 mg / dL. In another embodiment, the threshold level is 25 mg / dL.

根據另一方面，該方法包括一種用於治療患有2型糖尿病(T2DM)的患者中的高膽固醇血症的方法，該方法包括： (a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T2DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 According to another aspect, the method includes a method for treating hypercholesterolemia in a patient with type 2 diabetes (T2DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, Suffering from (i) T2DM, and (ii) insufficiently controlled hypercholesterolemia with the most tolerated statins; and (b) administering to the patient 75 mg, 150 mg, or 300 mg of specific binding human preprotein converting enzyme An antibody or antigen-binding fragment thereof of subtilin / kexin type 9 (PCSK9), wherein the patient is receiving concomitant insulin therapy.

在某些實施例中，該抗體或其抗原結合片段包含包含SEQ ID NO：1/6的HCVR/LCVR胺基酸序列對的重鏈和輕鏈CDR。在某些實施例中，該抗體或其抗原結合片段包含SEQ ID NO：2、3和4示出的三個重鏈CDR，和SEQ ID NO：7、8和10示出的三個輕鏈CDR。在某些實施例中，該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的重鏈可變區(HCVR)，和具有SEQ ID NO：6的胺基酸序列的輕鏈可變區(LCVR)。在某些實施例中，該抗體或其抗原結合片段與包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR的抗體或其抗原結合片段競爭結合。在某些實施例中，該抗體或其抗原結合片段與PCSK9的表位結合，該表位與包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR的抗體的表位相同。在某些實施例中，該抗體或其抗原結合片段與PCSK9的表位結合，該表位與包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR的抗體的表位重疊。 In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain CDR comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1/6. In certain embodiments, the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs shown in SEQ ID NOs: 2, 3, and 4 and three light chain chains shown in SEQ ID NOs: 7, 8, and 10 CDR. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1 and a light chain having an amino acid sequence of SEQ ID NO: 6 Chain variable region (LCVR). In certain embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof comprising an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 Competitive combination. In certain embodiments, the antibody or antigen-binding fragment thereof binds to an epitope of PCSK9, the epitope is associated with an HCVR comprising an amino acid sequence of SEQ ID NO: 1 and an amino acid having SEQ ID NO: 6 The epitopes of the LCVR antibodies are the same. In certain embodiments, the antibody or antigen-binding fragment thereof binds to an epitope of PCSK9, the epitope is associated with an HCVR comprising an amino acid sequence of SEQ ID NO: 1 and an amino acid having SEQ ID NO: 6 The sequences of the epitopes of the LCVR antibodies overlap.

在某些實施例中，該抗體或其抗原結合片段包含分別包含SEQ ID NO：85和89中示出的胺基酸序列的重鏈可變區(HCVR)和輕鏈可變區(LCVR)的互補決定區(CDR)。在某些實施例中，該抗體或其抗原結合片段包含具有SEQ ID NO：86、87、88、90、91和92的重鏈和輕鏈CDR胺基酸序列。在某些實施例中，該抗體或其抗原結合片段包含具有與SEQ ID NO：85中示出的胺基酸序列具有至少90%、95%或99%同一性的胺基酸序列的 HCVR，和具有與SEQ ID NO：89中示出的胺基酸序列具有至少90%、95%或99%同一性的胺基酸序列的LCVR。 In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR) comprising the amino acid sequences shown in SEQ ID NOs: 85 and 89, respectively. Complementarity determining region (CDR). In certain embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs: 86, 87, 88, 90, 91, and 92. In certain embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence having at least 90%, 95%, or 99% identity to the amino acid sequence shown in SEQ ID NO: 85, And an LCVR having an amino acid sequence having at least 90%, 95%, or 99% identity to the amino acid sequence shown in SEQ ID NO: 89.

在某些實施例中，該抗體或其抗原結合片段選自以下組成之群組：阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab和LY3015014。在某些實施例中，該抗體或其抗原結合片段是阿利庫單抗。 In certain embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of aliculumab, evocutumab, bococizumab, rodcizumab, ralpancizumab, and LY3015014. In certain embodiments, the antibody or antigen-binding fragment thereof is aliculumab.

在某些實施例中，本文所公開的方法進一步包括：(c)如果患者中的LDL-C水準低於閾值水準，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果，該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。在某些實施例中，該閾值水準是70mg/dL。 In certain embodiments, the methods disclosed herein further comprise: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses of 75 mg of the patient to the patient about every two weeks The antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks. In some embodiments, the threshold level is 70 mg / dL.

在某些實施例中，本文所公開的方法進一步包括：(c)如果，例如8週後，該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果，例如8週後，該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。在某些實施例中，該閾值水準是70mg/dL。 In certain embodiments, the methods disclosed herein further comprise: (c) administering one or more to the patient about every four weeks if, for example, 8 weeks later, the patient's LDL-C level is below a threshold level The following dose of 300 mg of the antibody or antigen-binding fragment thereof, or if, for example, after 8 weeks, the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg are administered approximately every two weeks The antibody or antigen-binding fragment thereof. In some embodiments, the threshold level is 70 mg / dL.

在某些實施例中，該抗體或其抗原結合片段皮下施用。 In certain embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

在某些實施例中，該患者進一步接受伴隨脂質修飾治療(LMT)。在某些實施例中，該LMT選自以下組成之群組：他汀類、膽固醇吸收抑制劑、纖維酸類、菸鹼酸類、ω-3脂肪酸和膽汁酸螯合劑。在某些實施例中，該LMT是他汀類治療。在某些實施例中，該他汀類選自以下組成之群組：阿托伐他汀、瑞舒伐他汀、辛伐他汀、普伐他汀、洛伐他汀、氟伐他汀、匹伐他汀和西立伐他汀。在某些實施例中，該他汀類治療是最大耐受劑量的他汀類治療。在某些實施例中，該膽固醇吸收抑制劑是依折麥布。 In certain embodiments, the patient further receives concomitant lipid modification therapy (LMT). In certain embodiments, the LMT is selected from the group consisting of: statins, cholesterol absorption inhibitors, cellulates, nicotinic acids, omega-3 fatty acids, and bile acid sequestrants. In certain embodiments, the LMT is a statin therapy. In certain embodiments, the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and cilivastatin Vastatin. In certain embodiments, the statin treatment is a maximum tolerated dose of statin treatment. In certain embodiments, the cholesterol absorption inhibitor is ezetimibe.

在某些實施例中，該患者對他汀類不耐受。 In certain embodiments, the patient is intolerant to statins.

在某些實施例中，該胰島素治療選自以下組成之群組：人胰島素、甘精胰島素、谷賴胰島素、地特胰島素、賴脯胰島素、德穀胰島素、門冬胰島素和基礎胰島素。 In certain embodiments, the insulin treatment is selected from the group consisting of: human insulin, insulin glargine, insulin glutamine, insulin detemir, insulin lispro, insulin deglutamine, insulin aspart, and basal insulin.

在某些實施例中，該患者除胰島素治療之外進一步接受伴隨抗糖尿病治療。在某些實施例中，另外的抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油0-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 In certain embodiments, the patient further receives concomitant anti-diabetic therapy in addition to insulin therapy. In certain embodiments, additional anti-diabetic treatments are selected from the group consisting of: glucagon-like peptide 1 (GLP-1) therapy, gastrointestinal peptides, glucagon receptor agonists or antagonists, Glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone releasing hormone antagonists or inverse agonists, xenin, xenin analogs, biguanides, sulfonylureas, meglitinides , Thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, peroxisome proliferator activation Receptor (PPAR-) (α, γ, or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) agonist, GPR40 agonist , GPR120 agonist, GPR142 agonist, systemic or low absorption TGR5 agonist, diabetes immunotherapy, anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, adenosine monophosphate-activated protein kinase (AMPK) stimulation Agent, inhibitor of 11-β-hydroxysteroid dehydrogenase 1, glucokinase activator, diglycerol 0-fluorenyl transferase (DG AT) inhibitors, modulators of glucose transporter-4, somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

在某些實施例中，該抗體或其抗原結合片段降低該患者的LDL-C水準，例如降低至少30%、35%、40%或45%。在某些實施例中，該抗體或其抗原結合片段降低該患者的非HDL-C水準，例如降低至少20%、25%、30%或35%。在某些實施例中，該抗體或其抗原結合片段降低該患者的載脂蛋白C3(ApoC3)水準(例如，12或24週的治療後，降低至少約6.0%、約6.5%、約7.0%或約7.5%)。在某些實施例中，該抗體或其抗原結合片段減少該患者中的脂蛋白顆粒的數量(例如，12或24週的治療後，減少至少約20%、約30%、約40%或約50%)。在其他實施例中，該抗體或其抗原結合片段減小該患者中的脂蛋白顆粒的尺寸(例如，12或24週的治療後，減小至少約1.5%、約2%、約2.5%或約3%)。 In certain embodiments, the antibody or antigen-binding fragment thereof reduces the patient's LDL-C level, for example, by at least 30%, 35%, 40%, or 45%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient, such as by at least 20%, 25%, 30%, or 35%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the apolipoprotein C3 (ApoC3) level of the patient (e.g., at least about 6.0%, about 6.5%, about 7.0% after 12 or 24 weeks of treatment Or about 7.5%). In certain embodiments, the antibody or antigen-binding fragment thereof reduces the number of lipoprotein particles in the patient (e.g., after 12 or 24 weeks of treatment, a reduction of at least about 20%, about 30%, about 40%, or about 50%). In other embodiments, the antibody or antigen-binding fragment thereof reduces the size of lipoprotein particles in the patient (e.g., after 12 or 24 weeks of treatment, a reduction of at least about 1.5%, about 2%, about 2.5%, or About 3%).

根據另一方面，該方法包括一種用於治療患有2型糖尿病(T2DM)的患者中的高膽固醇血症的方法，該方法包括： (a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T2DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；(b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果，例如8週後，該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果，例如8週後，該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR，和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。 According to another aspect, the method includes a method for treating hypercholesterolemia in a patient with type 2 diabetes (T2DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, Suffering from (i) T2DM, and (ii) treatment of insufficiently controlled hypercholesterolemia with maximally tolerated statins; (b) administering to the patient 75 mg of subtilis that specifically binds to human preprotein converting enzymes every two weeks / Kexin 9 (PCSK9) antibody or antigen-binding fragment thereof; and (c) if, for example, after 8 weeks, the LDL-C level in the patient is less than 70 mg / dL, the patient is administered about every two weeks One or more of the following doses of 75 mg of the antibody or antigen-binding fragment thereof, or if, for example, after 8 weeks, the LDL-C level in the patient is greater than or equal to 70 mg / dL, one or more are administered approximately every two weeks The antibody or antigen-binding fragment thereof at a dose of 150 mg, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 And wherein the patient is receiving concomitant insulin therapy.

根據另一方面，該方法包括一種用於治療患有2型糖尿病(T2DM)的患者中的高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T2DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；(b)每四週向該患者施用300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果，例如8週後，該患者中的LDL-C水準高於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果，例如8週後，該患者中的LDL-C水準低於或等於閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR，和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。在一個實施例中，該閾值水準是15mg/dL。在另一個實施例中，該閾值水準是25mg/dL。 According to another aspect, the method includes a method for treating hypercholesterolemia in a patient with type 2 diabetes (T2DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, Suffering from (i) T2DM, and (ii) insufficiently controlled hypercholesterolemia treated with the most tolerated statins; (b) administering to the patient 300 mg every four weeks specifically binding human proprotein converting enzyme subtilin / kexin type 9 (PCSK9) antibody or antigen-binding fragment thereof; and (c) if, for example, after 8 weeks, the patient's LDL-C level is above a threshold level, the patient is administered one or more patients approximately every four weeks Less than 300 mg of the antibody or antigen-binding fragment thereof, or if, for example, after 8 weeks, the LDL-C level in the patient is below or equal to the threshold level, one or more of the following doses are administered approximately every two weeks 150 mg of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 and wherein The patient received concomitant insulin therapy . In one embodiment, the threshold level is 15 mg / dL. In another embodiment, the threshold level is 25 mg / dL.

根據另一方面，該方法包括一種用於治療患有T2DM和動脈粥樣硬化性心血管疾病(ASCVD)的患者中的高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T2DM、(ii)ASCVD和(iii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 According to another aspect, the method includes a method for treating hypercholesterolemia in a patient with T2DM and atherosclerotic cardiovascular disease (ASCVD), the method comprising: (a) selecting an insulin-treated Patients with high cardiovascular risk who have (i) T2DM, (ii) ASCVD, and (iii) under-controlled hypercholesterolemia with maximum tolerated statins; and (b) administer 75mg, 150mg Or 300 mg of an antibody or antigen-binding fragment thereof that specifically binds the human proprotein converting enzyme subtilin / kexin type 9 (PCSK9), wherein the patient is receiving concomitant insulin therapy.

在某些實施例中，該ASCVD被定義為冠心病(CHD)、缺血性中風或外周動脈疾病。在某些實施例中，該CHD包含急性心肌梗死、無症狀性心肌梗死和不穩定型心絞痛。 In certain embodiments, the ASCVD is defined as coronary heart disease (CHD), ischemic stroke, or peripheral arterial disease. In certain embodiments, the CHD comprises acute myocardial infarction, asymptomatic myocardial infarction, and unstable angina.

在某些實施例中，每兩週向該患者施用75mg的該抗體或抗原結合片段。在某些實施例中，每兩週向該患者施用150mg的該抗體或抗原結合片段。在某些實施例中，每四週向該患者施用300mg的該抗體或抗原結合片段。 In certain embodiments, the patient is administered 75 mg of the antibody or antigen-binding fragment every two weeks. In certain embodiments, the patient is administered 150 mg of the antibody or antigen-binding fragment every two weeks. In certain embodiments, the patient is administered 300 mg of the antibody or antigen-binding fragment every four weeks.

在某些實施例中，該抗體或其抗原結合片段包含包含SEQ ID NO：1/6的HCVR/LCVR胺基酸序列對的重鏈和輕鏈CDR。在某些實施例中，該抗體或其抗原結合片段包含SEQ ID NO：2、3和4中示出的三個重鏈CDR，和SEQ ID NO：7、8和10中示出的三個輕鏈CDR。在某些實施例中，該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的重鏈可變區(HCVR)，和具有SEQ ID NO：6的胺基酸序列的輕鏈可變區(LCVR)。在某些實施例中，該抗體或其抗原結合片段與PCSK9的表位結合，該表位與包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR的抗體結合的表位相同。在某些實施例中，該抗體或其抗原結合片段與PCSK9的表位結合，該表位與包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR的抗體的表位重疊。 In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain CDR comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1/6. In certain embodiments, the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs shown in SEQ ID NOs: 2, 3, and 4, and three of the heavy chain CDRs shown in SEQ ID NOs: 7, 8, and 10 Light chain CDR. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1 and a light chain having an amino acid sequence of SEQ ID NO: 6 Chain variable region (LCVR). In certain embodiments, the antibody or antigen-binding fragment thereof binds to an epitope of PCSK9, the epitope is associated with an HCVR comprising an amino acid sequence of SEQ ID NO: 1 and an amino acid having SEQ ID NO: 6 The sequences of the LCVR antibodies bind to the same epitope. In certain embodiments, the antibody or antigen-binding fragment thereof binds to an epitope of PCSK9, the epitope is associated with an HCVR comprising an amino acid sequence of SEQ ID NO: 1 and an amino acid having SEQ ID NO: 6 The sequences of the epitopes of the LCVR antibodies overlap.

在某些實施例中，該抗體或其抗原結合片段包含分別包含SEQ ID NO：85和89中示出的胺基酸序列的重鏈可變區(HCVR)和輕鏈可變區(LCVR)的互補決定區(CDR)。在某些實施例中，該抗體或其抗原結合片段包含具有SEQ ID NO：86、87、88、90、91和92的重鏈和輕鏈CDR胺基酸序列。在某些實施例中，該抗體或其抗原結合片段包含具有與SEQ ID NO：85中示出的腔基酸序列具有至少90%、95%或99%同一性的胺基酸序列的HCVR，和具有與SEQ ID NO：89中示出的胺基酸序列具有至少90%、95%或99%同一性的胺基酸序列的LCVR。 In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR) comprising the amino acid sequences shown in SEQ ID NOs: 85 and 89, respectively. Complementarity determining region (CDR). In certain embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs: 86, 87, 88, 90, 91, and 92. In certain embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence having at least 90%, 95%, or 99% identity to the cavity acid sequence shown in SEQ ID NO: 85, And an LCVR having an amino acid sequence having at least 90%, 95%, or 99% identity to the amino acid sequence shown in SEQ ID NO: 89.

在某些實施例中，該方法進一步包括：(c)如果該患者中的LDL-C水準低於閾值水準，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 In certain embodiments, the method further comprises: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses of 75 mg of the antibody or The antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

在某些實施例中，該方法進一步包括：(c)如果該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 In certain embodiments, the method further comprises: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses of 300 mg of the antibody or the antibody to the patient approximately every four weeks An antigen-binding fragment, or if the LDL-C level in the patient is greater than or equal to the threshold level, about one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered about every two weeks.

在某些實施例中，該閾值水準是70mg/dL。 In some embodiments, the threshold level is 70 mg / dL.

在某些實施例中，該胰島素治療選自以下組成之群組：人胰島素、甘精胰島素、谷賴胰島素、地特胰島素、賴脯胰島素、德穀胰島素、門冬胰島素和基礎胰島素。在某些實施例中，該患者除胰島素治療之外進一步接受伴隨抗糖尿病治療。在某些實施例中，另外的抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油O-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 In certain embodiments, the insulin treatment is selected from the group consisting of: human insulin, insulin glargine, insulin glutamine, insulin detemir, insulin lispro, insulin deglutamine, insulin aspart, and basal insulin. In certain embodiments, the patient further receives concomitant anti-diabetic therapy in addition to insulin therapy. In certain embodiments, additional anti-diabetic treatments are selected from the group consisting of: glucagon-like peptide 1 (GLP-1) therapy, gastrointestinal peptides, glucagon receptor agonists or antagonists, Glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone releasing hormone antagonists or inverse agonists, xenin, xenin analogs, biguanides, sulfonylureas, meglitinides , Thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, peroxisome proliferator activation Receptor (PPAR-) (α, γ, or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) agonist, GPR40 agonist , GPR120 agonist, GPR142 agonist, systemic or low absorption TGR5 agonist, diabetes immunotherapy, anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, adenosine monophosphate-activated protein kinase (AMPK) stimulation Agent, 11-β-hydroxysteroid dehydrogenase 1 inhibitor, glucokinase activator, diglycerol O-fluorenyl transferase (DG AT) inhibitors, modulators of glucose transporter-4, somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

在某些實施例中，該抗體或其抗原結合片段降低該患者的LDL-C水準，例如降低至少30%、35%、40%或45%。在某些實施例中，該抗體或其抗原結合片段降低該患者的非HDL-C水準，例如降低至少20%、25%、30%、35%。在某些實施例中，該抗體或其抗原結合片段降低該患者的ApoC3水準。在某些實施例中，該抗體或其抗原結合片段減小該患者中的脂蛋白顆粒的數量和/或尺寸。在某些實施例中，該抗體或其抗原結合片段：(a)不影響該患者的血紅蛋白A1c(HbA1c)水準；和/或(b)不影響該患者的空腹血糖(FPG)水準。 In certain embodiments, the antibody or antigen-binding fragment thereof reduces the patient's LDL-C level, for example, by at least 30%, 35%, 40%, or 45%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the non-HDL-C level of the patient, for example by at least 20%, 25%, 30%, 35%. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the ApoC3 level of the patient. In certain embodiments, the antibody or antigen-binding fragment thereof reduces the number and / or size of lipoprotein particles in the patient. In certain embodiments, the antibody or antigen-binding fragment thereof: (a) does not affect the patient's hemoglobin A1c (HbA1c) level; and / or (b) does not affect the patient's fasting blood glucose (FPG) level.

根據另一方面，該方法包括一種用於治療患有T2DM和ASCVD的患者中的高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T2DM、(ii)ASCVD和(iii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症； (b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，和(c)如果該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR，和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。 According to another aspect, the method includes a method for treating hypercholesterolemia in a patient with T2DM and ASCVD, the method comprising: (a) selecting a high cardiovascular risk patient receiving insulin therapy, who has ( i) T2DM, (ii) ASCVD, and (iii) treatment of inadequately controlled hypercholesterolemia with maximally tolerated statins; (b) administering to the patient 75 mg of bispecific subtilisin that specifically binds to human preprotein converting enzyme Antibody or antigen-binding fragment thereof of bacteriocin / kexin type 9 (PCSK9), and (c) if the LDL-C level in the patient is below 70 mg / dL, one or more of the following are administered to the patient approximately every two weeks A dose of 75 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to 70 mg / dL, one or more of the following doses of 150 mg of the antibody or antigen-binding agent are administered approximately every two weeks A fragment, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 1, and an LCVR having an amino acid sequence of SEQ ID NO: 6, and wherein the patient receives concomitant insulin therapy.

從回顧隨後的詳細描述，其他實施例將變得顯而易見。 Other embodiments will become apparent from a review of the detailed description that follows.

圖1是例示說明本文實例2中描述的研究的主要階段的總體設計的圖。該研究包括篩選期、雙盲治療期和安全性觀察期。 FIG. 1 is a diagram illustrating the overall design of the main stages of the study described in Example 2 herein. The study included a screening period, a double-blind treatment period, and a safety observation period.

圖2是顯示根據IVRS的患有1型糖尿病的患者的ITT群體中計算的LDL-C水準的從基線的百分比變化的LS平均值(+/-SE)的圖。最小二乘(LS)平均值和標準誤差(SE)獲得自重複測量的混合效應模型(MMRM)分析。該模型包括治療組的固定分類效應、按照IVRS的隨機化層、時間點、治療組與時間點的交互作用、層(strata)與時間點的交互作用、治療組與層的交互作用、治療組與層與時間點的交互作用、以及基線計算的LDL-C值和基線值與時間點交互作用的連續性固定協變量。MMRM模型對ITT群體中的所有患者(即1型和2型糖尿病患者)進行。 FIG. 2 is a graph showing the LS average (+/- SE) of the percentage change from baseline of LDL-C levels calculated in the ITT population of patients with type 1 diabetes according to IVRS. Least squares (LS) mean and standard error (SE) were obtained from a mixed effects model (MMRM) analysis of repeated measurements. The model includes the fixed classification effect of the treatment group, the randomization layer according to IVRS, the time point, the interaction between the treatment group and the time point, the interaction between the strata and the time point, the interaction between the treatment group and the layer, and the treatment group. Interactions with layers and time points, as well as continuous fixed covariates for baseline calculations of LDL-C values and interactions between baseline values and time points. The MMRM model is performed on all patients in the ITT population (ie, patients with type 1 and type 2 diabetes).

圖3是顯示根據IVRS的患有2型糖尿病的患者的ITT群體中計算的LDL-C水準的從基線的百分比變化的LS平均值(+/-SE)的圖。最小二乘(LS)平均值和標準誤差(SE)獲得自重複測量的混合效應模型(MMRM)分析。該模型包括治療組的固定分類效應、按照IVRS的隨機化層、時間點、治療組與時間點的交互作用、層與時間點的交互作用、治療組與層的交互作用、治療組與層與時間點的交互作用、以及基線計算的LDL-C值和基線值與時間點交互作用的連續性固定協變量。MMRM模型對ITT群體中的所有患者(即1型和2型糖尿病患者)進行。 Figure 3 is a graph showing the LS mean (+/- SE) of the percentage change from baseline of LDL-C levels calculated in the ITT population of patients with type 2 diabetes according to IVRS. Least squares (LS) mean and standard error (SE) were obtained from a mixed effects model (MMRM) analysis of repeated measurements. The model includes the fixed classification effect of the treatment group, the randomized layer according to IVRS, the time point, the interaction between the treatment group and the time point, the interaction between the layer and the time point, the interaction between the treatment group and the layer, the treatment group and the layer and The interactions at time points, and the LDL-C values calculated at baseline and the continuity of the interactions between baseline values and time points are fixed covariates. The MMRM model is performed on all patients in the ITT population (ie, patients with type 1 and type 2 diabetes).

圖4是顯示在患有2型糖尿病和ASCVD的ITT群體中非HDL-C、LDL-C、ApoB和LDL-PN從基線到第24週的百分比變化的圖。 Figure 4 is a graph showing the percentage change in non-HDL-C, LDL-C, ApoB, and LDL-PN from baseline to week 24 in ITT populations with type 2 diabetes and ASCVD.

圖5是顯示在患有2型糖尿病和ASCVD的ITT群體中在第24週達到非HDL-C<100mg/dL、LDL-C<70mg/dL和ApoB<80mg/dL的個體的百分比的圖。 Figure 5 is a graph showing the percentage of individuals who achieved non-HDL-C <100 mg / dL, LDL-C <70 mg / dL, and ApoB <80 mg / dL in the ITT population with type 2 diabetes and ASCVD at week 24.

該方法不限於所描述的具體的方法和實驗條件，因為這些方法和條件可以變化。還應理解，本文所使用的術語僅用於描述具體的實施例的目的，並不意欲是限制性的，因為本發明的方法的範圍會僅受所附發明申請專利範圍的限制。 The method is not limited to the specific methods and experimental conditions described, as these methods and conditions can vary. It should also be understood that the terminology used herein is used only for the purpose of describing specific embodiments and is not intended to be limiting, since the scope of the method of the present invention will be limited only by the scope of the patent application of the attached invention.

除非另有定義，本文所使用的所有技術和科學術語具有與本領域普通技術人員通常理解的含義相同的含義。如本文所使用，術語“約”，當用於提及具體列舉的數值時，意指該值可以與所列舉的值相差不超過1%。例如，如本文所使用，表達“約100”包括99和101以及它們之間的所有值(例如，99.1、99.2、99.3、99.4等)。 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. As used herein, the term "about" when used in reference to a particular recited value means that the value may differ from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values between them (eg, 99.1, 99.2, 99.3, 99.4, etc.).

儘管可以使用與本文所述的那些類似或等同的任何方法和材料，但現在描述優選的方法和材料。本文提及的所有出版物均通過引用以其整體併入本文。 Although any methods and materials similar or equivalent to those described herein can be used, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

用於治療在胰島素治療過程中的患有高膽固醇血症和糖尿病的患者的方法Method for treating patients with hypercholesterolemia and diabetes during insulin therapy

提供了用於治療在胰島素治療過程中的患有高膽固醇血症的糖尿病患者的方法和組合物。根據某些實施例，這些方法導致這些患者的血清中脂蛋白水準(例如，LDL-C和/或Lp(a))的降低。 Methods and compositions are provided for treating diabetic patients with hypercholesterolemia during insulin therapy. According to some embodiments, these methods result in a reduction in the level of lipoproteins (eg, LDL-C and / or Lp (a)) in the serum of these patients.

本公開內容還提供了PCSK9抑制劑(例如，特異性結合PCSK9(例如，人類PCSK9)的抗體或其抗原結合片段或包含PCSK9抑制劑的組合物，其用於治療在胰島素治療過程中的患有高膽固醇血症的糖尿病患者。在某些實施例中，PCSK9抑制劑或組合物在降低這樣的患者的血清中的脂蛋白(例如，LDL-C和/或Lp(a))的水準中是有用的。 The present disclosure also provides a PCSK9 inhibitor (eg, an antibody or an antigen-binding fragment thereof that specifically binds PCSK9 (eg, human PCSK9) or a composition comprising a PCSK9 inhibitor for use in treating a patient suffering from insulin therapy Patients with diabetes with hypercholesterolemia. In certain embodiments, a PCSK9 inhibitor or composition is at a level that reduces lipoproteins (eg, LDL-C and / or Lp (a)) in the serum of such patients useful.

如本文所使用的，術語“脂蛋白”意指含有蛋白質和脂質二者的生物分子顆粒。脂蛋白的實例包括，例如低密度脂蛋白(LDL)、極低密度脂蛋白(VLDL)、中密度脂蛋白(IDL)和脂蛋白(a)(Lp(a))。 As used herein, the term "lipoprotein" means a biomolecule particle containing both protein and lipid. Examples of lipoproteins include, for example, low density lipoprotein (LDL), very low density lipoprotein (VLDL), medium density lipoprotein (IDL), and lipoprotein (a) (Lp (a)).

糖尿病(Diabetes mellitus)，通常簡稱為糖尿病(diabetes)，是一群代謝疾病，其中人具有高血糖水準，因為身體不產生足夠的胰島素，或者因為細胞對所產生的胰島素不響應。糖尿病的最常見類型是：(1)1型糖尿病，其中身體不能產生胰島素；(2)2型糖尿病，其中身體不能適當利用胰島素，並且伴隨有隨著時間的推移胰島素缺乏的增加；(3)妊娠期糖尿病，其中女性由於其妊娠而患糖尿病。所有形式的糖尿病都增加長期併發症的風險，這些併發症通常在許多年之後發生。這些長期併發症中的大多數是基於對血管的損傷，並且可以分成兩類：由大血管的動脈粥樣硬化引起的“大血管”疾病和由小血管的損傷引起的“微血管”疾病。大血管疾病病況的實例是缺血性心臟病、心肌梗塞、中風和外周血管疾病。微血管疾病的實例是糖尿病性視網膜病變、糖尿病性腎病以及糖尿病性神經病。 Diabetes mellitus, commonly referred to as diabetes, is a group of metabolic diseases in which people have high blood glucose levels because the body does not produce enough insulin or because cells do not respond to the insulin produced. The most common types of diabetes are: (1) type 1 diabetes, where the body is unable to produce insulin; (2) type 2 diabetes, where the body is unable to properly use insulin, and is accompanied by an increase in insulin deficiency over time; (3) Gestational diabetes, in which women develop diabetes due to their pregnancy. All forms of diabetes increase the risk of long-term complications that often occur after many years. Most of these long-term complications are based on damage to blood vessels and can be divided into two categories: "macrovascular" diseases caused by atherosclerosis of large blood vessels and "microvascular" diseases caused by damage to small blood vessels. Examples of macrovascular disease conditions are ischemic heart disease, myocardial infarction, stroke, and peripheral vascular disease. Examples of microvascular diseases are diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

根據某些實施例，待治療的患者患有1型糖尿病(T1DM)或2型糖尿病(T2DM)並且正在接受胰島素治療。在某些實施例中，患者已被診斷患有T1DM或T2DM至少一年。在某些實施例中，患者在30歲之前被診斷患有T1DM。在某些實施例中，T1DM患者具有低於0.2pmol/mL的C肽水準。在某些實施例中，患者具有低於10%的糖基化血紅蛋白(HbA1c)水準。 According to some embodiments, the patient to be treated has type 1 diabetes (T1DM) or type 2 diabetes (T2DM) and is receiving insulin therapy. In certain embodiments, the patient has been diagnosed with T1DM or T2DM for at least one year. In certain embodiments, the patient is diagnosed with T1DM before the age of 30. In certain embodiments, a T1DM patient has a C-peptide level below 0.2 pmol / mL. In certain embodiments, the patient has a level of glycosylated hemoglobin (HbA1c) of less than 10%.

根據某些實施例，待治療的患者具有通過脂質修飾治療(LMT)未充分控制的高膽固醇血症。如果LMT至少4週後患者的血清LDL-C濃度未降至公認的醫學上可接受的水準，例如低於70mg/dL，則認為高膽固醇血症通過LMT未充分控制(考慮到患者的冠心病的相對風險)。在某些實施例中，LMT是最大耐受的他汀類治療。如本文所使用，“最大耐受的他汀類治療”意指可被施用至患者同時不會在該患者中引起不可接受的不良副作用的最高劑量的他汀類。例如，本文所公開的方法包括治療患有高膽固醇血症患有T1DM或T2DM的患者，該高膽固醇血症通過日劑量的選自以下組成之群組的他汀類未充分控制：阿托伐他汀(包括阿托伐他汀+依折麥布)、瑞舒伐他汀、西立伐他汀、匹伐他汀、氟伐他汀、洛伐他汀，辛伐他汀(包括辛伐他汀+依折麥布)、普伐他汀，以及它們的組合。在某些實施例中，如果患者對該治療不耐受，則患者不接受伴隨他汀類治療。例如，他汀類不耐受患者可具有不同於由於扭傷或創傷引起的症狀的在他汀類治療過程中開始或增加並且當他汀類治療停止時也停止的骨骼肌相關症狀，諸如疼、痛、虛弱或痙攣。 According to certain embodiments, the patient to be treated has hypercholesterolemia that is not sufficiently controlled by lipid modification therapy (LMT). If the serum LDL-C concentration of a patient does not drop to a recognized medically acceptable level after at least 4 weeks of LMT, such as below 70 mg / dL, hypercholesterolemia is considered to be insufficiently controlled by LMT (taking into account the patient's coronary heart disease Relative risk). In certain embodiments, LMT is the most tolerated statin therapy. As used herein, "maximum tolerated statin therapy" means the highest dose of statins that can be administered to a patient without causing unacceptable adverse side effects in the patient. For example, the methods disclosed herein include treating patients with T1DM or T2DM with hypercholesterolemia that is not adequately controlled by daily doses of statins selected from the group consisting of: atorvastatin (Including atorvastatin + ezetimibe), rosuvastatin, cerivastatin, pitavastatin, fluvastatin, lovastatin, simvastatin (including simvastatin + ezetimibe), Pravastatin, and their combinations. In certain embodiments, if the patient is intolerant to the treatment, the patient is not receiving concomitant statin therapy. For example, patients with statin intolerance may have skeletal muscle related symptoms, such as pain, pain, weakness, that start or increase during statin treatment and stop when statin treatment is stopped, as opposed to symptoms due to sprains or trauma. Or cramps.

患者選擇Patient selection

本發明的方法和組合物用於治療患有高膽固醇血症和糖尿病並正在接受胰島素治療的患者。待治療的患者還可以表現出一種或多種另外的選擇標準。例如，如果患者具有大於或等於70mg/dL、100mg/dL或130mg/dL的計算的LDL-C水準，則可以選擇患者進行治療。可以用最大耐受劑量的他汀類任選地與至少一種其他脂質修飾治療(LMT)組合治療患者持續至少4週，或者其中如果患者他汀類不耐受，患者已經用最佳劑量的至少一種非他汀類LMT治療持續至少4週。最大耐受劑量的他汀類可以定義為，例如，基於區域實踐或當地指南規定的劑量，或者是由於對兒科患者的當地處方信息中規定的較高劑量的不利反應而被最大耐受的劑量。他汀類不耐受可以定義為，例如，由於不同於由於扭傷或創傷引起的症狀的在他汀類治療過程中開始或增加並且當他汀類治療停止時也停止的骨骼肌相關症狀而不能耐受至少2種他汀類：最低每日起始劑量的一種他汀類，以及任何劑量的另一種他汀類。未接受他汀類的每日方案(例如，每週1至3次)的患者也被認為不能耐受日劑量。 The methods and compositions of the present invention are used to treat patients suffering from hypercholesterolemia and diabetes and undergoing insulin therapy. The patient to be treated may also exhibit one or more additional selection criteria. For example, if a patient has a calculated LDL-C level greater than or equal to 70 mg / dL, 100 mg / dL, or 130 mg / dL, the patient may be selected for treatment. Patients can be treated with a maximum tolerated dose of statins, optionally in combination with at least one other lipid modification therapy (LMT), for at least 4 weeks, or where the patient has been treated with an optimal dose of at least one non- Statin LMT treatment lasts at least 4 weeks. The maximum tolerated dose of a statin can be defined, for example, as a dose prescribed based on regional practice or local guidelines, or as a dose that is most tolerated due to an adverse reaction to a higher dose prescribed in the local prescription information for a pediatric patient. Statin intolerance can be defined, for example, as intolerance due to skeletal muscle-related symptoms that start or increase during statin therapy and stop when statin therapy is stopped, unlike symptoms due to sprains or trauma. 2 statins: one statin with the lowest daily starting dose, and another statin at any dose. Patients who do not receive a daily regimen of statins (eg, 1 to 3 times per week) are also considered to be intolerant to the daily dose.

另外，如果患者具有高心血管(CV)風險，則可以選擇該患者進行治療。在某些實施例中，高CV風險患者具有心血管疾病(CVD)和/或至少一種另外的CV風險因子的記錄歷史。CVD包括但不限於冠心病(CHD)和CHD風險等危症(equivalent)。CHD包括但不限於急性心肌梗死(MI)、無症狀性MI、不穩定性心絞痛、冠狀血管再生成過程(coronary revascularization procedure)(例如，經皮冠狀動脈介入(PCI)或冠狀動脈旁路移植手術(CABG))和臨床上顯著的CHD(例如，通過侵入性或非侵入性測試諸如冠狀動脈造影術、使用跑步機的壓力測試、負荷超聲心動圖或核成像來診斷)。CHD風險等危症包括但不限於外周動脈疾病(例如，如實例2的納入標準中所述的)和先前的具有動脈粥樣硬化血栓起源的缺血性中風，具有持續超過24小時的局灶性缺血性神經缺陷。CV危險因素包括但不限於高血壓、近期吸煙、男性年齡45歲、女性年齡55歲、微量/大量白蛋白尿的病史、糖尿病視網膜病變的病史、早發性CHD的家族史(55歲的年齡以前的父親或兄弟；65歲的年齡以前的母親或姐妹)、低HDL-C(男性<40mg/dL[1.0mmol/L]，和女性<50mg/dL[1.3mmol/L])，以及記錄的慢性腎病(CKD)(例如，如實例2的納入標準中所限定的)。 In addition, if a patient has a high cardiovascular (CV) risk, the patient can be selected for treatment. In certain embodiments, a high CV risk patient has a track record of cardiovascular disease (CVD) and / or at least one additional CV risk factor. CVD includes, but is not limited to, coronary heart disease (CHD) and risk of CHD. CHD includes, but is not limited to, acute myocardial infarction (MI), asymptomatic MI, unstable angina, coronary revascularization procedures (e.g., percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG)) and clinically significant CHD (eg, diagnosed by invasive or non-invasive tests such as coronary angiography, stress testing using a treadmill, stress echocardiography, or nuclear imaging). Critical risks such as CHD include, but are not limited to, peripheral arterial disease (e.g., as described in the inclusion criteria of Example 2) and previous ischemic strokes with atherosclerotic thrombus origin, with focal disease lasting longer than 24 hours Ischemic nerve defect. CV risk factors include, but are not limited to, hypertension, recent smoking, and male age 45 years old, female age 55 years old, history of micro / large albuminuria, history of diabetic retinopathy, family history of early-onset CHD (father or brother before 55 years old; mother or sister before 65 years old), low HDL- C (<40 mg / dL [1.0 mmol / L] for men, and <50 mg / dL [1.3 mmol / L] for women), and chronic kidney disease (CKD) recorded (for example, as defined in the inclusion criteria of Example 2) .

在某些實施例中，高CV風險患者患有動脈粥樣硬化性心血管疾病(ASCVD)。在某些實施例中，ASCVD被限定為冠狀動脈心臟病(CHD)、缺血性中風或外周動脈疾病。在某些實施例中，CHD包括急性心肌梗塞、無症狀性心肌梗塞和不穩定型心絞痛。在某些實施例中，CHD被限定為急性心肌梗塞、無症狀性心肌梗塞或不穩定性心絞痛。 In certain embodiments, patients at high CV risk have atherosclerotic cardiovascular disease (ASCVD). In certain embodiments, ASCVD is defined as coronary heart disease (CHD), ischemic stroke, or peripheral arterial disease. In certain embodiments, CHD includes acute myocardial infarction, asymptomatic myocardial infarction, and unstable angina. In certain embodiments, CHD is defined as acute myocardial infarction, asymptomatic myocardial infarction, or unstable angina.

胰島素治療Insulin therapy

如本文所示，選擇用本發明方法治療的糖尿病患者已接受並繼續接受包含胰島素或其衍生物的胰島素治療。市場上的胰島素在胰島素的來源方面不同(例如，牛、豬、人胰島素)並且還在它們的組成方面不同，由此可以影響作用的特徵(作用的開始和作用的持續時間)。通過組合不同的胰島素產品，可能獲得多種作用特徵並且建立盡可能接近生理的血糖水準。例示性胰島素治療可包括天然存在的胰島素，諸如人胰島素，以及具有延長的作用持續時間的經修飾的胰島素，諸如甘精胰島素(Gly(A21)-Arg(B31)-Arg(B32)人胰島素，例如，Lantus^®)。甘精胰島素作為酸性澄清溶液注射，並且由於其在皮下組織的生理pH範圍內的溶液性質，作為穩定的六聚體締合物沉澱。甘精胰島素每日注射一次，並且由於其平坦的血清譜和相應的夜間低血糖風險的降低而比其他長活性胰島素上值得注意(Schubert-Zsilavecz et al.,2：125-130(2001))。甘精胰島素可以高於100U/mL的濃度施用，例如，270-330U/mL的甘精胰島素或300U/mL的甘精胰島素(如EP 2387989中所公開的)，其他例示性胰島素治療包括：谷賴胰島素(例如Apidra^®)、地特胰島素(例如Levemir^®)、賴脯胰島素(例如Humalog^®、Liprolog^®)、德穀胰島素(例如DegludecPlus^®、IdegLira(NN9068))，門冬胰島素和門冬製劑(例如NovoLog^®)、基礎胰島素和類似物(例如LY2605541、LY2963016、NN1436)、聚乙二醇化賴脯胰島素(例如LY-275585)、長效胰島素(例如NN1436、Insumera(PE0139)、AB-101、AB-102、Sensulin LLC)、中效胰島素(例如Humulin^®N、Novolin^®N)、速效和短效胰島素(例如Humulin^®R、Novolin^®R、Linjeta^®(VIAject^®)、PH20胰島素、NN1218、HinsBet^®)、預混胰島素、SuliXen^®、NN1045、胰島素加Symlin^®、PE-0139、ACP-002水凝膠胰島素，以及口服、可吸入、經皮和口服或舌下胰島素(例如Exubera^®、Nasulin^®、Afrezza^®、胰島素tregopil、TPM-02胰島素、Capsulin^®、Oral-lyn^®、Cobalamin^®口服胰島素、ORMD-0801、Oshadi口服胰島素、NN1953、NN1954、NN1956、VIAtab^®)。同樣合適的是通過雙功能接頭與白蛋白或另外的蛋白質結合的那些胰島素衍生物。 As shown herein, diabetics who choose to be treated with the methods of the invention have received and continue to receive insulin therapy comprising insulin or a derivative thereof. Insulins on the market differ in their source of insulin (e.g., bovine, pig, human insulin) and also in their composition, which can affect the characteristics of the effect (the onset of the effect and the duration of the effect). By combining different insulin products, it is possible to obtain multiple action characteristics and establish blood glucose levels as close to physiological as possible. Exemplary insulin treatments may include naturally occurring insulins, such as human insulin, and modified insulins with extended duration of action, such as insulin glargine (Gly (A21) -Arg (B31) -Arg (B32) human insulin, For example, Lantus ^® ). Insulin glargine is injected as an acidic clear solution, and because of its solution properties in the physiological pH range of the subcutaneous tissue, it precipitates as a stable hexamer association. Insulin glargine is injected once a day and is more noteworthy than other long-acting insulins due to its flat serum profile and correspondingly reduced risk of nocturnal hypoglycemia (Schubert-Zsilavecz et al., 2: 125-130 (2001)) . Insulin glargine can be administered at a concentration above 100 U / mL, for example, 270-330 U / mL insulin glargine or 300 U / mL insulin glargine (as disclosed in EP 2387989). Other exemplary insulin treatments include: Lai insulin (such as Apidra ^®), insulin detemir (eg Levemir ^®), insulin lispro (such as Humalog ^{^®,} Liprolog ^®), Germany Valley insulin (eg ^{DegludecPlus ®, IdegLira (NN9068))} , aspart and insulin aspart preparations (e.g. NovoLog ^®), and basal insulin analogues (e.g. LY2605541, LY2963016, NN1436), pEGylated insulin lispro (e.g. LY-275585), long-acting insulin (e.g. NN1436, Insumera (PE0139), AB -101, AB-102, Sensulin LLC), intermediate-acting insulin (e.g., ^{^{Humulin ® N, Novolin ® N)}} , fast-acting and short-acting insulin (e.g., ^{^{Humulin ® R, Novolin ® R,}} Linjeta ® (VIAject ®), PH20 insulin, NN1218, HinsBet ^® ), pre-mixed insulin, SuliXen ^® , NN1045, insulin plus Symlin ^® , PE-0139, ACP-002 hydrogel insulin, and oral, inhalable, transdermal, and oral or sublingual insulin (such as Exubera ^® , Nasu lin ^® , Afrezza ^® , insulin tregopil, TPM-02 insulin, Capsulin ^® , Oral-lyn ^® , Cobalamin ^® oral insulin, ORMD-0801, Oshadi oral insulin, NN1953, NN1954, NN1956, VIAtab ^® ). Also suitable are those insulin derivatives that bind to albumin or another protein via a bifunctional linker.

PCSK9抑制劑PCSK9 inhibitor

該方法包括向患者施用包含PCSK9抑制劑的治療組合物。如本文所使用的，“PCSK9抑制劑”是與人類PCSK9結合或交互作用並在體外或體內抑制PCSK9的正常生物學功能的任何用劑。PCSK9抑制劑類別的非限制性實例包括小分子PCSK9拮抗劑，PCSK9表現或活性的基於核酸的抑制劑(例如，siRNA或反義)，與PCSK9特異***互作用的基於肽的分子(例如，肽體(peptibody))，與PCSK9特異***互作用的受體分子，包含LDL受體的配體結合部分的蛋白質，PCSK9結合支架分子(例如，DARPin、HEAT重複蛋白、ARM重複蛋白、三角形四肽重複蛋白(tetratricopeptide repeat protein)、基於纖連蛋白的支架構建體和基於天然存在的重複蛋白的其他支架等)，[參見，例如，Boersma and Pluckthun,2011,Curr.Opin.Biotechnol.22：849-857，以及其中引用的參考文獻]，和抗PCSK9適配體或其部分。根據某些實施例，可以用於本發明方法的上下文的PCSK9抑制劑是抗PCSK9抗體或特異性結合人類PCSK9的抗體的抗原結合片段。 The method includes administering to a patient a therapeutic composition comprising a PCSK9 inhibitor. As used herein, a "PCSK9 inhibitor" is any agent that binds or interacts with human PCSK9 and inhibits the normal biological function of PCSK9 in vitro or in vivo. Non-limiting examples of PCSK9 inhibitor classes include small molecule PCSK9 antagonists, nucleic acid-based inhibitors (e.g., siRNA or antisense) that PCSK9 displays or activity, peptide-based molecules (e.g., peptides) that specifically interact with PCSK9 (Peptibody), a receptor molecule that specifically interacts with PCSK9, a protein containing a ligand-binding portion of an LDL receptor, and a PCSK9-binding scaffold molecule (e.g., DARPin, HEAT repeat protein, ARM repeat protein, triangular tetrapeptide repeat Protein (tetratricopeptide repeat protein), fibronectin-based scaffold constructs, and other scaffolds based on naturally-occurring repeat proteins, etc., [see, for example, Boersma and Pluckthun, 2011, Curr. Opin. Biotechnol . 22: 849-857 , And references cited therein], and anti-PCSK9 aptamers or parts thereof. According to certain embodiments, a PCSK9 inhibitor that can be used in the context of the methods of the invention is an anti-PCSK9 antibody or an antigen-binding fragment of an antibody that specifically binds human PCSK9.

如本文所使用的，術語“人類前蛋白轉化酶枯草菌素/kexin 9型”或“人類PCSK9”或“hPCSK9”是指具有SEQ ID NO：197中所示的核酸序列和SEQ ID NO：198的胺基酸序列的PCSK9，或其生物學上的活性片段。 As used herein, the term "human preprotein converting enzyme subtilin / kexin type 9" or "human PCSK9" or "hPCSK9" means having the nucleic acid sequence shown in SEQ ID NO: 197 and SEQ ID NO: 198 The amino acid sequence of PCSK9, or a biologically active fragment thereof.

如本文所使用的，術語“抗體”意欲指包含四條多肽鏈(通過二硫鍵相互連接的兩條重(H)鏈和兩條輕(L)鏈)的免疫球蛋白分子，以及其多聚體(例如，IgM)。每條重鏈包含重鏈可變區(本文縮寫為HCVR或V_H)和重鏈恒定區。重鏈恒定區包含三個結構域，C_H1、C_H2和C_H3。每條輕鏈包含輕鏈可變區(本文中縮寫為LCVR或V_L)和輕鏈恒定區。輕鏈恒定區包含一個結構域(C_L1)。V_H和V_L區可以進一步細分為稱為互補決定區(CDR)的高變區，其散佈有稱為框架區(FR)的更保守的區域。每個V_H和V_L由三個CDR和四個FR組成，按照以下順序從胺基末端到羧基末端排列：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在不同的實施例中，抗PCSK9抗體(或其抗原結合部分)的FR可以與人種系序列相同，或者可以是天然的或人工修飾的。可以基於兩個或更多個CDR的並行分析來定義胺基酸共有序列。 As used herein, the term "antibody" is intended to refer to an immunoglobulin molecule comprising four polypeptide chains (two heavy (H) chains and two light (L) chains interconnected by disulfide bonds), as well as its multimerization (E.g., IgM). Each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or _VH ) and a heavy chain constant region. The heavy chain constant region comprises three domains, C _{_H} 1, C _H 2 and C _H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V _L) and a light chain constant region. The light chain constant region contains a domain (C _L 1). The V _H and V _L regions can be further subdivided into hypervariable regions called complementarity determining regions (CDR), which are interspersed with more conserved regions called framework regions (FR). Each V _H and V _L consists of three CDRs and four FRs, arranged from the amino terminal to the carboxy terminal in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FR of the anti-PCSK9 antibody (or antigen-binding portion thereof) may be the same as the human germline sequence, or it may be natural or artificially modified. An amino acid consensus sequence can be defined based on a parallel analysis of two or more CDRs.

如本文所使用的，術語“抗體”還包括完整抗體分子的抗原結合片段。如本文所使用的，術語抗體的“抗原結合部分”、抗體的“抗原結合片段”等包括特異性結合抗原以形成複合物的任何天然存在的、可酶促獲得的、合成的或遺傳改造的多肽或糖蛋白。抗體的抗原結合片段可以例如使用任何合適的標準技術，諸如蛋白水解消化或涉及操縱和表達編碼抗體可變結構域和任選恒定結構域的DNA的重組基因工程技術，衍生自完整抗體分子。這樣的DNA是已知的和/或可容易地從例如商業來源，DNA文庫(包括例如，噬菌體-抗體文庫)獲得的，或可以是合成的。可以對DNA進行測序和化學操作或使用分子生物學技術進行操作，例如，以將一個或多個可變和/或恒定結構域安排成合適的構型，或以引入密碼子、產生半胱胺酸殘基、修飾、添加或刪除胺基酸等。 As used herein, the term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered that specifically binds an antigen to form a complex. Polypeptide or glycoprotein. Antigen-binding fragments of an antibody can be derived from intact antibody molecules, for example, using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving manipulation and expression of DNA encoding the antibody's variable and optionally constant domains. Such DNA is known and / or can be easily obtained from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthetic. DNA can be sequenced and chemically manipulated or manipulated using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, produce cysteamine Acid residues, modification, addition or deletion of amino acids, and the like.

抗原結合片段的非限制性實例包括：(i)Fab片段；(ii)F(ab')2片段；(iii)Fd片段；(iv)Fv片段；(v)單鏈Fv(scFv)分子；(vi)dAb片段；和(vii) 由模擬抗體的高變區的胺基酸殘基組成的最小識別單位(例如，分離的互補決定區(CDR)，諸如CDR3肽)，或受約束的(constrained)FR3-CDR3-FR4肽。其他工程改造的分子，諸如結構域特異性抗體，單結構域抗體，結構域缺失抗體，嵌合抗體，CDR移植抗體，雙抗體，三抗體，四抗體，微抗體，納米抗體(例如，單價納米抗體、二價納米抗體等)，小模塊化免疫藥物(SMIP)和鯊魚可變IgNAR結構域也包括在如本文所使用的表達“抗原結合片段”內。 Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F (ab ') 2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) a dAb fragment; and (vii) a minimal recognition unit (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide) consisting of amino acid residues that mimic the hypervariable region of an antibody, or constrained ( constrained) FR3-CDR3-FR4 peptide. Other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabody, tri-body, tetra-body, micro-body, nanobody (e.g., monovalent nano Antibodies, bivalent Nanobodies, etc.), small modular immunodrugs (SMIP), and shark variable IgNAR domains are also included in the expression "antigen-binding fragments" as used herein.

抗體的抗原結合片段通常會包含至少一個可變結構域。可變結構域可以具有任何大小或胺基酸組成，並且通常會包含與一個或多個框架序列相鄰或與一個或多個框架序列一起在框內的至少一個CDR。在具有與V_L結構域相連的V_H結構域的抗原結合片段中，V_H和V_L結構域可以相對於彼此以任何合適的排列放置。例如，可變區可以是二聚體並含有V_H-V_H、V_H-V_L或V_L-V_L二聚體。或者，抗體的抗原結合片段可含有單體V_H或V_L結構域。 The antigen-binding fragment of an antibody will typically contain at least one variable domain. The variable domain can be of any size or amino acid composition, and will typically contain at least one CDR adjacent to or in frame with one or more framework sequences. Antigen binding fragment thereof having a V _H domain and V _L domain linked in, V _H domains and V _L, are placed relative to each other in any suitable arrangement. For example, the variable region may be a dimer and contain V _H -V _H , V _H -V _L, or V _L -V _L dimer. Alternatively, antigen-binding fragments of antibodies may contain a monomer V _L or V _H domain.

在某些實施例中，抗體的抗原結合片段可含有與至少一個恒定結構域共價連接的至少一個可變結構域。可以在抗體的抗原結合片段中發現的可變和恒定結構域的非限制性例示性結構包括：(i)V_H-C_H1；(ii)V_H-C_H2；(iii)V_H-C_H3；(iv)V_H-C_H1-C_H2；(v)V_H-C_H1-C_H2-C_H3；(vi)V_H-C_H2-C_H3；(vii)V_H-C_L；(viii)V_L-C_H1；(ix)V_L-C_H2；(x)V_L-C_H3；(xi)V_L-C_H1-C_H2；(xii)V_L-C_H1-C_H2-C_H3；(xiii)V_L-C_H2-C_H3；和(xiv)V_L-C_L。在包括以上示出的任何例示性結構在內的可變和恒定結構域的任何結構中，可變和恒定結構域可以彼此直接連接或可以通過完整或部分鉸鏈或接頭區連接。鉸鏈區可以由至少2個(例如，5、10、15、20、40、60或更多個)胺基酸組成，這導致單個多肽分子中相鄰可變和/或恒定結構域之間的柔性或半柔性連接。此外，抗體的抗原結合片段可以包括彼此非共價連接和/或與一個或多個單體V_H或V_L結構域(例如，通過二硫鍵)結合的以上示出的任何可變和恒定結構域的同源二聚體或異源二聚體(或其他多聚體)。 In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary structures of variable and constant domains that can be found in the antigen-binding fragments of antibodies include: (i) V _H -C _H 1; (ii) V _H -C _H 2; (iii) V _H -C _H 3; (iv) V _H -C _H 1-C _H 2; (v) V _H -C _H 1-C _H 2-C _H 3; (vi) V _H -C _H 2-C _H 3 (Vii) V _H -C _L ; (viii) V _L -C _H 1; (ix) V _L -C _H 2; (x) V _L -C _H 3; (xi) V _L -C _H 1- C _H 2; (xii) V _L -C _H 1-C _H 2-C _H 3; (xiii) V _L -C _H 2-C _H 3; and (xiv) V _L -C _L. In any structure of the variable and constant domains, including any of the exemplary structures shown above, the variable and constant domains may be directly connected to each other or may be connected through a full or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids, which results in a single polypeptide molecule between adjacent variable and / or constant domains. Flexible or semi-flexible connection. In addition, antigen-binding fragments of antibodies may include a non-covalently linked to each other and / or with one or more monomers V _H or V _L domains (e.g., by disulfide bonds) shown above bound to any variable and constant A homodimer or heterodimer (or other multimer) of a domain.

與完整抗體分子一樣，抗原結合片段可以是單特異性的或多特異性的(例如，雙特異性的)。抗體的多特異性抗原結合片段通常會包含至少兩個不同的可變結構域，其中每個可變結構域能夠特異性結合一個單獨的抗原或同一抗原上的不同表位。任何多特異性抗體形式，包括本文所公開的例示性雙特異性抗體形式，可以使用本領域可獲得的常規技術適用于本發明方法的抗體的抗原結合片段的上下文。 Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, each of which is capable of specifically binding a single antigen or a different epitope on the same antigen. Any multispecific antibody form, including the exemplary bispecific antibody forms disclosed herein, may be used in the context of an antigen-binding fragment of an antibody suitable for use in the methods of the invention using conventional techniques available in the art.

抗體的恒定區在抗體固定補體和介導細胞依賴性細胞毒性的能力中是重要的。因此，可以基於是否需要抗體介導細胞毒性來選擇抗體的同種型。 The constant region of an antibody is important in its ability to immobilize complement and mediate cell-dependent cytotoxicity. Therefore, the isotype of an antibody can be selected based on whether the antibody is required to mediate cytotoxicity.

如本文所使用的，術語“人類抗體”意欲包括具有衍生自人種系免疫球蛋白序列的可變區和恒定區的抗體。儘管如此，人類抗體可包含不由人種系免疫球蛋白序列編碼的胺基酸殘基(例如，通過體外隨機或位點特異性誘變或通過體內體細胞突變引入的突變)，例如在CDR中，特別是在CDR3中。然而，如本文所使用的，術語“人類抗體”不意欲包括其中衍生自另外的哺乳動物物種(例如小鼠)的種系的CDR序列已經移植到人框架序列上的抗體。 As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, human antibodies may contain amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo), such as in CDRs , Especially in CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (eg, mouse) have been grafted onto human framework sequences.

如本文所使用的，術語“重組人類抗體”意欲包括通過重組手段製備、表現、產生或分離的所有人類抗體，諸如使用轉染到宿主細胞中的重組表現載體表現的抗體(以下進一步描述的)，從重組體分離的抗體，組合人類抗體文庫(以下進一步描述的)，從對於人類免疫球蛋白基因轉基因的動物(例如，小鼠)分離的抗體，(參見，例如，Taylor et al.(1992)Nucl.Acids Res.20：6287-6295)或通過涉及將人類免疫球蛋白基因序列剪接至其他DNA序列的任何其他手段製備、表現、產生或分離的抗體。這樣的重組人類抗體具有衍生自人種系免疫球蛋白序列的可變區和恒定區。然而，在某些實施例中，這樣的重組人類抗體經歷體外誘變(或者，當使用對於人類Ig序列轉基因的動物時，經歷體內體細胞誘變)，並且因此重組抗體的V_H和V_L區的胺基酸序列是這樣的序列：當其衍生自人種系V_H和V_L序列並與之相關的序列時，在體內可能不天然存在於人類抗體種系庫中。 As used herein, the term "recombinant human antibody" is intended to include all human antibodies made, expressed, produced, or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (further described below) , Antibodies isolated from recombinants, combined with human antibody libraries (described further below), antibodies isolated from animals (eg, mice) transgenic for human immunoglobulin genes, (see, eg, Taylor et al. (1992 ) Nucl. Acids Res. 20: 6287-6295) or antibodies prepared, expressed, produced or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the recombinant antibody V _H and V _L, amino acid sequence region of the sequences that is: when it is derived from human germline V _H and V _L, and the time sequence with related sequences, may not naturally exist in vivo in the human antibody germline database.

人類抗體可以與鉸鏈異質性有關的兩種形式存在。在一種形式中，免疫球蛋白分子包含約150-160kDa的穩定四鏈構建體，其中二聚體通過鏈間重鏈二硫鍵保持在一起。在第二種形式中，二聚體不經由鏈間二硫鍵連接，並且形成約75-80kDa的分子，其由共價偶聯的輕鏈和重鏈組成(半抗體)。即使在親和純化後，這些形式也極難分離。 Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of about 150-160 kDa, in which the dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not connected via interchain disulfide bonds and form a molecule of about 75-80 kDa, which consists of covalently coupled light and heavy chains (half antibodies). These forms are extremely difficult to separate even after affinity purification.

在各種完整IgG同種型中出現第二種形式的頻率是由於，但不限於，與抗體的鉸鏈區同種型有關的結構差異。人類IgG4鉸鏈的鉸鏈區中的單個胺基酸置換可以顯著將第二種形式(Angal et al.(1993)Molecular Immunology 30：105)的出現降低至使用人IgG1鉸鏈通常觀察到的水準。本發明的方法包括在鉸鏈、C_H2或C_H3區具有一個或多個突變的抗體，其可以是例如在生產中所希望的以改善所希望的抗體形式的產率。 The frequency of the second form in various intact IgG isotypes is due to, but not limited to, structural differences related to the isoform of the hinge region of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30: 105) to a level commonly observed with human IgG1 hinges. The method of the present invention comprises the hinge, C _H 2 or C _H 3 region having one or more mutations in the antibody, which may be, for example, in production to improve the desired form of the desired antibody yield.

如本文所使用的，“分離的抗體”意指已經從其天然環境的至少一種組分中鑒定和分離和/或回收的抗體。例如，已從生物體的至少一種組分或從其中天然存在或天然產生抗體的組織或細胞中分離或除去的抗體是為了本發明方法的目的的“分離的抗體”。分離的抗體還包括重組細胞內的原位抗體。分離的抗體是已經經歷至少一個純化或分離步驟的抗體。根據某些實施例，分離的抗體可以基本上不含其他細胞物質和/或化學物質。 As used herein, "isolated antibody" means an antibody that has been identified and isolated and / or recovered from at least one component of its natural environment. For example, an antibody that has been isolated or removed from at least one component of an organism or from a tissue or cell in which the antibody is naturally occurring or naturally occurring is an "isolated antibody" for the purposes of the methods of the invention. Isolated antibodies also include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has undergone at least one purification or separation step. According to some embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

術語“特異性結合”等意指抗體或其抗原結合片段與在生理條件下相對穩定的抗原形成複合物。用於確定抗體是否特異性結合抗原的方法是本領域公知的，並且包括例如，平衡透析、表面等離子體共振等。例如，在本方法的上下文中所使用的“特異性結合”PCSK9的抗體包括結合PCSK9或其部分的抗體，其K_D小於約1000nM，小於約500nM，小於約300nM，小於約200nM，小於約100nM，小於約90nM，小於約80nM，小於約70nM，小於約60nM，小於約50nM，小於約40nM，小於約30nM，小於約20nM，小於約10nM，小於約5nM，小於約4nM，小於約3nM，小於約2nM，小於約1nM或小於約0.5nM，如在表面等離子體共振測定中測量的。然而，特異性結合人類PCSK9的分離的抗體與其他抗原(諸如來自其他(非人類)物種的PCSK9分子)具有交叉反應性。 The terms "specifically bind" and the like mean that the antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, in the context of the method used, "specific binding" of an antibody include antibodies that bind PCSK9 or PCSK9 portion which K _D of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100nM Less than about 90nM, less than about 80nM, less than about 70nM, less than about 60nM, less than about 50nM, less than about 40nM, less than about 30nM, less than about 20nM, less than about 10nM, less than about 5nM, less than about 4nM, less than about 3nM, less About 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured in a surface plasmon resonance assay. However, isolated antibodies that specifically bind to human PCSK9 are cross-reactive with other antigens, such as PCSK9 molecules from other (non-human) species.

與抗體從中衍生的相應種系(germline)序列相比，可用於本方法的抗PCSK9抗體可以在重鏈和輕鏈可變結構域的框架和/或CDR區中包含一個或多個胺基酸置換、***和/或缺失。通過將本文所公開的胺基酸序列與可從例如公共抗體序列數據庫獲得的種系序列進行比較，可以容易地確定這樣的突變。該方法包括使用衍生自本文所公開的任何胺基酸序列的抗體及其抗原結合片段，其中一個或多個框架和/或CDR區內的一個或多個胺基酸突變為抗體從中衍生的種系序列的相應殘基，或突變為另一人種系序列的相應殘基，或突變為相應種系殘基的保守性胺基酸置換(這樣的序列變化在本文中統稱為“種系突變”)。本領域普通技術人員從本文所公開的重鏈和輕鏈可變區序列開始，可以容易地產生許多抗體和抗原結合片段，其包含一個或多個個體種系突變(individual germline mutation)或其組合。在某些實施例中，V_H和/或V_L結構域內的所有框架和/或CDR殘基被突變回在抗體從中衍生的原始種系序列中發現的殘基。在其他實施例中，僅將某些殘基突變回原始種系序列，例如，僅在FR1的前8個胺基酸內或在FR4的最後8個胺基酸內發現的突變殘基，或僅在CDR1、CDR2或CDR3中發現的突變殘基。在其他實施例中，將一個或多個框架和/或CDR殘基突變為不同種系序列的相應殘基(即，與抗體最初從中衍生的種系序列不同的種系序列)。此外，抗體可以含有框架和/或CDR區內的兩個或更多個種系突變的任何組合，例如，其中某些個體殘基突變為特定種系序列的相應殘基，而不同於原始種系序列的某些其他殘基被保持或突變為不同種系序列的相應殘基。一旦獲得，可以容易地測試含有一個或多個種系突變的抗體和抗原結合片段的一個或多個所需要的特性，諸如改善的結合特異性、增加的結合親和力、改善或增強的拮抗性或激動性的生物學特性(可視情況而定)、降低的免疫原性等。以這種一般方式獲得的抗體和抗原結合片段的使用包括在本方法中。 Compared to the corresponding germline sequences from which the antibody is derived, the anti-PCSK9 antibodies useful in this method may contain one or more amino acids in the framework and / or CDR regions of the variable domains of the heavy and light chains. Substitutions, insertions and / or deletions. Such mutations can be easily determined by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, a public antibody sequence database. The method includes using an antibody derived from any amino acid sequence disclosed herein and an antigen-binding fragment thereof, wherein one or more amino acids in one or more framework and / or CDR regions are mutated to a species from which the antibody is derived. Corresponding residues of the germline sequence, or mutations to the corresponding residues of another human germline sequence, or conservative amino acid substitutions of the corresponding germline residues (such sequence changes are collectively referred to herein as "germline mutations" ). Those of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce many antibodies and antigen-binding fragments that contain one or more individual germline mutations or combinations thereof . In certain embodiments, V _H, and / or all of the framework and / or CDR residues V _L domain of the original is mutated back to germline sequences found in antibodies derived from a residue. In other embodiments, only certain residues are mutated back to the original germline sequence, for example, mutated residues found only within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or Mutated residues found only in CDR1, CDR2 or CDR3. In other embodiments, one or more framework and / or CDR residues are mutated to corresponding residues of a different germline sequence (ie, a germline sequence that is different from the germline sequence from which the antibody was originally derived). In addition, antibodies may contain any combination of two or more germline mutations in the framework and / or CDR regions, for example, where certain individual residues are mutated to corresponding residues of a particular germline sequence, and differ from the original species Certain other residues of the germline sequence are maintained or mutated to corresponding residues of different germline sequences. Once obtained, one or more of the required characteristics, such as improved binding specificity, increased binding affinity, improved or enhanced antagonisticity or agonism, can be easily tested for antibodies and antigen-binding fragments containing one or more germline mutations. Biological characteristics (as the case may be), reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained in this general manner is included in the method.

該方法包括使用包含具有一個或多個保守性置換的本文所公開的任何HCVR、LCVR和/或CDR胺基酸序列的變體的抗PCSK9抗體。例如，本發明的方法包括使用具有HCVR、LCVR和/或CDR胺基酸序列的抗PCSK9抗體，該HCVR、LCVR和/或CDR胺基酸序列相對于本文所公開的任何HCVR、LCVR和/或CDR胺基酸序列具有例如10個或更少，8個或更少，6個或更少，4個或更少等的保守胺基酸置換。 The method includes using an anti-PCSK9 antibody comprising a variant of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, the methods of the invention include using an anti-PCSK9 antibody having an HCVR, LCVR, and / or CDR amino acid sequence relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein The CDR amino acid sequence has, for example, conservative amino acid substitutions of 10 or less, 8 or less, 6 or less, 4 or less, and the like.

如本文所使用的，術語“表面等離子體共振”指一種光學現象，其允許例如使用BIAcore^TM系統(Biacore Life Sciences division of GE Healthcare,Piscataway,NJ)，通過檢測生物傳感器基質(matrix)內的蛋白質濃度的變化來分析實時交互作用。 As used herein, the term "surface plasmon resonance" refers to an optical phenomenon that allows, for example, the detection of proteins within a biosensor matrix using the BIAcore ^TM system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). Change in concentration to analyze real-time interactions.

如本文所使用的，術語“K_D”意欲指特定抗體-抗原交互作用的平衡解離常數。 As used herein, the term "K _D " is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

術語“表位”是指與稱為抗原互補位的抗體分子的可變區中的特定抗原結合位點交互作用的抗原決定簇。單個抗原可具有多於一個表位。因此，不同的抗體可以結合抗原上的不同區域，並且可以具有不同的生物學作用。表位可以是具有構象的也可以是線性的。通過來自線性多肽鏈的不同區段的空間並置的胺基酸產生構象表位。線性表位是由多肽鏈中的相鄰胺基酸殘基產生的表位。在某些情況下，表位可包括抗原上的糖、磷醯基或磺醯基的部分。 The term "epitope" refers to an epitope that interacts with a particular antigen-binding site in the variable region of an antibody molecule called an epitope. A single antigen may have more than one epitope. Therefore, different antibodies can bind different regions on the antigen and can have different biological effects. Epitope can be conformational or linear. Conformational epitopes are generated by sterically juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is an epitope generated from an adjacent amino acid residue in a polypeptide chain. In some cases, an epitope may include a sugar, phosphonium, or sulfonyl moiety on an antigen.

根據某些實施例，該方法中所使用的抗PCSK9抗體是具有pH依賴性結合特徵的抗體。如本文所使用的，表述“pH依賴性結合”意指抗體或其抗原結合片段表現出“與中性pH相比，在酸性pH下與PCSK9的結合降低”(為了本公開的目的，可以互換地使用兩種表述)。例如，“具有pH依賴性結合特徵的抗體”包括抗體及其抗原結合片段，其在中性pH下比在酸性pH下以更高親和力結合PCSK9。在某些實施例中，抗體和抗原結合片段結合PCSK9，在中性pH下的親和力比在酸性pH下高至少3、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100或更多倍。 According to some embodiments, the anti-PCSK9 antibody used in the method is an antibody with pH-dependent binding characteristics. As used herein, the expression "pH-dependent binding" means that the antibody or antigen-binding fragment thereof exhibits "reduced binding to PCSK9 at acidic pH compared to neutral pH" (for the purposes of this disclosure, interchangeable Use two expressions). For example, "antibodies with pH-dependent binding characteristics" include antibodies and antigen-binding fragments thereof that bind PCSK9 with a higher affinity at neutral pH than at acidic pH. In certain embodiments, the antibody and antigen-binding fragment bind to PCSK9 and have an affinity at neutral pH that is at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 higher than at acidic pH. , 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more times.

根據這方面，具有pH依賴性結合特徵的抗PCSK9抗體相對於親本抗PCSK9抗體可具有一個或多個胺基酸變異。例如，具有pH依賴性結合特徵的抗PCSK9抗體可含有一個或多個組胺酸置換或***，例如，在親本抗PCSK9抗體的一個或多個CDR中。因此，根據某些實施例，提供了包括施用抗PCSK9抗體的方法，該抗PCSK9抗體除了用組胺酸殘基置換親本抗體的一個或多個CDR的一個或多個胺基酸之外，包含與親本抗PCSK9抗體的CDR胺基酸序列相同的CDR胺基酸序列(例如，重鏈和輕鏈CDR)。具有pH依賴性結合的抗PCSK9抗體可以具有例如1、2、3、4、5、6、7、8、9或更多個組胺酸置換，這些置換或者在親本抗體的單個CDR內或散佈於親本抗PCSK9抗體的多個(例如，2、3、4、5或6個)CDR內。例如，本發明的方法包括使用具有pH依賴性結合的抗PCSK9抗體，其包含親本抗PCSK9抗體的HCDR1中的一個或多個組胺酸置換、HCDR2中的一個或多個組胺酸置換、HCDR3中的一個或多個組胺酸置換、LCDR1中的一個或多個組胺酸置換、LCDR2中的一個或多個組胺酸置換、和/或LCDR3中的一個或多個組胺酸置換。 According to this aspect, an anti-PCSK9 antibody having a pH-dependent binding characteristic may have one or more amino acid variations relative to a parental anti-PCSK9 antibody. For example, an anti-PCSK9 antibody with pH-dependent binding characteristics may contain one or more histidine substitutions or insertions, for example, in one or more CDRs of a parental anti-PCSK9 antibody. Thus, according to certain embodiments, there is provided a method comprising administering an anti-PCSK9 antibody, in addition to replacing one or more amino acids of one or more CDRs of the parent antibody with a histidine residue, Contains CDR amino acid sequences that are identical to the CDR amino acid sequences of the parental anti-PCSK9 antibody (eg, heavy and light chain CDRs). Anti-PCSK9 antibodies with pH-dependent binding may have, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or more histidine substitutions, either within a single CDR of the parent antibody or Interspersed within multiple (eg, 2, 3, 4, 5, or 6) CDRs of a parental anti-PCSK9 antibody. For example, the methods of the invention include using an anti-PCSK9 antibody with pH-dependent binding comprising one or more histidine substitutions in HCDR1 of the parental anti-PCSK9 antibody, one or more histidine substitutions in HCDR2, One or more histidine substitutions in HCDR3, one or more histidine substitutions in LCDR1, one or more histidine substitutions in LCDR2, and / or one or more histidine substitutions in LCDR3 .

如本文所使用的，表述“酸性pH”意指pH為6.0或更低(例如，小於約6.0、小於約5.5、小於約5.0等)。表述“酸性pH”包括約6.0、5.95、5.90、5.85、5.8、5.75、5.7、5.65、5.6、5.55、5.5、5.45、5.4、5.35、5.3、5.25、5.2、5.15、5.1、5.05、5.0或更小的pH值。如本文所使用的，表述“中性pH”是指約7.0至約7.4的pH。表述“中性pH”包括約7.0、7.05、7.1、7.15、7.2、7.25、7.3、7.35和7.4的pH。 As used herein, the expression "acidic pH" means a pH of 6.0 or lower (eg, less than about 6.0, less than about 5.5, less than about 5.0, etc.). The expression "acidic pH" includes about 6.0, 5.95, 5.90, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or more Small pH. As used herein, the expression "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pHs of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

可用于本發明的方法的上下文中的抗PCSK9抗體的非限制性實例包括例如阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab、LY3015014或任何前述抗體的抗原結合部分。 Non-limiting examples of anti-PCSK9 antibodies that can be used in the context of the methods of the invention include, for example, aliculumab, evocutumab, bococizumab, rodecizumab, ralpancizumab, LY3015014, or the antigen-binding portion of any of the foregoing antibodies.

人類抗體的製備Preparation of human antibodies

用於在轉基因小鼠中生成人類抗體的方法是本領域已知的。任何這樣的已知方法可用于本發明的方法的上下文中以製備特異性結合人類PCSK9的人類抗體。 Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used in the context of the method of the invention to produce a human antibody that specifically binds human PCSK9.

使用VELOCIMMUNE^TM技術(參見，例如，US 6,596,541，Regeneron Pharmaceuticals)或用於生成單克隆抗體的任何其他已知方法，最初分離了具有人可變區和小鼠恒定區的針對PCSK9的高親和力嵌合抗體。VELOCIMMUNE®技術涉及產生轉基因小鼠，該轉基因小鼠具有與內源小鼠恒定區基因座可操作地連接的人重鏈和輕鏈可變區的基因組，從而小鼠應答抗原刺激而產生包含人可變區和小鼠恒定區的抗體。將編碼抗體的重鏈和輕鏈的可變區的DNA分離並與編碼人重鏈和輕鏈恒定區的DNA可操作地連接。然後在能夠表現完整人類抗體的細胞中表現該DNA。 Using VELOCIMMUNE ^™ technology (see, for example, US 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, high affinity chimerics against PCSK9 with human variable regions and mouse constant regions were originally isolated antibody. VELOCIMMUNE® technology involves generating transgenic mice that have a genome of human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, so that mice respond to antigenic stimulation to produce human-containing human Antibodies to variable and mouse constant regions. DNA encoding the variable regions of the heavy and light chains of the antibody is isolated and operably linked to DNA encoding the constant regions of the human heavy and light chains. This DNA is then expressed in cells capable of expressing intact human antibodies.

一般地，用感興趣的抗原攻擊VELOCIMMUNE®小鼠，並從表現抗體的小鼠中回收淋巴細胞(諸如B細胞)。淋巴細胞可以與骨髓瘤細胞系融合以製備永生雜交瘤細胞系，並且篩選和選擇這樣的雜交瘤細胞系以鑒定產生對感興趣的抗原特異的抗體的雜交瘤細胞系。可以分離編碼重鏈和輕鏈可變區的DNA並連接到重鏈和輕鏈的所需要的同種型恒定區。這樣的抗體蛋白質可以在細胞(諸如CHO細胞)中產生。或者，可以直接從抗原特異性淋巴細胞中分離編碼抗原特異性嵌合抗體或輕鏈和重鏈可變結構域的DNA。 Generally, VELOCIMMUNE® mice are challenged with an antigen of interest and lymphocytes (such as B cells) are recovered from mice expressing antibodies. Lymphocytes can be fused with myeloma cell lines to make immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific for the antigen of interest. DNA encoding the heavy and light chain variable regions can be isolated and linked to the required isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells, such as CHO cells. Alternatively, DNA encoding antigen-specific chimeric antibodies or light and heavy chain variable domains can be isolated directly from antigen-specific lymphocytes.

最初，分離具有人可變區和小鼠恒定區的高親和力嵌合抗體。使用本領域技術人員已知的標準方法表徵和選擇抗體的所希望的特徵，包括親和力、選擇性、表位等。用所希望的人恒定區替換小鼠恒定區以生成全人類抗體，例如野生型或修飾的IgG1或IgG4。雖然選擇的恒定區可根據具體用途而變化，但高親和力抗原結合和靶特異性特徵存在于可變區中。 Initially, high-affinity chimeric antibodies with human variable regions and mouse constant regions were isolated. Standard methods known to those skilled in the art are used to characterize and select the desired characteristics of the antibody, including affinity, selectivity, epitope, and the like. The mouse constant region is replaced with the desired human constant region to generate fully human antibodies, such as wild-type or modified IgG1 or IgG4. Although the selected constant region may vary depending on the particular application, high affinity antigen binding and target specific characteristics are present in the variable region.

一般而言，當通過與固定在固相上或在溶液相中的抗原結合來測量時，可以使用的抗體具有高親和力，如上所述。用所希望的人恒定區替換小鼠恒定區以生成全人類抗體。雖然選擇的恒定區可根據具體用途而變化，但高親和力抗原結合和靶特異性特徵存在于可變區中。 In general, when measured by binding to an antigen immobilized on a solid phase or in a solution phase, antibodies that can be used have high affinity, as described above. The mouse constant region is replaced with the desired human constant region to generate fully human antibodies. Although the selected constant region may vary depending on the particular application, high affinity antigen binding and target specific characteristics are present in the variable region.

可用於該方法的上下文中的特異性結合PCSK9的人類抗體或抗體的抗原結合片段的具體實例包括包含三個重鏈CDR(HCDR1、HCDR2和HCDR3)的任何抗體或抗原結合片段，該三個重鏈CDR是在具有選自由SEQ ID NO：1和11組成的組的胺基酸序列的重鏈可變區(HCVR)中含有的，或是與其具有至少90%、至少95%、至少98%或至少99%序列同一性的基本相似的序列中含有的。或者，可用于該發明的方法的上下文中的特異性結合PCSK9的人類抗體或抗體的抗原結合片段的具體實例包括包含三個重鏈CDR(HCDR1、HCDR2和HCDR3)的任何抗體或抗原結合片段，該三個重鏈CDR是在具有選自由以下組成的群組的胺基酸序列的重鏈可變區(HCVR)中含有的：SEQ ID NO 37、45、53、61、69、77、85、93、101、109、117、125、133、141、149、157、165、173、181和189，或是與其具有至少90%、至少95%、至少98%或至少99%的序列同一性的基本相似的序列中含有的。抗體或抗原結合片段可包含三個輕鏈CDR(LCVR1、LCVR2、LCVR3)，該三個輕鏈CDR是在具有選自由SEQ ID NO 6和15組成的組的胺基酸序列的輕鏈可變區(LCVR)中含有的，或或是與其具有至少90%、至少95%、至少98%或至少99%序列同一性的基本相似的序列中含有的。或者，抗體或抗原結合片段可包含三個輕鏈CDR(LCVR1、LCVR2、LCVR3)，該三個輕鏈CDR是在具有選擇由以下組成的群組的胺基酸序列的輕鏈可變區中含有的：SEQ ID NO 41、49、57、65、73、81、89、97、105、113、121、129、137、145、153、161、169、177、185和193，或是在與其具有至少90%、至少95%、至少98%或至少99%序列同一性的基本相似的序列中含有的。 Specific examples of human antibodies or antibody-binding fragments that specifically bind to PCSK9 that can be used in the context of this method include any antibody or antigen-binding fragment comprising three heavy chain CDRs (HCDR1, HCDR2, and HCDR3), which three The chain CDR is contained in or has at least 90%, at least 95%, or at least 98% of the heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 and 11. Or contained in a substantially similar sequence with at least 99% sequence identity. Alternatively, specific examples of human antibodies or antigen-binding fragments that specifically bind to PCSK9 that can be used in the context of the methods of the invention include any antibody or antigen-binding fragment comprising three heavy chain CDRs (HCDR1, HCDR2 and HCDR3), The three heavy chain CDRs are contained in a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of: SEQ ID NOs 37, 45, 53, 61, 69, 77, 85 , 93, 101, 109, 117, 125, 133, 141, 149, 157, 165, 173, 181, and 189, or have at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with them Contained in a substantially similar sequence. The antibody or antigen-binding fragment may comprise three light chain CDRs (LCVR1, LCVR2, LCVR3), which are variable at a light chain having an amino acid sequence selected from the group consisting of SEQ ID NOs 6 and 15 Contained in a region (LCVR), or is contained in a sequence that is substantially similar to at least 90%, at least 95%, at least 98%, or at least 99% of its sequence identity. Alternatively, the antibody or antigen-binding fragment may comprise three light chain CDRs (LCVR1, LCVR2, LCVR3) in a light chain variable region having an amino acid sequence selected from the group consisting of Contains: SEQ ID NO 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 161, 169, 177, 185, and 193, or Contained in a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

使用最佳序列比對在參考胺基酸序列的整個長度上(即用SEQ ID NO鑒定的胺基酸序列)和/或在兩個胺基酸序列之間的最佳序列比對的區域上，確定兩個胺基酸序列之間的序列同一性，其中最佳序列比對可以用本領域已知的工具(例如，Align)，使用標准設置，最好是EMBOSS：：needle，Matrix：Blosum62，Gap Open 10.0，Gap Extend 0.5獲得。 Use optimal sequence alignment over the entire length of the reference amino acid sequence (i.e., the amino acid sequence identified with SEQ ID NO) and / or over the region of the optimal sequence alignment between the two amino acid sequences To determine the sequence identity between two amino acid sequences, where the best sequence alignment can be performed using tools known in the art (eg, Align), using standard settings, preferably EMBOSS :: needle, Matrix: Blosum62 , Gap Open 10.0, Gap Extend 0.5.

在某些實施例中，抗體或抗原結合蛋白包含來自選自由SEQ ID NO：1/6和11/15組成的組的重鏈和輕鏈可變區胺基酸序列對(HCVR/LCVR)的六個CDR(HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3)。或者，在某些實施例中，抗體或抗原結合蛋白包含來自選自由以下組成的群組的重鏈和輕鏈可變區胺基酸序列對(HCVR/LCVR)的六個CDR(HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3)：SEQ ID NO：37/41、45/49、53/57、61/65、69/73、77/81、85/89、93/97、101/105、109/113、117/121、125/129、133/137、141/145、149/153、157/161、165/169、173/177、181/185和189/193。 In certain embodiments, the antibody or antigen-binding protein comprises a heavy and light chain variable region amino acid sequence pair (HCVR / LCVR) from the group selected from the group consisting of SEQ ID NOs: 1/6 and 11/15. Six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3). Alternatively, in certain embodiments, the antibody or antigen-binding protein comprises six CDRs (HCDR1, HCDR2) from a heavy and light chain variable region amino acid sequence pair (HCVR / LCVR) selected from the group consisting of , HCDR3, LCDR1, LCDR2 and LCDR3): SEQ ID NO: 37/41, 45/49, 53/57, 61/65, 69/73, 77/81, 85/89, 93/97, 101/105, 109/113, 117/121, 125/129, 133/137, 141/145, 149/153, 157/161, 165/169, 173/177, 181/185 and 189/193.

在某些實施例中，可用於該方法的抗PCSK9抗體或抗原結合蛋白具有選自SEQ ID NO：2/3/4/7/8/10(mAb316P[也稱為“REGN727”或“阿利庫單抗”])和12/13/14/16/17/18(mAb300N)(參見美國專利申請公開號2010/0166768)和12/13/14/16/17/18的 HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3胺基酸序列，其中SEQ ID NO：16包含胺基酸殘基30處的組胺酸置換亮胺酸(L30H)。 In certain embodiments, an anti-PCSK9 antibody or antigen-binding protein useful in the method has a member selected from the group consisting of SEQ ID NO: 2/3/4/7/8/10 (mAb316P [also known as "REGN727" or "Aliku MAb "]) and 12/13/14/16/17/18 (mAb300N) (see U.S. Patent Application Publication No. 2010/0166768) and HCDR1 / HCDR2 / HCDR3 / of 12/13/14/16/17/18 LCDR1 / LCDR2 / LCDR3 amino acid sequence, wherein SEQ ID NO: 16 comprises a histidine substituted leucine (L30H) at amino acid residue 30.

在某些實施例中，抗體或抗原結合蛋白包含選自由SEQ ID NO：1/6和11/15組成的組的的HCVR/LCVR胺基酸序列對。在某些例示性實施例中，抗體或抗原結合蛋白包含SEQ ID NO：1的HCVR胺基酸序列和SEQ ID NO：6的LCVR胺基酸序列。在某些例示性實施例中，抗體或抗原結合蛋白包含SEQ ID NO：11的HCVR胺基酸序列和SEQ ID NO：15的LCVR胺基酸序列。在某些例示性實施例中，抗體或抗原結合蛋白包含SEQ ID NO：11的HCVR胺基酸序列和SEQ ID NO：15的LCVR胺基酸序列，該SEQ ID NO：15包含胺基酸殘基30處的組胺酸置換亮胺酸(L30H)。 In certain embodiments, the antibody or antigen binding protein comprises an HCVR / LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 1/6 and 11/15. In certain exemplary embodiments, the antibody or antigen binding protein comprises the HCVR amino acid sequence of SEQ ID NO: 1 and the LCVR amino acid sequence of SEQ ID NO: 6. In certain exemplary embodiments, the antibody or antigen binding protein comprises the HCVR amino acid sequence of SEQ ID NO: 11 and the LCVR amino acid sequence of SEQ ID NO: 15. In certain exemplary embodiments, the antibody or antigen binding protein comprises the HCVR amino acid sequence of SEQ ID NO: 11 and the LCVR amino acid sequence of SEQ ID NO: 15, which SEQ ID NO: 15 comprises an amino acid residue Histidine at group 30 replaced leucine (L30H).

藥物組合物和施用方法Pharmaceutical composition and method of administration

本方法包括向患者施用PCSK9抑制劑，其中PCSK9抑制劑包含在藥物組合物中。用提供合適的轉移、遞送、耐受等的合適的載體、賦形劑和其它劑配製藥物組合物。在所有藥物化學家都知道的配方中可以發現許多合適的製劑：Remington's Pharmaceutical Sciences,Mack Publishing Company,Easton,PA。這些製劑包括例如粉末、糊劑、軟膏、凝膠劑、蠟、油、脂質、含有囊泡的脂質(陽離子或陰離子)(諸如LIPOFECTIN^TM)、DNA綴合物、無水吸收糊劑、水包油和油包水乳劑、乳劑碳蠟(多種分子量的聚乙二醇)、半固體凝膠和含有碳蠟的半固體混合物。還參見Powell et al."Compendium of excipients for parenteral formulations" PDA(1998)J Pharm Sci Technol 52：238-311。 The method includes administering a PCSK9 inhibitor to a patient, wherein the PCSK9 inhibitor is included in a pharmaceutical composition. Pharmaceutical compositions are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like. Many suitable formulations can be found in formulations known to all medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, vesicle-containing lipids (cationic or anionic) (such as LIPOFECTIN ^™ ), DNA conjugates, anhydrous absorption pastes, oil-in-water And water-in-oil emulsions, emulsion carbon waxes (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing carbon waxes. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52: 238-311.

可用于本發明方法的上下文中的包含抗PCSK9抗體的例示性藥物製劑包括US 8,795,669(尤其是描述例示性的包含阿利庫單抗的製劑)或WO2013/166448或WO2012/168491中所述的任何製劑。 Exemplary pharmaceutical formulations comprising anti-PCSK9 antibodies that can be used in the context of the methods of the invention include US 8,795,669 (especially describing exemplary formulations comprising aliculumab) or any of the formulations described in WO2013 / 166448 or WO2012 / 168491 .

已知多種遞送系統並且其可用於施用藥物組合物，其例如包封在脂質體，微粒，微囊劑，能夠表達突變病毒的重組細胞，受體介導的內吞作用(參見，例如，Wu et al.,1987,J.Biol.Chem.262：4429-4432)。施用方法包括但不限於皮內、肌內、腹膜內、靜脈內、皮下，鼻內、硬膜外和口服途徑。組合物可以通過任何方便的途徑施用，例如通過輸注或丸注射(bolus injection)，通過上皮或粘膜皮膚襯裡(例如口腔粘膜、直腸和腸粘膜等)吸收，並且可以與其他生物活性劑一起施用。 A variety of delivery systems are known and can be used to administer pharmaceutical compositions, such as encapsulated in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262: 4429-4432). Methods of administration include, but are not limited to, the intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The composition can be administered by any convenient route, such as by infusion or bolus injection, absorbed by epithelial or mucosal skin linings (such as oral mucosa, rectum and intestinal mucosa, etc.), and can be administered with other bioactive agents.

可以用標準針頭和注射器皮下或靜脈內遞送藥物組合物。另外，關於皮下遞送，筆遞送裝置易於應用於遞送藥物組合物。這樣的筆遞送裝置可以是可重複使用的或一次性的。可重複使用的筆輸送裝置通常利用含有藥物組合物的可替換筆芯(cartridge)。一旦施用了筆芯內的所有藥物組合物並且筆芯是空的，就可以容易地丟棄空筆芯並用含有藥物組合物的新筆芯替換。然後可以重複使用筆遞送裝置。在一次性筆遞送裝置中，沒有可替換的筆芯。相反，一次性筆遞送裝置預填充有保持在裝置內的貯存器中的藥物組合物。一旦清空儲存器的藥物組合物，就丟棄整個裝置。 Pharmaceutical compositions can be delivered subcutaneously or intravenously with standard needles and syringes. In addition, with regard to subcutaneous delivery, a pen delivery device is easily applied to deliver a pharmaceutical composition. Such a pen delivery device may be reusable or disposable. Reusable pen delivery devices typically utilize replaceable cartridges containing pharmaceutical compositions. Once all the pharmaceutical composition in the refill is applied and the refill is empty, the empty refill can be easily discarded and replaced with a new refill containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there are no replaceable refills. In contrast, disposable pen delivery devices are pre-filled with a pharmaceutical composition held in a reservoir within the device. Once the reservoir of the pharmaceutical composition is emptied, the entire device is discarded.

許多可重複使用的筆和自動注射器遞送裝置具有皮下遞送藥物組合物的應用。實例包括但不限於AUTOPEN^TM(Owen Mumford,Inc.,Woodstock,UK)，DISETRONIC^TM筆(Disetronic Medical Systems,Bergdorf,Switzerland)，HUMALOG MIX 75/25^TM筆，HUMALOG^TM筆，HUMALIN 70/30^TM筆(Eli Lilly and Co.,Indianapolis,IN)，NOVOPEN^TM I、II和III(Novo Nordisk,Copenhagen,Denmark)，NOVOPEN JUNIOR^TM(Novo Nordisk,Copenhagen,Denmark)，BD^TM筆(Becton Dickinson,Franklin Lakes,NJ)，OPTIPEN^TM，OPTIPEN PRO^TM，OPTIPEN STARLET^TM和OPTICLIK^TM(sanofi-aventis,Frankfurt,Germany)，僅舉幾例。具有皮下遞送本發明的方法的藥物組合物的應用的一次性筆遞送裝置的實例包括但不限於SOLOSTAR^TM筆(sanofi-aventis)、FLEXPEN^TM(Novo Nordisk)和KWIKPEN^TM(Eli Lilly)、SURECLICK^TM自動注射器(Amgen,Thousand Oaks,CA)、PENLET^TM(Haselmeier,Stuttgart,Germany)、EPIPEN(Dey,L.P.)和HUMIRA^TM筆(Abbott Labs,Abbott Park IL)，僅舉幾例。 Many reusable pen and autoinjector delivery devices have applications for subcutaneous delivery of pharmaceutical compositions. Examples include but are not limited to AUTOPEN ^TM (Owen Mumford, Inc., Woodstock, UK), DISETRONIC ^TM pens (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25 ^TM pens, HUMALOG ^TM pens, HUMALIN 70/30 ^TM pens (Eli Lilly and Co., Indianapolis, IN), NOVOPEN ^TM I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR ^TM (Novo Nordisk, Copenhagen, Denmark), BD ^TM pens (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN ^™ , OPTIPEN PRO ^™ , OPTIPEN STARLET ^™ and OPTICLIK ^™ (sanofi-aventis, Frankfurt, Germany), to name a few. Examples of disposable pen delivery devices with applications for subcutaneous delivery of the pharmaceutical composition of the method of the invention include, but are not limited to, SOLOSTAR ^TM pens (sanofi-aventis), FLEXPEN ^TM (Novo Nordisk), and KWIXPEN ^TM (Eli Lilly), SURECLICK ^TM Autoinjectors (Amgen, Thousand Oaks, CA), PENLET ^™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA ^™ pens (Abbott Labs, Abbott Park IL), to name a few.

在某些情況下，藥物組合物可以在控釋體系中遞送。在一個實施例中，可以使用泵(參見Langer，同上；Sefton,1987,CRC Crit.Ref.Biomed.Eng.14：201)。在另一個實施例中，可以使用聚合物材料；參見，Medical Applications of Controlled Release,Langer and Wise(eds.),1974,CRC Pres.,Boca Raton,Florida。在還另一個實施例中，控釋體系可以放置在組合物的靶標的附近，因此僅需要全身劑量的一小部分(參見，例如，Goodson,1984,Medical Applications of Controlled Release，在前，第2卷，第115-138頁)。其他控釋體系在Langer,1990,Science 249：1527-1533的綜述中討論。 In some cases, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201). In another embodiment, polymer materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed near the target of the composition, so only a small part of the systemic dose is required (see, for example, Goodson, 1984, Medical Applications of Controlled Release, op. Vol., Pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249: 1527-1533.

可注射製劑可包括用於靜脈內、皮下、皮內和肌內注射，滴注輸注等的劑型。這些可注射製劑可通過已知方法製備。例如，可注射製劑可以例如通過將上述抗體或其鹽溶解、懸浮或乳化在無菌水性介質或常規用於注射的油性介質中來製備。作為注射用水性介質，有例如生理鹽水、含有葡萄糖和其他助劑等的等滲溶液等，它們可以與適當的增溶劑(諸如醇(例如，乙醇)、多元醇(例如，丙二醇、聚乙二醇)、非離子表面活性劑[例如，聚山梨醇酯80，HCO-50(氫化蓖麻油的聚氧乙烯(50mol)加成化合物)]等)一起使用。作為油性介質，採用例如芝麻油、大豆油等，其可以與增溶劑(諸如苯甲酸苄酯、苯甲醇等)組合使用。由此製備的注射劑優選填充在適當的安瓿中。 Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, infusion, and the like. These injectable preparations can be prepared by known methods. For example, injectable preparations can be prepared, for example, by dissolving, suspending or emulsifying the above-mentioned antibodies or their salts in a sterile aqueous medium or an oily medium conventionally used for injection. As the aqueous medium for injection, there are, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, etc., and they can be mixed with appropriate solubilizers such as alcohols (for example, ethanol), polyols (for example, propylene glycol, polyethylene glycol, etc.). Alcohol), nonionic surfactants [for example, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) addition compound of hydrogenated castor oil)], etc.) are used together. As the oily medium, for example, sesame oil, soybean oil, etc. are used, which can be used in combination with a solubilizer such as benzyl benzoate, benzyl alcohol, and the like. The injection thus prepared is preferably filled in a suitable ampoule.

有利地，將上述用於口服或腸胃外使用的藥物組合物製備成適於配合一定劑量的活性成分的單位劑量的劑型。這樣的單位劑量的劑型包括例如片劑、丸劑、膠囊劑、注射劑(安瓿劑)、栓劑等。 Advantageously, the above-mentioned pharmaceutical composition for oral or parenteral use is prepared into a unit-dose dosage form suitable for compounding a certain dose of the active ingredient. Such unit-dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories and the like.

劑量dose

施用于患者的PCSK9抑制劑(例如，抗PCSK9抗體)的量通常是治療有效量。如本文所使用的，短語“治療有效量”意指PCSK9抑制劑的劑量，其導致選自以下組成之群組的一個或多個參數的可檢測的降低(從基線降低至少約5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%或更多)：LDL-C、ApoB、ApoB100、非HDL-C、總膽固醇、VLDL-C、甘油三酯、ApoC3、TRL顆粒、Lp(a)和殘餘膽固醇。 The amount of a PCSK9 inhibitor (eg, an anti-PCSK9 antibody) administered to a patient is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means a dose of a PCSK9 inhibitor that results in a detectable reduction in one or more parameters selected from the group consisting of at least about 5% reduction from baseline, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more): LDL-C, ApoB, ApoB100, non-HDL-C, total cholesterol, VLDL-C, triglycerides, ApoC3, TRL particles, Lp (a), and residual cholesterol.

在抗PCSK9抗體的情況下，治療有效量可以為約0.05mg至約600mg，例如，約0.05mg、約0.1mg、約1.0mg、約1.5mg、約2.0mg、約10mg、約20mg、約30mg、約40mg、約50mg、約60mg、約70mg、約75mg、約80mg、約90mg、約100mg、約110mg、約120mg mg、約130mg、約140mg、約160mg、約170mg、約180mg、約190mg、約200mg、約210mg、約220mg、約230mg、約240mg、約250mg、約260mg、約270mg、約280mg、約290mg、約300mg、約310mg、約320mg、約330mg、約340mg、約350mg、約360mg、約370mg、約380mg mg、約390mg、約400mg、約410mg、約420mg、約430mg、約440mg、約450mg、約460mg、約470mg、約480mg、約490mg、約500mg、約510mg、約520mg、約530mg、約540mg、約550mg、約560mg、約570mg、約580mg、約590mg或約600mg的抗PCSK9抗體。根據某些例示性實施例，治療有效量的抗PCSK9抗體是30mg、40mg或75mg(例如，在阿利庫單抗用於體重小於50kg，和/或小於或等於17歲的患者的情況下)，50mg、75mg或150mg(例如，阿利庫單抗用於體重大於或等於50kg，和/或小於或等於17歲的患者的情況下)，或者140mg或420mg(例如，在依伏庫單抗的情況下)。PCSK9抑制劑的其他劑量對於本領域普通技術人員會是顯而易見的。 In the case of an anti-PCSK9 antibody, the therapeutically effective amount may be about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg About 40mg, about 50mg, about 60mg, about 70mg, about 75mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg mg, about 130mg, about 140mg, about 160mg, about 170mg, about 180mg, about 190mg, About 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg , About 370mg, about 380mg mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, About 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg of an anti-PCSK9 antibody. According to certain exemplary embodiments, the therapeutically effective amount of the anti-PCSK9 antibody is 30 mg, 40 mg, or 75 mg (e.g., in the case of aliculumab for patients weighing less than 50 kg and / or less than or equal to 17 years of age), 50mg, 75mg, or 150mg (for example, if aliculumab is used for patients weighing 50kg or more and / or less than or equal to 17 years of age), or 140mg or 420mg (for example, in the case of evocutumab under). Other dosages of PCSK9 inhibitors will be apparent to those of ordinary skill in the art.

單一劑量中含有的抗PCSK9抗體的量可以以每千克患者體重的抗體的毫克數(即，mg/kg)的形式表示。例如，抗PCSK9抗體可以約0.0001至約10mg/kg體重的劑量施用至患者。 The amount of anti-PCSK9 antibody contained in a single dose can be expressed in milligrams (i.e., mg / kg) of the antibody per kilogram of the patient's body weight. For example, an anti-PCSK9 antibody may be administered to a patient at a dose of about 0.0001 to about 10 mg / kg body weight.

施用方案Application schedule

根據某些實施例，可以在限定的時間過程中向受試者施用多劑量的PCSK9抑制劑(即，包含PCSK9抑制劑的藥物組合物)(例如，除了每日治療性他汀類方案或其他背景LMT之外)。根據該方面的方法包括向受試者順序施用多劑量的PCSK9抑制劑。如本文所使用的，“順序施用”意指每個劑量的PCSK9抑制劑在不同的時間點，例如在隔開預定間隔(例如，數小時、數天、數周或數月)的不同日向受試者施用。本方法包括向患者順序施用單一初始劑量的PCSK9抑制劑，隨後施用一個或多個第二劑量的PCSK9抑制劑，並且任選地隨後施用一個或多個第三劑量的PCSK9抑制劑。 According to certain embodiments, multiple doses of a PCSK9 inhibitor (i.e., a pharmaceutical composition comprising a PCSK9 inhibitor) may be administered to a subject over a defined period of time (e.g., in addition to a daily therapeutic statin regimen or other context Outside LMT). A method according to this aspect includes sequentially administering multiple doses of a PCSK9 inhibitor to a subject. As used herein, "sequential administration" means that each dose of the PCSK9 inhibitor is administered to the subject at different points in time, such as on different days at predetermined intervals (e.g., hours, days, weeks, or months). Test subject administration. The method includes sequentially administering a single initial dose of PCSK9 inhibitor to a patient, followed by one or more second doses of PCSK9 inhibitor, and optionally subsequent administration of one or more third doses of PCSK9 inhibitor.

術語“初始劑量”、“第二劑量”和“第三劑量”指各個劑量的包含PCSK9抑制劑的藥物組合物的施用的時間順序。因此，“初始劑量”是在治療方案開始時施用的劑量(也稱為“基線劑量”)；“第二劑量”是初始劑量後施用的劑量；“第二劑量”是在第二劑量後施用的劑量。初始、第二和第三劑量可以全部含有相同量的PCSK9抑制劑，但通常在施用頻率方面可能彼此不同。然而，在某些實施例中，在初始、第二和/或第三劑量中含有的PCSK9抑制劑的量在治療過程中彼此不同(例如，酌情向上或向下調整)。在某些實施例中，在治療方案開始時施用兩個或更多個(例如，2、3、4或5個)劑量作為“負荷劑量”，隨後是在較不頻繁的基礎上施用的後續劑量(例如，“維持劑量“)。 The terms "initial dose", "second dose", and "third dose" refer to the chronological order of administration of each dose of the PCSK9 inhibitor-containing pharmaceutical composition. Thus, the "initial dose" is the dose administered at the beginning of the treatment protocol (also known as the "baseline dose"); the "second dose" is the dose administered after the initial dose; the "second dose" is administered after the second dose The dose. The initial, second and third doses may all contain the same amount of PCSK9 inhibitor, but generally may differ from each other in terms of frequency of administration. However, in certain embodiments, the amounts of PCSK9 inhibitor contained in the initial, second, and / or third doses are different from each other during the course of treatment (eg, adjusted up or down as appropriate). In certain embodiments, two or more (eg, 2, 3, 4 or 5) doses are administered as a "loading dose" at the beginning of a treatment regimen, followed by subsequent administrations administered on a less frequent basis A dose (eg, a "maintenance dose").

根據例示性實施例，每個第二和/或第三劑量緊接前一劑量後1至26(例如，1、1½、2、2½、3、3½、4、4½、5、5½、6、6½、7、7½、8、8½、9、9½、10、10½、11、11½、12、12½、13、13½、14、14½、15、15½、16、16½、17、17½、18、18½、19、19½、20、20½、21、21½、22、22½、23、23½、24、24½、25、25½、26、26½或更多)周施用。如本文所使用的，短語“緊接前一劑量”意指在多次施用的順序中，在沒有介入劑量的情況下在順序中的恰好下一劑量的施用之前被施用至患者的抗原結合分子的劑量。 According to an exemplary embodiment, each second and / or third dose is 1 to 26 immediately after the previous dose (for example, 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½ or more). As used herein, the phrase "immediately previous dose" means the antigen binding that is administered to a patient in the sequence of multiple administrations, without the intervention dose, just before the administration of the next dose in the sequence. The dose of the molecule.

根據該方面的方法可以包括向患者施用任何數量的第二和/或第三劑量的PCSK9抑制劑。例如，在某些實施例中，僅向患者施用單個第二劑量。在其他實施例中，向患者施用兩個或更多個(例如，2、3、4、5、6、7、8或更多個)第二劑量。同樣地，在某些實施例中，僅向患者施用單個第三劑量。在其他實施例中，向患者施用兩個或更多個(例如，2、3、4、5、6、7、8或更多個)第三劑量。 The method according to this aspect may include administering to the patient any number of second and / or third doses of the PCSK9 inhibitor. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, the patient is administered two or more (eg, 2, 3, 4, 5, 6, 7, 8, or more) second doses. Likewise, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, the patient is administered two or more (eg, 2, 3, 4, 5, 6, 7, 8, or more) third doses.

在涉及多個第三劑量的實施例中，每個第二劑量可以與其他第二劑量相同的頻率施用。例如，可以在緊接前一劑量後1至2、4、6、8或更多週向患者施用每個第二劑量。類似地，在涉及多個第三劑量的實施例中，每個第三劑量可以與其他第三劑量相同的頻率施用。例如，可以在緊接前一劑量後1至2、4、6、8或更多週向患者施用每個第三劑量。或者，向患者施用的第三和/或第三劑量的頻率可在治療方案的過程中變化。施用的頻率也可以在治療過程中由醫生根據臨床檢查後個體患者的需要進行調整。 In embodiments involving multiple third doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1 to 2, 4, 6, 8, or more weeks immediately after the previous dose. Similarly, in embodiments involving multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 1 to 2, 4, 6, 8, or more weeks immediately after the previous dose. Alternatively, the frequency of the third and / or third dose administered to a patient may vary during the course of a treatment regimen. The frequency of administration can also be adjusted by the doctor during the treatment according to the needs of the individual patient after the clinical examination.

本發明的方法包括包含上升滴定(up-titrate)選項(在本文中也稱為“劑量改變”)的施用方案。如本文所使用的，“上調滴定選項”意指在接受特定數量的劑量的PCSK9抑制劑後，如果患者尚未實現一個或多個確定的治療參數的指定降低，則此後增加PCSK9抑制劑的劑量。例如，在包括以每兩週一次的頻率向患者施用75mg劑量的抗PCSK9抗體的治療方案的情況下，如果在8週後(即，在第0週、第2週、第4週、第6週和第8週施用的5個劑量)，患者尚未達到小於70mg/dL的血清LDL-C濃度，然後此後將抗PCSK9抗體的劑量增加至例如每兩週一次施用150mg(例如，從第10週或第12週或之後開始)。 The methods of the invention include an administration regimen comprising an up-titrate option (also referred to herein as "dose change"). As used herein, "up-titration titration option" means that after receiving a specific number of doses of a PCSK9 inhibitor, the patient thereafter increases the dose of the PCSK9 inhibitor if the patient has not achieved the specified reduction in one or more identified treatment parameters. For example, in the case of a treatment regimen that involves administering a 75 mg dose of anti-PCSK9 antibody to a patient at a frequency of every two weeks, if after 8 weeks (ie, at week 0, week 2, week 4, week 6 5 doses administered at weeks and 8 weeks), the patient has not reached a serum LDL-C concentration of less than 70 mg / dL, and thereafter the dose of the anti-PCSK9 antibody is increased to, for example, 150 mg once every two weeks (for example, from week 10 Or starting on or after the 12th week).

在某些實施例中，以約75mg的劑量以每兩週一次的頻率向患者施用特異性結合PCSK9的抗體或其抗原結合片段。在某些實施例中，如果在一個或多個、兩個或更多個、三個或更多個、四個或更多個或者五個或更多個劑量後測量的患者的LDL-C<70mg/dL，則保持約75mg劑量。在某些實施例中，如果在一個或多個、兩個或更多個、三個或更多個、四個或更多個、或五個或更多個劑量後測量的患者的LDL-C仍然70mg/dL，則停止約75mg劑量，並且隨後以約150mg的劑量以每兩週一次的頻率向患者施用特異性結合PCSK9的該抗體或其抗原結合片段。 In certain embodiments, an antibody or an antigen-binding fragment thereof that specifically binds PCSK9 is administered to a patient at a frequency of once every two weeks at a dose of about 75 mg. In certain embodiments, if the patient's LDL-C is measured after one or more, two or more, three or more, four or more, or five or more doses <70mg / dL, then maintain about 75mg dose. In certain embodiments, if a patient's LDL is measured after one or more, two or more, three or more, four or more, or five or more doses C still 70 mg / dL, then stop the dose of about 75 mg, and then administer the antibody or antigen-binding fragment thereof that specifically binds PCSK9 to the patient at a frequency of about 150 mg every two weeks.

在某些實施例中，以約300mg的劑量以每四週一次的頻率向患者施用特異性結合PCSK9的抗體或其抗原結合片段。在某些實施例中，如果在一個或多、兩個或更多個、三個或更多個、四個或更多個或五個或更多個劑量後測量的患者的LDL-C<70mg/dL，則保持約300mg劑量。在某些實施例中，如果在一個或多、兩個或更多個、三個或更多個、四個或更多個或五個或更多個劑量後測量的患者的LDL-C仍然70mg/dL，則停止約300mg劑量，並且隨後以約150mg的劑量以每兩週一次的頻率向患者施用該特異性結合PCSK9的抗體或其抗原結合片段。 In certain embodiments, an antibody or antigen-binding fragment thereof that specifically binds PCSK9 is administered to a patient at a frequency of about 300 mg every four weeks. In certain embodiments, if the patient's LDL-C is measured after one or more, two or more, three or more, four or more or five or more doses, 70mg / dL, then maintain about 300mg dose. In some embodiments, if the patient's LDL-C is still measured after one or more, two or more, three or more, four or more or five or more doses 70 mg / dL, then stop the dose of about 300 mg, and then administer the antibody that specifically binds PCSK9 or its antigen-binding fragment to the patient at a frequency of about 150 mg every two weeks.

在某些實施例中，以約150mg的劑量以每兩週一次的頻率向患者施用特異性結合PCSK9的抗體或其抗原結合片段。 In certain embodiments, an antibody or an antigen-binding fragment thereof that specifically binds PCSK9 is administered to the patient at a frequency of about 150 mg every two weeks.

在某些實施例中，當以約150mg的劑量以每兩週一次的頻率向患者施用特異性結合PCSK9的抗體或其抗原結合片段時，如果在至少一個劑量或至少兩個、三個、四個或五個連續劑量後測量的患者的LDL-C<10、15、20或25mg/dL，則停止約150mg劑量，隨後以約75mg的劑量以每兩週一次的頻率向患者施用該特異性結合PCSK9的抗體或其抗原結合片段。雖然不希望受理論束縛，但假設非常低的LDL-C水準(例如，<10、15、20或25mg/dL)可加重糖尿病。在某些實施例中，約150mg劑量以恒定劑量向患者施用。在某些實施例中，在如本文公開的劑量調整後(例如，從每兩週約75mg，或從每四週約300mg調整)向患者施用約150mg劑量。 In certain embodiments, when a patient is administered an antibody or antigen-binding fragment thereof that specifically binds PCSK9 at a dose of about 150 mg every two weeks, if at least one dose or at least two, three, four LDL-C of patients measured after one or five consecutive doses <10, 15, 20, or 25 mg / dL, then discontinuing the dose of about 150 mg and then administering this specificity to the patient at a frequency of about 75 mg at a bi-weekly frequency An antibody that binds PCSK9 or an antigen-binding fragment thereof. Although not wishing to be bound by theory, it is hypothesized that very low LDL-C levels (eg, <10, 15, 20, or 25 mg / dL) can exacerbate diabetes. In certain embodiments, a dose of about 150 mg is administered to a patient at a constant dose. In certain embodiments, the patient is administered a dose of about 150 mg after a dose adjustment as disclosed herein (eg, adjusted from about 75 mg every two weeks, or from about 300 mg every four weeks).

組合治療Combination therapy

如本文其他地方所述的，該方法可包括將PCSK9抑制劑與患者先前處方的脂質修飾治療(LMT)聯合(“除了患者先前處方的脂質修飾治療(LMT)之外”還將PCSK9抑制劑)向患者施用。LMT包括但不限於他汀類、纖維酸類、菸鹼酸類(例如，菸鹼酸及其衍生物)、膽汁酸螯合劑、依折麥布(ezetimibe)、洛美他派(lomitapide)、植物甾醇，奧利司他(orlistat)等。例如，可以與穩定的每日治療他汀類方案聯合向患者施用PCSK9抑制劑。在本發明方法的上下文中可以與PCSK9抑制劑聯合施用的例示性每日治療他汀類方案包括，例如，阿托伐他汀(每日10、20、40或80mg)、(阿托伐他汀/依折麥布每日10/10或40/10mg)、瑞舒伐他汀(每日5、10或20mg)，西立伐他汀(每日0.4或0.8mg)，匹伐他汀(每日1、2或4mg)，氟伐他汀(每日20、40或80mg)，辛伐他汀(每日5、10、20、40或80mg)，辛伐他汀/依折麥布(每日10/10、20/10、10/10或80/10mg)，洛伐他汀(每日10、20、40或80mg)，普伐他汀(每日10、20、40或80mg)，以及它們的組合。在某些實施例中，他汀類治療是對於患者的最大耐受的他汀類治療。在本發明方法的上下文中可以與PCSK9抑制劑聯合施用的其他LMT包括，例如，(1)抑制膽固醇攝取和/或膽汁酸再吸收的劑(例如，依折麥布)；(2)增加脂蛋白分解代謝的劑(諸如菸鹼酸)；和/或(3)在膽固醇諸如22-羥基膽固醇消除中起作用的LXR轉錄因子的活化劑。 As described elsewhere herein, the method can include combining a PCSK9 inhibitor with a patient's previously prescribed lipid modification therapy (LMT) ("aside from the patient's previously prescribed lipid modification therapy (LMT)", a PCSK9 inhibitor) Administration to patients. LMT includes, but is not limited to, statins, cellulosics, nicotinic acids (e.g., nicotinic acid and its derivatives), bile acid sequestrants, ezetimibe, lomitapide, phytosterols, Orlistat and so on. For example, a PCSK9 inhibitor can be administered to a patient in combination with a stable daily treatment statin regimen. Exemplary daily treatment statin regimens that can be administered in combination with PCSK9 inhibitors in the context of the methods of the invention include, for example, atorvastatin (10, 20, 40, or 80 mg daily), (atorvastatin / edor Zymebu daily (10/10 or 40/10 mg), rosuvastatin (5, 10 or 20 mg daily), cerivastatin (0.4 or 0.8 mg daily), pitavastatin (1,2 daily) Or 4 mg), fluvastatin (20, 40, or 80 mg daily), simvastatin (5, 10, 20, 40, or 80 mg daily), simvastatin / ezetimibe (10/10, 20 daily / 10, 10/10 or 80/10 mg), lovastatin (10, 20, 40 or 80 mg daily), pravastatin (10, 20, 40 or 80 mg daily), and combinations thereof. In certain embodiments, the statin therapy is the statin therapy that is most tolerated for the patient. Other LMTs that can be administered in combination with PCSK9 inhibitors in the context of the methods of the invention include, for example, (1) agents that inhibit cholesterol uptake and / or bile acid reabsorption (e.g., ezetimibe); (2) increase lipids Proteolytic agents (such as nicotinic acid); and / or (3) activators of LXR transcription factors that play a role in the elimination of cholesterol such as 22-hydroxycholesterol.

根據某些實施例，提供了包括將PCSK9抑制劑(例如，抗PCSK9抗體，諸如阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab或LY3015014)與血管生成素樣蛋白3的抑制劑(例如，抗 ANGPTL3抗體，諸如REGN1500)、血管生成素樣蛋白4的抑制劑(例如，抗ANGPTL4抗體，諸如美國專利號9,120,851中稱為“H1H268P”或“H4H284P”的抗ANGPTL4抗體)或血管生成素樣蛋白8的抑制劑(例如，抗ANGPTL8抗體)組合向患者施用的方法。 According to certain embodiments, there is provided a combination of an PCSK9 inhibitor (e.g., an anti-PCSK9 antibody, such as aliculumab, evocutumab, bococizumab, rodecizumab, ralpancizumab or LY3015014) and angiopoietin-like protein 3 Inhibitors (eg, anti-ANGPTL3 antibodies, such as REGN1500), inhibitors of angiopoietin-like protein 4 (eg, anti-ANGPTL4 antibodies, such as anti-ANGPTL4 antibodies referred to as "H1H268P" or "H4H284P" in US Patent No. 9,120,851) Or a method of administering an inhibitor of angiopoietin-like protein 8 (eg, an anti-ANGPTL8 antibody) to a patient in combination.

根據某些實施例，提供了包括除胰島素治療之外，還將PCSK9抑制劑(例如，抗PCSK9抗體，諸如阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab或LY3015014)與另外的抗糖尿病治療組合向患者施用的方法。例示性的另外的抗糖尿病治療包括但不限於：(a)Rote Liste 2016中提及的所有藥物，(例如Rote Liste 2014第12章中提及的所有抗糖尿病藥)，Rote Liste 2016第06章中提及的所有減肥劑或食欲抑制劑，在Rote Liste 2016第58章中提及的所有降脂劑，Rote Liste 2016第17章中提及的所有抗高血壓藥，Rote Liste中提及的所有保腎藥，或Rote Liste 2016第36章中提到的所有利尿劑；(b)胰高血糖素樣肽1(GLP-1)治療，包括GLP-1、GLP-1類似物和GLP-1受體促效劑，例如：GLP-1(7-37)、GLP-1(7-36)醯胺、利西拉來(lixisenatide，例如Lyxumia^®)，艾塞那肽(exenatide，例如毒蜥外泌肽-4、r毒蜥外泌肽-4、Byetta^®、Bydureon^®、艾塞那肽NexP)，艾塞那肽-LAR、利拉魯肽(liraglutide，例如Victoza^®)、司美魯肽(semaglutide)、他泊魯肽(taspoglutide)、阿必魯肽(albiglutide)、度拉糖肽(dulaglutide)、白蛋白-高血糖素樣肽-1(albugon)，胃泌酸調節素、京尼平苷(geniproside)、ACP-003、CJC-1131、CJC-1134-PC、GSK-2374697、PB-1023、TTP-054、langlenatide(HM-11260C)、CM-3、GLP-1 Eligen、AB-201、ORMD-0901、NN9924、NN9926、NN9927、Nodexen、Viador-GLP-1、CVX-096、ZYOG-1、ZYD-1、ZP-3022、CAM-2036、DA-3091、DA-15864、ARI-2651、ARI-2255、艾塞那肽-XTEN(VRS-859)、艾塞那肽-XTEN+胰高血糖素-XTEN(VRS-859+AMX-808)和聚合物結合的GLP-1和GLP-1類似物；(c)雙GLP-1/GIP促效劑(例如RG-7697(MAR-701)、MAR-709、BHM081、BHM089、BHM098)；雙GLP-1/胰高血糖素受體促效劑(例如BHM-034、 OAP-189(PF-05212389、TKS-1225)、TT-401/402、ZP2929、LAPS-HMOXM25、MOD-6030)；(d)雙GLP-1/胃泌素促效劑(例如ZP-3022)；(e)胃腸肽，諸如肽YY3-36(PYY3-36)或其類似物和胰多肽(PP)或其類似物；(f)胰高血糖素受體促效劑或拮抗劑，葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑，生長激素釋放激素拮抗劑或反向促效劑，xenin及其類似物；(g)二肽基肽酶-IV(DPP-4)抑制劑，例如：阿格列汀(alogliptin，例如Nesina^®、Kazano^®)、利格列汀(linagliptin，例如Ondero^®、Trajenta^®、Tradjenta^®、Trayenta^®)、沙格列汀(saxagliptin，例如Onglyza^®、Komboglyze XR^®)，西他列汀(sitagliptin，例如Januvia^®、Xelevia^®、Tesavel^®、Janumet^®、Velmetia^®、Juvisync^®、Janumet XR^®)、安奈格列汀(anagliptin)、替格列汀(teneligliptin，例如Tenelia^®)、曲格列汀(trelagliptin)、維格列汀(vildagliptin，例如Galvus^®、Galvumet^®)、吉格列汀(gemigliptin)、奧格列汀(omarigliptin)、依沃格列汀(evogliptin)、度格列汀(dutogliptin)、DA-1229、MK-3102、KM-223、KRP-104、PBL-1427、鹽酸皮諾沙星(Pinoxacin hydrochloride)和Ari-2243；(h)鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑，例如：卡格列淨(canagliflozin)，達格列淨(dapagliflozin)，瑞格列淨(remogliflozin)，依碳酸瑞格列淨(remogliflozin etabonate)，舍格列淨(sergliflozin)，恩格列淨(empagliflozin)，伊格列淨(ipragliflozin)，托格列淨(tofogliflozin)，魯格列淨(luseogliflozin)，埃格列淨(ertugliflozin)，EGT-0001442，LIK-066，SBM-TFC-039和KGA-3235(DSP-3235)；(i)SGLT-2和SGLT-1的雙重抑制劑(例如LX-4211、LIK066)；(j)SGLT-1抑制劑(例如LX-2761、KGA-3235)或與抗肥胖藥物諸如回腸膽汁酸轉移(IBAT)抑制劑組合的SGLT-1抑制劑(例如GSK-1614235+GSK-2330672)；(k)雙胍類(例如二甲雙胍、丁二胍、苯乙雙胍)；(l)噻唑烷二酮類(例如吡格列酮(pioglitazone)、羅格列酮(rosiglitazone))，格列酮類似物(例如洛貝格列酮(lobeglitazone))；(m)過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑(例如，沙羅格列紮(saroglitazar，(例如Lipaglyn^®)、GFT-505)或PPARγ部分促效劑(例如Int-131)；(n)磺醯脲類(例如甲苯磺丁脲、格列本脲(glibenclamide)，格列美脲(glimepiride)，Amaryl^®，格列吡嗪(glipizide))和氯茴苯酸類(美格列奈s，例如那格列奈(nateglinide)，瑞格列奈(repaglinide)，米格列奈(mitiglinide))；(o)α-葡糖苷酶抑制劑(例如阿卡波糖，米格列醇，伏格列波糖)；(q)胰澱素和胰澱素類似物(例如普蘭林肽，Symlin^®)；(p)G蛋白偶聯受體119(GPR119)促效劑(例如GSK-1292263、PSN-821、MBX-2982、APD-597、ARRY-981、ZYG-19、DS-8500、HM-47000、YH-Chem1)；(q)GPR40促效劑(例如TUG-424、P-1736、P-11187、JTT-851、GW9508、CNX-011-67、AM-1638、AM-5262)；(r)GPR120促效劑和GPR142促效劑；(s)全身性或低吸收性TGR5(GPBAR1=G蛋白偶聯的膽汁酸受體1)促效劑(例如INT-777、XL-475、SB756050)；(t)糖尿病免疫治療，例如：口服C-C趨化因子受體2型(CCR-2)拮抗劑(例如CCX-140、JNJ-41443532)，白細胞介素1β(IL-1β)拮抗劑(例如AC-201)，或口服單克隆抗體(MoA)(例如甲氮醯胺(methalozamide)、VVP808、PAZ-320、P-1736、PF-05175157、PF-04937319)；(v)用於治療代謝綜合征和糖尿病的抗炎劑，例如：核因子κB抑制劑(例如Triolex^®)；(w)腺苷單磷酸激活蛋白激酶(AMPK)刺激劑，例如：Imeglimin(PXL-008)、Debio-0930(MT-63-78)、R-118；(x)11-β-羥基類固醇脫氫酶1(11-β-HSD-1)的抑制劑(例如LY2523199、BMS770767、RG-4929、BMS816336、AZD-8329、HSD-016、BI-135585)；(y)葡糖激酶活化劑(例如PF-04991532、TTP-399(GK1-399)、GKM-001(ADV-1002401)、ARRY-403(AMG-151)、TAK-329、TMG-123、ZYGK1)； (z)二醯基甘油O-醯基轉移酶(DGAT)的抑制劑(例如pradigastat(LCQ-908))、蛋白酪胺酸磷酸酶1的抑制劑(如trodusquemine)、葡萄糖-6-磷酸酶的抑制劑、果糖-1,6-二磷酸酶的抑制劑、糖原磷酸化酶的抑制劑、磷酸烯醇丙酮酸羧激酶的抑制劑、糖原合成酶激酶的抑制劑、丙酮酸脫氫酶激酶的抑制劑；(aa)葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑(例如MK-4256)；(bb)一種或多種降脂劑也適合作為組合配偶物，例如：3-羥基-3-甲基戊二醯-輔酶-A-還原酶(HMG-CoA-還原酶)抑制劑，諸如辛伐他汀(例如Zocor^®、Inegy^®、Simcor^®)，阿托伐他汀(例如Sortis^®、Caduet^®)，瑞舒伐他汀(例如Crestor^®)，普伐他汀(例如Lipostat^®、Selipran^®)，氟伐他汀(例如Lescol^®)，匹伐他汀(例如Livazo^®、Livalo^®)，洛伐他汀(例如Mevacor^®、Advicor^®)，美伐他汀(mevastatin，例如Compactin^®)，利伐他汀(rivastatin)，西立伐他汀(Lipobay^®)，纖維酸諸如苯紮貝特(bezafibrate，例如Cedur^®延遲)，環丙貝特(ciprofibrate，例如Hyperlipen^®)，非諾貝特(fenofibrate，例如Antara^®、Lipofen^®、Lipanthyl^®)，吉非貝齊(gemfibrozil，例如Lopid^®、Gevilon^®)，依託貝特(etofibrate)，雙貝特(simfibrate)，氯煙貝特(ronifibrate)，克利貝特(clinofibrate)，氯貝胺(clofibride)，菸鹼酸及其衍生物(例如菸鹼酸，包括菸鹼酸的緩釋製劑)，菸鹼酸受體1促效劑(如GSK-256073)，PPAR-δ促效劑，乙醯輔酶A-乙醯轉移酶(ACAT)抑制劑(例如阿伐麥布(avasimibe))，膽固醇吸收抑制劑(例如依折麥布、Ezetrol^®、Zetia^®、Liptruzet^®、Vytorin^®、S-556971)，膽汁酸結合物質(例如消膽胺(cholestyramine)、考來維侖(colesevelam))，回腸膽汁酸轉運(IBAT)抑制劑(如GSK-2330672、LUM-002)，微粒體甘油三酯轉運蛋白(MTP)抑制劑(例如洛美他派(lomitapide(AEGR-733))、SLx-4090、granotapide)，前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的調節劑(例如阿利庫單抗(REGN727/SAR236553)、AMG-145、LGT-209、PF-04950615、MPSK3169A、ILY3015014、ALD-306、ALN-PCS、BMS-962476、SPC5001、ISIS-394814、1B20、LGT-210、1D05、BMS-PCSK9Rx-2、SX-PCK9、RG7652)，LDL受體上調劑，例如肝臟選擇性甲狀腺激素受體β促效劑(例如伊泊替羅 (eprotirome)(KB-2115))、MB07811、sobetirome(QRX-431)、VLA-3196、ZYT1)，HDL升高化合物諸如：膽固醇酯轉運蛋白(CETP)抑制劑(例如安塞曲匹(anacetrapib)(MK0859))、達塞曲匹(dalcetrapib)、依塞曲匹(evacetrapib)、JTT-302、DRL-17822、TA-8995、R-1658、LY-2484595、DS-1442)，或雙CETP/PCSK9抑制劑(例如K-312)，ATP結合盒(ABC1)調節劑，脂質代謝調節劑(例如BMS-823778、TAP-301、DRL-21994、DRL-21995)，磷脂酶A2(PLA2)抑制劑(例如達普拉締(darapladib)、Tyrisa^®、伐瑞拉地(varespladib)、利拉地(rilapladib))，ApoA-I增強劑(例如RVX-208、CER-001、MDCO-216、CSL-112)，膽固醇合成抑制劑(例如ETC-1002)，脂質代謝調節劑(例如BMS-823778、TAP-301、DRL-21994、DRL-21995)和ω-3脂肪酸及其衍生物(例如二十碳五烯酸乙基(AMR101)，Epanova^®、AKR-063、NKPL-66、PRC-4016、CAT-2003)；(cc)溴隱亭(bromocriptine，例如Cycloset^®、Parlodel^®)，芬特明(phentermine)和芬特明製劑或組合(例如Adipex-P、Ionamin、Qsymia^®)，苄非他明(benzphetamine，例如Didrex^®)，安非拉酮(diethylpropion，例如Tenuate^®)，苯甲曲秦(phendimetrazin，例如Adipost^®、Bontril^®)，安非他酮(bupropion)和組合(例如Zyban^®、Wellbutrin XL^®、Contrave^®、Empatic^®)，***(sibutramine，例如Reductil^®、Meridia^®)，托吡酯(topiramat，例如Topamax^®)，唑尼沙胺(zonisamid，例如Zonegran^®)，替索芬辛(tesofensine)，阿片類拮抗劑，諸如納曲酮(naltrexone，例如Naltrexin^®，納曲酮+安非他酮)，***素受體1(CB1)拮抗劑(例如TM-38837)，黑色素濃縮激素(MCH-1)拮抗劑(例如BMS-830216、ALB-127158(a))，MC4受體促效劑和部分促效劑(例如AZD-2820、RM-493)，神經肽Y5(NPY5)或NPY2拮抗劑(例如維奈呱利(velneperit)、S-234462)，NPY4促效劑(例如PP-1420)，β-3-腎上腺素能受體促效劑，瘦蛋白或瘦蛋白模擬物，5-羥色胺2c(5HT2c)受體的促效劑(例如氯卡色林(lorcaserin)，Belviq^®)，普蘭林肽/美曲普汀(pramlintide/metreleptin)，脂肪酶抑制劑諸如西替司他(cetilistat，例如Cametor^®)，奧利司他(例如Xenical^®、Calobalin^®)，血管生成抑制劑(例如ALS-L1023)，倍他司汀(betahistidin)和組胺H3拮抗劑(例如HPP-404)，AgRP(刺豚鼠相關蛋白)抑制劑(例如TTP-435)，血清素再攝取抑制劑諸如氟西汀(fluoxetine，例如Fluctine^®)，度洛西汀(duloxetine，例如Cymbalta^®)，雙或三單胺攝取抑制劑(多巴胺，去甲腎上腺素和血清素再攝取)諸如舍曲林(sertraline，如Zoloft^®)，特索芬辛(tesofensine)，蛋胺酸胺基肽酶2(MetAP2)抑制劑(例如貝洛拉尼(beloranib))和抗成纖維細胞生長因子受體4(FGFR4)產生的反義寡核苷酸(例如ISIS-FGFR4Rx)或抗增殖蛋白靶向肽-1(例如Adipotide^®)；和(dd)一氧化氮供體，AT1拮抗劑或血管緊縮素II(AT2)受體拮抗劑，諸如替米沙坦(telmisartan，例如Kinzal^®、Micardis^®)，坎地沙坦(candesartan，例如Atacand^®、Blopress^®)，纈沙坦(valsartan，例如Diovan^®、Co-Diovan^®)，洛沙坦(losartan，例如Cosaar^®)，依普羅沙坦(eprosartan，例如Teveten^®)，厄貝沙坦(irbesartan，例如Aprovel^®、CoAprovel^®)，奧美沙坦(olmesartan，例如Votum^®、Olmetec^®)，他索沙坦(tasosartan)，阿齊沙坦(azilsartan，例如Edarbi^®)，雙重血管緊張素受體阻滯劑(雙重ARB)，血管緊縮素轉換酶(ACE)抑制劑，ACE-2激活劑，腎素抑制劑，前腎素抑制劑，內皮素轉換酶(ECE)抑制劑，內皮素受體(ET1/ETA)阻滯劑，內皮素拮抗劑，利尿劑，醛固酮拮抗劑，醛固酮合成酶抑制劑，α-受體阻滯劑，α-2腎上腺素能受體的拮抗劑，β-受體阻滯劑，混合α-受體/β-受體阻滯劑，鈣拮抗劑，鈣通道阻滯劑(CCB)，鈣通道阻滯劑地爾硫卓(diltiazem)的鼻用製劑(例如CP-404)，雙重鹽皮質激素/CCB，中樞作用抗高血壓藥，中性內肽酶的抑制劑，胺基肽酶-A抑制劑，血管肽抑制劑，雙重血管肽抑制劑諸如腦啡肽酶-ACE抑制劑或腦啡肽酶-ECE抑制劑，雙作用AT受體-腦啡肽酶抑制劑，雙重AT1/ETA拮抗劑，晚期糖基化終產物(AGE)破壞劑，重組腎酶，血壓疫苗諸如抗RAAS(腎素-血管緊縮素-醛固酮-系統)疫苗，AT1-或AT2-疫苗，基於高血壓藥物基因組學的藥物，諸如具有抗高血壓反應的遺傳多態性的調節劑，凝血細胞聚集抑制劑和其它；和(ee)它們合適的組合。 According to certain embodiments, it is provided to include a PCSK9 inhibitor in addition to insulin therapy (eg, an anti-PCSK9 antibody, such as aliculumum, evocutumab, bococizumab, rodecizumab, ralpancizumab, or LY3015014) Method of administering to a patient in combination with additional anti-diabetic treatment. Exemplary additional anti-diabetic treatments include, but are not limited to: (a) all drugs mentioned in Rote Liste 2016 (eg, all anti-diabetics mentioned in Chapter 12 of Rote Liste 2014), chapter 06 of Rote Liste 2016 All weight loss or appetite suppressants mentioned in Rote Liste 2016, all lipid-lowering agents mentioned in Chapter 58, all antihypertensive drugs mentioned in Rote Liste 2016 Chapter 17, all mentioned in Rote Liste All kidney medications, or all diuretics mentioned in Chapter 36 of Rote Liste 2016; (b) Glucagon-like peptide 1 (GLP-1) treatment, including GLP-1, GLP-1 analogs, and GLP- 1 receptor agonists, such as: GLP-1 (7-37), GLP-1 (7-36) amide, lixisenatide (such as Lyxumia ^® ), exenatide (such as poison lizard outside exendin -4, outside r exendin -4, Byetta ^{^®,} Bydureon ^®, exenatide NexP), exenatide -LAR, liraglutide (liraglutide, such as Victoza ^®), US Secretary Semaglutide, taspoglutide, albiglutide, dulaglutide, albumin-glucagon-like peptide-1 (albugon), gastric acid regulation , Geniproside, ACP-003, CJC-1131, CJC-1134-PC, GSK-2374697, PB-1023, TTP-054, langlenatide (HM-11260C), CM-3, GLP-1 Eligen , AB-201, ORMD-0901, NN9924, NN9926, NN9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, ZP-3022, CAM-2036, DA-3091, DA-15864 , ARI-2651, ARI-2255, Exenatide-XTEN (VRS-859), Exenatide-XTEN + Glucagon-XTEN (VRS-859 + AMX-808), and polymer-bound GLP-1 Analogs with GLP-1; (c) Double GLP-1 / GIP agonists (eg RG-7697 (MAR-701), MAR-709, BHM081, BHM089, BHM098); double GLP-1 / glucagon Receptor agonists (e.g. BHM-034, OAP-189 (PF-05212389, TKS-1225), TT-401 / 402, ZP2929, LAPS-HMOXM25, MOD-6030); (d) double GLP-1 / stomach Secretin agonists (e.g. ZP-3022); (e) gastrointestinal peptides, such as peptide YY3-36 (PYY3-36) or its analogues and pancreatic polypeptide (PP) or its analogues; (f) glucagon Receptor agonists or antagonists, glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone releasing hormone antagonists or inverse agonists, xenin and its analogs (G) Dipeptidyl peptidase-IV (DPP-4) inhibitors, such as alogliptin (eg Nesina ^® , Kazano ^® ), linagliptin (eg Ondero ^® , Trajenta ^® , Tradjenta ^® , Trayenta ^® ), saxagliptin (such as Onglyza ^® , Komboglyze XR ^® ), sitagliptin (such as Januvia ^® , Xelevia ^® , Tesavel ^® , Janumet ^® , Velmetia ^® , Juvisync ^® , Janumet XR ^® ), anagliptin, teneligliptin (such as Tenelia ^® ), trelagliptin (villagagtin), vildagliptin (vildagliptin (such as Galvus ^® , Galvumet ^® ), giglipid Gemigliptin, omarigliptin, evogliptin, dutogliptin, DA-1229, MK-3102, KM-223, KRP-104, PBL-1427, Pinoxacin hydrochloride and Ari-2243; (h) sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, such as canagliflozin, dapagliflozin, Regligliflozin, remogliflozin etabo nate), sergliflozin, empagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, ertugliflozin EGT-0001442, LIK-066, SBM-TFC-039 and KGA-3235 (DSP-3235); (i) dual inhibitors of SGLT-2 and SGLT-1 (e.g. LX-4211, LIK066); (j) SGLT-1 inhibitors (e.g. LX-2761, KGA-3235) or SGLT-1 inhibitors (e.g. GSK-1614235 + GSK-2330672) in combination with anti-obesity drugs such as ileal bile acid transfer (IBAT) inhibitors; (k ) Biguanides (such as metformin, succinidine, phenformin); (1) thiazolidinediones (such as pioglitazone, rosiglitazone), glitazone analogs (such as loberger (Lobeglitazone)); (m) peroxisome proliferator-activated receptor (PPAR-) (α, γ, or α / γ) agonists or modulators (for example, saroglitazar, ( For example Lipaglyn ^® ), GFT-505) or PPARγ partial agonists (such as Int-131); (n) sulfonylureas (such as tolbutamide, glibenclamide, glimepiride ), Amaryl ^® , Lattice Glipizide) and meglitinide (Meglitinide s, such as nateglinide, repaglinide, mitiglinide); (o) α- glucosidase inhibitors (e.g. acarbose, miglitol, voglibose); (Q) amylin and amylin analogs (e.g. ^{pramlintide, Symlin ®); (p)} G Protein-coupled receptor 119 (GPR119) agonists (e.g. GSK-1292263, PSN-821, MBX-2982, APD-597, ARRY-981, ZYG-19, DS-8500, HM-47000, YH-Chem1) (Q) GPR40 agonist (e.g. TUG-424, P-1736, P-11187, JTT-851, GW9508, CNX-011-67, AM-1638, AM-5262); (r) GPR120 agonist And GPR142 agonists; (s) systemic or low-absorption TGR5 (GPBAR1 = G-protein-coupled bile acid receptor 1) agonists (such as INT-777, XL-475, SB756050); (t) diabetes Immunotherapy, for example: oral CC chemokine receptor type 2 (CCR-2) antagonists (such as CCX-140, JNJ-41443532), interleukin 1β (IL-1β) antagonists (such as AC-201), Or oral monoclonal antibody (MoA) (e.g., metalozamide, VVP808, PAZ-320, P-1736, PF-05175157, PF-04937319); (v) anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, such as: nuclear factor kappa B inhibitors (such as Triolex ^® ); (w) adenosine monophosphate-activated protein kinase (AMPK) stimulants, such as: Imeglimin (PXL -008), Debio-0930 (MT-63-78), R-118; (x) inhibitors of 11-β-hydroxysteroid dehydrogenase 1 (11-β-HSD-1) (e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016, BI-135585); (y) glucokinase activators (e.g. PF-04991532, TTP-399 (GK1-399), GKM-001 (ADV-1002401) ARRY-403 (AMG-151), TAK-329, TMG-123, ZYGK1); (z) inhibitors of diamidyl glycerol O-fluorenyl transferase (DGAT) (e.g. pradigastat (LCQ-908)), Inhibitors of protein tyrosine phosphatase 1 (such as trodusquemine), inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-diphosphatase, inhibitors of glycogen phosphorylase, phosphoenol Inhibitors of pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrogenase kinase; (aa) modulators of glucose transporter-4, somatostatin receptor 3 agonists (e.g., MK-4256); (bb) one or more lipid-lowering agents are also suitable As a combination partner, for example: 3-hydroxy-3-methylglutaryl XI - -A- CoA reductase (HMG-CoA- reductase) inhibitor, such as simvastatin (e.g. Zocor ^{^{^®,}} Inegy ^®, Simcor ^® ), Atorvastatin (such as Sortis ^® , Caduet ^® ), rosuvastatin (such as Crestor ^® ), pravastatin (such as Lipostat ^® , Selipran ^® ), fluvastatin (such as Lescol ^® ), and pitavastatin (such as For example, Livazo ^® , Livalo ^® ), lovastatin (such as Mevacor ^® , Advicor ^® ), mevastatin (such as Compactin ^® ), rivastatin, lipivastatin (Lipobay ^® ), cellulosic acids such as bezafibrate (bezafibrate, e.g. delay Cedur ^®), ciprofibrate (ciprofibrate, e.g. Hyperlipen ^®), fenofibrate (of fenofibrate, e.g. ^{^{^{Antara ®, Lipofen ®, Lipanthyl ®}}} ), gemfibrozil (the gemfibrozil, For example, Lopid ^® , Gevilon ^® ), etofibrate, simfibrate, ronifibrate, clinofibrate, clofibride, nicotinic acid and its derivatives Sustained release systems such as nicotinic acid, including nicotinic acid Agent), nicotinic acid receptor 1 agonist (such as GSK-256073), PPAR-δ agonist, acetamidine coenzyme A-acetamidine transferase (ACAT) inhibitor (for example, avasimibe) , cholesterol absorption inhibitors (e.g. ^{^{ezetimibe, Ezetrol ®, Zetia ®, Liptruzet}} ®, Vytorin ®, S-556971), bile acid binding agent (e.g., cholestyramine (, cholestyramine), colesevelam (colesevelam)) Ileal bile acid transport (IBAT) inhibitors (such as GSK-2330672, LUM-002), microsomal triglyceride transporter (MTP) inhibitors (such as lomitapide (AEGR-733)), SLx- 4090, granapapide), modulators of the proprotein-converting enzyme subtilisin / kexin 9 (PCSK9) (e.g., aliculumab (REGN727 / SAR236553), AMG-145, LGT-209, PF-04950615, MPSK3169A, ILY3015014, ALD-306, ALN-PCS, BMS-962476, SPC5001, ISIS-394814, 1B20, LGT-210, 1D05, BMS-PCSK9Rx-2, SX-PCK9, RG7652), LDL receptor up-regulators, such as liver-selective thyroid Hormone receptor beta agonists (e.g. eprotirome (KB-2115)), MB07811, sobetirome (QRX-431), VLA-3196, ZYT1), HDL-elevating compounds : Cholesteryl ester transporter (CETP) inhibitors (such as anacetrapib (MK0859)), dalcetrapib, evacetrapib, JTT-302, DRL-17822, TA- 8995, R-1658, LY-2484595, DS-1442), or dual CETP / PCSK9 inhibitors (such as K-312), ATP binding cassette (ABC1) modulators, lipid metabolism regulators (such as BMS-823778, TAP- 301, DRL-21994, DRL- 21995), phospholipase A2 (PLA2) inhibitors (e.g. Dabura association (darapladib), Tyrisa ^®, the cutting Pereira (varespladib), Lila ground (rilapladib)), ApoA- I enhancers (e.g. RVX-208, CER-001, MDCO-216, CSL-112), cholesterol synthesis inhibitors (e.g. ETC-1002), lipid metabolism regulators (e.g. BMS-823778, TAP-301, DRL-21994 , DRL-21995) and omega-3 fatty acids and their derivatives (such as ethyl eicosapentaenoate (AMR101), Epanova ^® , AKR-063, NKPL-66, PRC-4016, CAT-2003); (cc ) Bromocriptine (such as Cycloset ^® , Parlodel ^® ), phentermine and phentermine preparations or combinations (such as Adipex-P, Ionamin, Qsymia ^® ), benzephetamine (such as Didrex ^® ), Diethylpropion (diethylpropion, e.g. Tenuate ^®), phendimetrazine (phendimetrazin, e.g. Adipost ^{^®,} Bontril ^®), bupropion (bupropion in), and combinations (e.g. ^{^{Zyban ®, Wellbutrin XL ®, Contrave}} ®, Empatic ®) , Sibutramine (such as Reductil ^® , Meridia ^® ), topiramat (such as Topamax ^® ), zonisamid (such as Zonegran ^® ), tesofensine (tesofensine), opioid antagonists, such as naltrexone (naltrexone, e.g. Naltrexin ^®, naltrexone + bupropion), cannabinoid receptor 1 (CB1) antagonists (e.g., TM-38837), melanin-concentrating hormone (MCH-1) antagonist (e.g. BMS-830216, ALB-127158 (a)), MC4 receptor agonist and partial agonist (such as AZD-2820, RM-493), neuropeptide Y5 (NPY5) or NPY2 antagonist (such as Veneratib (velneperit), S-234462), NPY4 agonist (such as PP-1420), β-3-adrenergic receptor agonist, leptin or leptin mimic, serotonin 2c (5HT2c) receptor agonists (e.g., lorcaserin (lorcaserin), Belviq ^®), pramlintide / metreleptin (pramlintide / metreleptin) Lipase inhibitors such as orlistat cetirizine (cetilistat, e.g. Cametor ^®), orlistat (e.g. Xenical ^{^®,} Calobalin ^®), angiogenesis inhibitors (e.g., ALS-L1023), betahistine (betahistidin) group and amine H3 antagonists (e.g. HPP-404), AgRP (agouti related protein) inhibitors (e.g., TTP-435), serotonin reuptake inhibitors such as fluoxetine (fluoxetine, e.g. Fluctine ^®), duloxetine ( duloxetine, such as Cymbalta ^® ), bi- or tri-monoamine uptake inhibitors (dopamine, norepinephrine and serotonin reuptake) such as sertraline (such as Zoloft ^® ), tesofensine, methofamine Acid aminopeptidase 2 (MetAP2) inhibitors (e.g. beloranib) and antisense oligonucleotides (e.g. ISIS-FGFR4Rx) produced by anti-fibroblast growth factor receptor 4 (FGFR4) or anti- proliferation protein targeting peptide-1 (e.g. Adipotide ^®); and (dd) a nitric oxide donor, or antagonists of AT1 angiotensin II (AT2) receptor antagonists, such as telmisartan (telmisartan, e.g. Kinzal ^® , Micardis ^®), candesartan (candesartan, e.g. Atacand ^{^®,} Blopress ^®), valine Tan (valsartan, e.g. ^{^{Diovan ®, Co-Diovan ®)}} , losartan (losartan, e.g. Cosaar ^®), eprosartan (eprosartan, e.g. Teveten ^®), irbesartan (irbesartan, e.g. Aprovel ^{^®,} CoAprovel ^® ), olmesartan (olmesartan, for example Votum ^{^®,} Olmetec ^®), tasosartan (tasosartan), azilsartan (azilsartan, such as Edarbi ^®), dual angiotensin receptor blockers (dual ARB), Angiotensin converting enzyme (ACE) inhibitor, ACE-2 activator, renin inhibitor, prorenin inhibitor, endothelin converting enzyme (ECE) inhibitor, endothelin receptor (ET1 / ETA) blocker , Endothelin antagonists, diuretics, aldosterone antagonists, aldosterone synthase inhibitors, alpha-blockers, alpha-2 adrenergic antagonists, beta-blockers, mixed alpha- Receptor / β-blockers, calcium antagonists, calcium channel blockers (CCB), nasal preparations of calcium channel blocker diltiazem (e.g. CP-404), dual mineralocorticoids / CCB , Centrally acting antihypertensive drugs, inhibitors of neutral endopeptidases, aminopeptidase-A inhibitors, vasopeptide inhibitors Preparations, dual vasopeptide inhibitors such as enkephalinase-ACE inhibitor or enkephalinase-ECE inhibitor, double acting AT receptor-enkephalinase inhibitor, dual AT1 / ETA antagonist, late glycosylation End-product (AGE) disrupting agents, recombinant renal enzymes, blood pressure vaccines such as anti-RAAS (renin-angiotensin-aldosterone-system) vaccine, AT1- or AT2- vaccines, drugs based on hypertension pharmacogenomics, such as those with anti- Modulators of genetic polymorphisms of hypertension response, inhibitors of thrombocyte aggregation and others; and (ee) suitable combinations thereof.

在某些實施例中，另外的抗糖尿病治療是GLP-1治療(例如，利西拉來)。在某些實施例中，GLP-1治療用甲硫胺酸(例如L-甲硫胺酸或D-甲硫胺酸)配製。在某些實施例中，GLP-1治療的製劑中不存在或基本上不存在聚山梨醇酯(例如聚山梨醇酯20、聚山梨醇酯80)，泊洛沙姆(poloxamer，例如泊洛沙姆188)，苯紮氯銨，組胺酸，賴胺酸和/或EDTA。在某些實施例中，GLP-1治療的製劑不含或基本上不含表面活性劑，諸如多元醇(例如聚丙二醇、聚乙二醇、泊洛沙姆、Pluronics、Tetronics)，多元醇的部分和脂肪酸酯和醚，諸如甘油和山梨糖醇的那些(例如，Span.RTM.、Tween.RTM.、Myrj.RTM.、Brij.RTM.、Cremophor.RTM)。GLP-1治療的製劑可包含合適的防腐劑(例如，苯酚、間甲酚、苯甲醇和/或對羥基苯甲酸酯)和合適的張力調節劑(例如甘油、右旋糖、乳糖、山梨糖醇、甘露醇、葡萄糖、NaCl、鈣或鎂化合物諸如CaCl₂)。甘油、右旋糖、乳糖、山梨糖醇、甘露醇和葡萄糖的濃度通常在100-250mM的範圍內，NaCl的濃度最高達150mM。 In certain embodiments, the additional anti-diabetic treatment is a GLP-1 treatment (eg, lixisenatide). In certain embodiments, GLP-1 treatment is formulated with methionine (eg, L-methionine or D-methionine). In certain embodiments, polysorbates (e.g., polysorbate 20, polysorbate 80), poloxamer (e.g., poloxamer, etc.) are absent or substantially absent from the GLP-1 treated formulation. Sham 188), benzalkonium chloride, histidine, lysine and / or EDTA. In certain embodiments, formulations for GLP-1 treatment are free or substantially free of surfactants, such as polyols (eg, polypropylene glycol, polyethylene glycol, poloxamer, Pluronics, Tetronics), polyols Moieties and fatty acid esters and ethers, such as those of glycerol and sorbitol (eg, Span.RTM., Tween.RTM., Myrj.RTM., Brij.RTM., Cremophor.RTM). GLP-1 treated formulations may include suitable preservatives (e.g., phenol, m-cresol, benzyl alcohol, and / or parabens) and suitable tonicity modifiers (e.g., glycerol, dextrose, lactose, sorbitan Sugar alcohols, mannitol, glucose, NaCl, calcium or magnesium compounds such as CaCl ₂ ). The concentrations of glycerol, dextrose, lactose, sorbitol, mannitol and glucose are usually in the range of 100-250 mM, and the concentration of NaCl is up to 150 mM.

在某些實施例中，患者接受的胰島素治療與另外的抗糖尿病治療(例如，不是胰島素治療的任何前述抗糖尿病治療)組合。例如，在某些實施例中，抗糖尿病治療包括胰島素治療(例如甘精胰島素)和GLP-1治療(例如利西拉來)的組合。這些治療可以單獨提供或在單一藥物組合物中提供。例如，甘精胰島素和利西拉來可以配製在單一藥物組合物中(例如，Soliqua^® 100/33)用於每日注射。 In certain embodiments, the patient receives an insulin treatment in combination with an additional anti-diabetic treatment (eg, any of the aforementioned anti-diabetic treatments other than insulin treatment). For example, in certain embodiments, anti-diabetic treatment includes a combination of insulin treatment (eg, glargine) and GLP-1 treatment (eg, lixisenatide). These treatments can be provided separately or in a single pharmaceutical composition. For example, insulin glargine and lixisenatide may be formulated in a single pharmaceutical composition (e.g., Soliqua ^® 100/33) for daily injections.

在該方法的上下文中，可以在施用PCSK9抑制劑之前、同時或之後不久施用一種或多種另外的治療活性組分，例如以上列舉的任何劑或其衍生物；(為了本公開的目的，這樣的施用方案被認為是“與”另外的治療活性組分“組合”施用PCSK9抑制劑)。本發明的方法包括藥物組合物及其使用方法，其中PCSK9抑制劑與如本文其他地方所述的一個或多個另外的治療活性組分共同配製。 In the context of this method, one or more additional therapeutically active components, such as any of the agents listed above or derivatives thereof, may be administered before, at the same time or shortly after the administration of the PCSK9 inhibitor; (for the purposes of this disclosure, such The dosing regimen is considered to "administer a PCSK9 inhibitor" in combination with "additional therapeutically active components). The methods of the invention include pharmaceutical compositions and methods of using the same, wherein the PCSK9 inhibitor is co-formulated with one or more additional therapeutically active ingredients as described elsewhere herein.

施用PCSK9抑制劑作為添加(add-on)治療Administration of PCSK9 inhibitors as an add-on therapy

本發明的治療方法包括用PCSK9抑制劑(諸如特異性結合PCKS9的抗體或其抗原結合片段)治療患有高膽固醇血症和糖尿病的患者，其中PCSK9抑制劑可作為對患者的預先存在的胰島素治療和/或LMT(如果可適用的話)的添加治療施用，諸如作為患者的預先存在的每日治療性胰島素和/或他汀類方案的添加治療。 The treatment method of the present invention includes treating patients with hypercholesterolemia and diabetes with a PCSK9 inhibitor (such as an antibody or antigen-binding fragment thereof that specifically binds PCKS9), wherein the PCSK9 inhibitor can be used as a pre-existing insulin treatment for the patient And / or LMT (if applicable) add-on therapy, such as add-on therapy to a patient's pre-existing daily therapeutic insulin and / or statin regimen.

例如，該方法包括添加治療方案，其中PCSK9抑制劑作為對患者在接受PCSK9抑制劑之前接受的同樣的穩定的多次每日胰島素治療方案和/或每日治療他汀類方案(即相同給藥量的他汀類)的添加治療施用。在其他實施例中，PCSK9抑制劑作為對治療性胰島素和/或他汀類方案的添加治療施用，該治療性胰島素和/或他汀類方案包含比該患者在接受PCSK9抑制劑之前接受的胰島素和/或他汀類的劑量更多或更少的量的胰島素和/或他汀類。例如，在開始包含以特定給藥頻率和給藥量施用的PCSK9抑制劑的治療方案後，向患者施用或開處方的胰島素和/或他汀類的每日劑量可以與患者在開始PCSK9抑制劑治療方案之前服用的每日他汀類劑量相比(a)保持不變，(b)增加，或(c)減少(例如，上升滴定(up-titrate)或下降滴定(down-titrate))，這取決於患者的治療需要。 For example, the method includes adding a treatment regimen in which the PCSK9 inhibitor acts as the same stable multiple daily insulin treatment regimen and / or daily treatment statin regimen (i.e., the same dosage) that the patient receives before receiving the PCSK9 inhibitor. Statins). In other embodiments, the PCSK9 inhibitor is administered as an add-on therapy to a therapeutic insulin and / or statin regimen that comprises more insulin than the patient received before the PCSK9 inhibitor and / Or a statin dose of a greater or lesser amount of insulin and / or a statin. For example, after starting a treatment regimen comprising a PCSK9 inhibitor administered at a specific dosing frequency and dose, a daily dose of insulin and / or statins administered or prescribed to a patient can be compared with the patient at the beginning of PCSK9 inhibitor treatment. The daily statin dose taken before the regimen remains the same compared to (a), (b) increases, or (c) decreases (e.g., up-titrate or down-titrate), depending on To the patient's treatment needs.

治療功效Therapeutic effect

該方法導致一種或多種選自以下組成之群組的脂質組分的血清水準的降低：LDL-C、ApoB、ApoB100、非HDL-C、總膽固醇、VLDL-C、甘油三酯、Lp(a)、HDL-C、LDL顆粒數、LDL顆粒尺寸、ApoC3、ApoA-1、富含甘油三酯的脂蛋白膽固醇(TRL-C)和殘餘膽固醇。根據某些實施例，向患者施用包含PCSK9抑制劑的藥物組合物會導致從血清低密度脂蛋白膽固醇(LDL-C)的基線的平均百分比降低至少約25%、30%、35%、40%、45%、50%、55%、60%或更高；從ApoB的基線的平均百分比降低至少約25%、30%、35%、40%、45%、50%、55%、60%或更高；從ApoB100的基線的平均百分比降低至少約25%、30%、35%、40%、45%、50%、55%、60%或更高；從非HDL-C的基線的平均百分比降低至少約25%、30%、35%、40%、45%、50%、55%、60%或更高；從總膽固醇的基線的平均百分比降低至少約10%、15%、20%、25%、30%、35%、40%或更高；從VLDL-C的基線的平均百分比降低至少約5%、10%、15%、20%、25%、30%或更高；從甘油三酯的基線的平均百分比降低至少約5%、10%、15%、20%、25%、30%、 35%或更高；從LDL顆粒數量的基線的平均百分比降低至少約20%、25%、30%、35%、40%、45%、50%或更高；從LDL顆粒尺寸的基線的平均百分比降低至少約1.5%、2%、2.5%、3%、3.5%或4%或更多；從載脂蛋白C3(ApoC3)的基線的平均百分比降低至少約5%、5.5%、6.0%、6.5%、7.0%、7.5%、8.0%、9.0%、10%或更多；從HDL-C的基線的平均百分比增加至少約1%、2%、3%、4%、5%或更高；從ApoA-1的基線的平均百分比增加至少約1%、2%、3%、4%、5%或更高；從TRL-C的基線的平均百分比降低至少約5%、10%、15%、20%、25%、30%或更高；和/或從Lp(a)的基線的平均百分比降低至少約5%、10%、15%、20%、25%或更高。 This method results in a decrease in serum levels of one or more lipid components selected from the group consisting of: LDL-C, ApoB, ApoB100, non-HDL-C, total cholesterol, VLDL-C, triglycerides, Lp (a ), HDL-C, LDL particle number, LDL particle size, ApoC3, ApoA-1, triglyceride-rich lipoprotein cholesterol (TRL-C), and residual cholesterol. According to some embodiments, administering a pharmaceutical composition comprising a PCSK9 inhibitor to a patient results in a reduction in the average percentage from baseline of serum low-density lipoprotein cholesterol (LDL-C) by at least about 25%, 30%, 35%, 40% , 45%, 50%, 55%, 60% or higher; at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or 60% reduction from the average percentage of ApoB's baseline Higher; average percentage reduction from baseline of ApoB100 by at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or higher; average percentage from baseline of non-HDL-C Reduced by at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or more; the average percentage reduction from the baseline of total cholesterol was reduced by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40% or higher; average baseline reduction from VLDL-C by at least about 5%, 10%, 15%, 20%, 25%, 30% or higher; from glycerol Baseline average percentage reduction of triesters is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35% or higher; average percentage reduction from baseline of LDL particle number is at least about 20%, 25 %, 30%, 35%, 40%, 45%, 50% or higher; from the base of LDL particle size Average percentage reduction of at least about 1.5%, 2%, 2.5%, 3%, 3.5%, or 4% or more; average percentage reduction from baseline of apolipoprotein C3 (ApoC3) by at least about 5%, 5.5%, 6.0 %, 6.5%, 7.0%, 7.5%, 8.0%, 9.0%, 10% or more; an average percentage increase from the baseline of HDL-C of at least about 1%, 2%, 3%, 4%, 5% or Higher; average percentage increase from baseline of ApoA-1 by at least about 1%, 2%, 3%, 4%, 5% or higher; average percentage decrease from baseline of TRL-C by at least about 5%, 10% , 15%, 20%, 25%, 30% or more; and / or a reduction in the average percentage from the baseline of Lp (a) by at least about 5%, 10%, 15%, 20%, 25% or more.

本發明的方法包括治療接受胰島素治療的患有高膽固醇血症和T1DM的患者，該方法包括以每劑約75至150mg的給藥量，和約每兩週或每四週一次的給藥頻率，或根據本文所公開的上升滴定給藥方案的給藥方案，向患者施用多劑量的抗PCSK9抗體或其抗原結合片段。在用抗PCSK9抗體治療約8、10、12、14、16、18、20、22、24或更多周後，患者可表現出LDL-C水準從基線降低至少35%、50%或60%。在某些實施例中，在用抗PCSK9抗體治療一周或多周後，患者表現出LDL-C水準從基線降低約35%、50%或60%或更多。 The method of the present invention includes treating patients with hypercholesterolemia and T1DM who are receiving insulin therapy, the method comprising a dosage of about 75 to 150 mg per dose and a frequency of dosing about every two or four weeks, Alternatively, multiple doses of an anti-PCSK9 antibody or antigen-binding fragment thereof are administered to a patient according to the dosing regimen of the ascending titration dosing regimen disclosed herein. After treating with anti-PCSK9 antibody for about 8, 10, 12, 14, 16, 18, 20, 22, 24 or more weeks, patients can show a reduction in LDL-C levels from baseline by at least 35%, 50%, or 60% . In certain embodiments, after one or more weeks of treatment with an anti-PCSK9 antibody, the patient exhibits a decrease in LDL-C levels from baseline by about 35%, 50%, or 60% or more.

本發明的方法還包括治療接受胰島素治療的患有高膽固醇血症和T2DM的患者，該方法包括以每劑約75至150mg的給藥量，和約每兩週或每四週一次的給藥頻率，或根據本文所公開的上升滴定給藥方案的給藥方案，向患者施用多劑量的抗PCSK9抗體或其抗原結合片段。在用抗PCSK9抗體治療約8、10、12、14、16、18、20、22、24或更多週後，患者可表現出LDL-C水準從基線降低至少40%、48%或54%。在某些實施例中，在用抗PCSK9抗體治療一週或多週後，患者表現出LDL-C水準從基線降低約40%、48%或54%或更多。 The method of the present invention also includes treating patients with hypercholesterolemia and T2DM who are receiving insulin therapy, the method comprising a dosage of about 75 to 150 mg per dose, and a frequency of dosing about every two or four weeks Or, according to the dosing regimen of the ascending titration dosing regimen disclosed herein, a patient is administered multiple doses of an anti-PCSK9 antibody or an antigen-binding fragment thereof. After treating with anti-PCSK9 antibodies for about 8, 10, 12, 14, 16, 18, 20, 22, 24 or more weeks, patients can show a decrease in LDL-C levels from baseline by at least 40%, 48%, or 54% . In certain embodiments, after one or more weeks of treatment with an anti-PCSK9 antibody, the patient exhibits a decrease in LDL-C levels from baseline by about 40%, 48%, or 54% or more.

如本文所公開的，本發明的方法不改變患者的糖尿病參數。例如，在某些實施例中，該方法不影響(例如，不會有大於1%、2%、3%、4%、5%、6%、7%、8%、9%或10%的改變)患者的血紅蛋白A1c(HbA1c) 水準。在某些實施例中，該方法不影響(例如，不會有大於2%、4%、6%、8%、10%、12%、15%、18%或20%的改變)患者的空腹血糖(FPG)水準。 As disclosed herein, the methods of the invention do not alter the diabetes parameters of the patient. For example, in some embodiments, the method does not affect (e.g., no greater than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (Change) The patient's hemoglobin A1c (HbA1c) level. In certain embodiments, the method does not affect (e.g., no more than 2%, 4%, 6%, 8%, 10%, 12%, 15%, 18%, or 20% change) of the patient's fasting Blood glucose (FPG) level.

在另外的實施例中，本發明涉及特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段用於治療患有1型糖尿病(T1DM)的患者中的高膽固醇血症的用途。 In a further embodiment, the invention relates to an antibody or antigen-binding fragment thereof that specifically binds the human proprotein converting enzyme subtilin / kexin type 9 (PCSK9) for use in treating patients with type 1 diabetes (T1DM) Use of hypercholesterolemia.

在又另外的實施例中，本發明涉及治療患有1型糖尿病(T1DM)的患者中的高膽固醇血症的方法。 In yet another embodiment, the invention relates to a method of treating hypercholesterolemia in a patient with type 1 diabetes (T1DM).

在一個實施例中，該用途和/或方法包括以下步驟：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 In one embodiment, the use and / or method comprises the steps of: (a) selecting a high cardiovascular risk patient for insulin therapy, who has (i) T1DM, and (ii) by maximally tolerated statin therapy Insufficiently controlled hypercholesterolemia; and (b) administering to the patient 75 mg, 150 mg, or 300 mg of an antibody or antigen-binding fragment thereof that specifically binds to the human proprotein converting enzyme subtilin / kexin type 9 (PCSK9), wherein The patient received concomitant insulin therapy.

在該用途和/或方法的一個實施例中，每兩週向該患者施用75mg的該抗體或抗原結合片段。 In one embodiment of the use and / or method, the patient is administered 75 mg of the antibody or antigen-binding fragment every two weeks.

在該用途和/或方法的一個實施例中，每兩週向該患者施用150mg的該抗體或抗原結合片段。 In one embodiment of the use and / or method, the patient is administered 150 mg of the antibody or antigen-binding fragment every two weeks.

在該用途和/或方法的一個實施例中，每四週向該患者施用300mg的該抗體或抗原結合片段。 In one embodiment of the use and / or method, the patient is administered 300 mg of the antibody or antigen-binding fragment every four weeks.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段包含SEQ ID NO：2、3和4中示出的三個重鏈CDR，和SEQ ID NO：7、8和10中示出的三個輕鏈CDR。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs shown in SEQ ID NOs: 2, 3, and 4, and SEQ ID NOs: 7, 8, and 10 Three light chain CDRs are shown in.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的重鏈可變區(HCVR)，和具有SEQ ID NO：6的胺基酸序列的輕鏈可變區(LCVR)。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1, and a polypeptide having SEQ ID NO: 6 Light chain variable region (LCVR) of an amino acid sequence.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段選自以下組成之群組：阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab和LY3015014。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof is selected from the group consisting of: aliculumab, evocutumab, bococizumab, rodecizumab, ralpancizumab and LY3015014.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段是阿利庫單抗。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof is aliculumab.

在一個實施例中，該用途和/或方法進一步包括以下步驟：(c)如果該患者中的LDL-C水準低於閾值水準，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 In one embodiment, the use and / or method further comprises the steps of: (c) if the LDL-C level in the patient is below a threshold level, administering to the patient about one or more of the following doses about every two weeks 75 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

在一個實施例中，該用途和/或方法進一步包括以下步驟：(c)如果該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 In one embodiment, the use and / or method further comprises the steps of: (c) administering one or more of the following doses of 300 mg to the patient approximately every four weeks if the LDL-C level in the patient is below a threshold level The antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

在該用途和/或方法的一個實施例中，該閾值水準是70mg/dL。 In one embodiment of the use and / or method, the threshold level is 70 mg / dL.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段皮下施用。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof is administered subcutaneously.

在該用途和/或方法的一個實施例中，該患者進一步接受伴隨脂質修飾治療(LMT)。 In one embodiment of the use and / or method, the patient further receives concomitant lipid modification therapy (LMT).

在該用途和/或方法的一個實施例中，該LMT選自以下組成之群組：他汀類、膽固醇吸收抑制劑、纖維酸類、菸鹼酸類、ω-3脂肪酸和膽汁酸螯合劑。 In one embodiment of the use and / or method, the LMT is selected from the group consisting of: statins, cholesterol absorption inhibitors, cellulates, nicotinic acids, omega-3 fatty acids, and bile acid sequestrants.

在該用途和/或方法的一個實施例中，該LMT是他汀類治療。 In one embodiment of the use and / or method, the LMT is a statin therapy.

在該用途和/或方法的一個實施例中，該他汀類選自以下組成之群組：阿托伐他汀、瑞舒伐他汀、辛伐他汀、普伐他汀、洛伐他汀、氟伐他汀、匹伐他汀和西立伐他汀。 In one embodiment of the use and / or method, the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, Pitavastatin and cerivastatin.

在該用途和/或方法的一個實施例中，該他汀類治療是最大耐受的他汀類治療。 In one embodiment of the use and / or method, the statin treatment is a statin treatment that is most tolerated.

在該用途和/或方法的一個實施例中，該膽固醇吸收抑制劑是依折麥布。 In one embodiment of the use and / or method, the cholesterol absorption inhibitor is ezetimibe.

在該用途和/或方法的一個實施例中，該患者對他汀類不耐受。 In one embodiment of the use and / or method, the patient is intolerant to statins.

在該用途和/或方法的一個實施例中，該胰島素治療選自以下組成之群組：人胰島素、甘精胰島素、谷賴胰島素、地特胰島素、賴脯胰島素、德穀胰島素、門冬胰島素和基礎胰島素。 In one embodiment of the use and / or method, the insulin treatment is selected from the group consisting of: human insulin, insulin glargine, insulin glutamate, insulin detemir, insulin lispro, insulin deguer, insulin aspart And basal insulin.

在該用途和/或方法的一個實施例中，該患者除胰島素治療之外還接受伴隨抗糖尿病治療。 In one embodiment of the use and / or method, the patient receives concomitant anti-diabetic therapy in addition to insulin therapy.

在該用途和/或方法的一個實施例中，另外的伴隨抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油O-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 In one embodiment of the use and / or method, the additional concomitant anti-diabetic treatment is selected from the group consisting of: glucagon-like peptide 1 (GLP-1) therapy, gastrointestinal peptide, glucagon receptor A agonist or antagonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or antagonist, a growth hormone releasing hormone antagonist or inverse agonist, xenin, xenin analogs, biguanides, sulfonylurea Class, meglitinide, thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, Oxidase Proliferator Activated Receptor (PPAR-) (α, γ or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) GPR40 agonist, GPR120 agonist, GPR142 agonist, systemic or low-absorption TGR5 agonist, diabetes immunotherapy, anti-inflammatory agent for the treatment of metabolic syndrome and diabetes, adenosine monophosphate Activated protein kinase (AMPK) stimulant, inhibitor of 11-β-hydroxysteroid dehydrogenase 1, glucokinase activator, two Glycerol O- acyl transferase (the DGAT) inhibitor, glucose transporter-4 modulators of somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段將該患者的LDL-C水準降低至少30%、35%、40%或45%。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof reduces the patient's LDL-C level by at least 30%, 35%, 40%, or 45%.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段將該患者的非HDL-C水準降低至少25%、30%、35%或40%。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof reduces the patient's non-HDL-C level by at least 25%, 30%, 35%, or 40%.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段降低該患者的載脂蛋白C3(ApoC3)水準。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof reduces the apolipoprotein C3 (ApoC3) level of the patient.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段減少該患者中的脂蛋白顆粒的數量和/或尺寸。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof reduces the number and / or size of lipoprotein particles in the patient.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段：(a)不影響該患者的血紅蛋白A1c(HbA1c)水準；和/或(b)不影響該患者的空腹血糖(FPG)水準。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof: (a) does not affect the patient's hemoglobin A1c (HbA1c) level; and / or (b) does not affect the patient's fasting blood glucose ( FPG) level.

在另外的實施例中，本發明涉及用於治療患有1型糖尿病(T1DM)的患者中的高膽固醇血症的用途和/或方法，該方法包括以下步驟：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；(b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。 In a further embodiment, the present invention relates to the use and / or method for treating hypercholesterolemia in a patient with type 1 diabetes (T1DM), the method comprising the steps of: (a) selecting a patient for insulin therapy Patients with high cardiovascular risk who have (i) T1DM, and (ii) insufficiently controlled hypercholesterolemia with the best-tolerated statins; (b) administer 75 mg of specific binding to this patient every two weeks An antibody or an antigen-binding fragment thereof of a human proprotein-converting enzyme subtilin / kexin 9 (PCSK9); and (c) if the LDL-C level in the patient is below 70 mg / dL, the patient is referred to the patient approximately every two weeks One or more of the following doses of 75 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to 70 mg / dL, one or more of the following doses of 150 mg are administered approximately every two weeks. The antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 and wherein the patient receives Concomitant insulin therapy.

在另外的實施例中，本發明涉及用於治療患有2型糖尿病(T2DM)的患者中的高膽固醇血症的方法，該方法包括以下步驟：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 In a further embodiment, the invention relates to a method for treating hypercholesterolemia in a patient with type 2 diabetes (T2DM), the method comprising the steps of: (a) selecting a high cardiovascular risk for insulin therapy A patient with (i) T1DM, and (ii) treatment of insufficiently controlled hypercholesterolemia with maximally tolerated statins; and (b) administering to the patient 75 mg, 150 mg, or 300 mg prior to specifically binding to humans An antibody or antigen-binding fragment thereof of a protein converting enzyme subtilin / kexin type 9 (PCSK9), wherein the patient is receiving concomitant insulin therapy.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的重鏈可變區(HCVR)和具有SEQ ID NO：6的胺基酸序列的輕鏈可變區(LCVR)。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1 and an amine having SEQ ID NO: 6 Light chain variable region (LCVR) of the amino acid sequence.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段選自以下組成之群組：阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab和LY3015014。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof is selected from the group consisting of: aliculumab, evocutumab, bococizumab, rodecizumab, ralpancizumab, and LY3015014.

在該用途和/或方法的一個實施例中，進一步包括以下步驟：(c)如果該患者中的LDL-C水準低於閾值水準，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 In one embodiment of the use and / or method, further comprising the step of: (c) administering one or more of the following doses to the patient approximately every two weeks if the LDL-C level in the patient is below a threshold level 75 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks .

在該用途和/或方法的一個實施例中，進一步包括以下步驟：(c)如果該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 In one embodiment of the use and / or method, further comprising the step of: (c) administering one or more of the following doses to the patient about every four weeks if the LDL-C level in the patient is below a threshold level 300 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段係皮下施用。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof is administered subcutaneously.

在該用途和/或方法的一個實施例中，另外的抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油O-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 In one embodiment of the use and / or method, the additional anti-diabetic treatment is selected from the group consisting of: glucagon-like peptide 1 (GLP-1) treatment, gastrointestinal peptide, glucagon receptor Agents or antagonists, glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone releasing hormone antagonists or inverse agonists, xenin, xenin analogs, biguanides, sulfonylureas , Meglitinide, thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, peroxidation Proteasome Proliferator Activated Receptor (PPAR-) (α, γ or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) agonist Agents, GPR40 agonists, GPR120 agonists, GPR142 agonists, systemic or low-absorption TGR5 agonists, diabetes immunotherapy, anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, adenosine monophosphate activation Protein kinase (AMPK) stimulant, inhibitor of 11-β-hydroxysteroid dehydrogenase 1, glucokinase activator, difluorenyl Inhibitors of glycerol O-fluorenyl transferase (DGAT), modulators of glucose transporter-4, somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段將該患者的非HDL-C水準降低至少20%、25%、30%或35%。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof reduces the patient's non-HDL-C level by at least 20%, 25%, 30%, or 35%.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段降低該患者的ApoC3水準。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof reduces the ApoC3 level of the patient.

在另外的實施例中，本發明涉及用於治療患有2型糖尿病(T2DM)的患者中的高膽固醇血症的用途和/或方法，該方法包括以下步驟：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T2DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。 In a further embodiment, the present invention relates to the use and / or method for treating hypercholesterolemia in a patient with type 2 diabetes (T2DM), the method comprising the steps of: (a) selecting a patient for insulin therapy Patients with high cardiovascular risk who have (i) T2DM, and (ii) under-controlled hypercholesterolemia with maximum tolerated statins; and (b) specificity of 75 mg administered to this patient every two weeks An antibody or antigen-binding fragment thereof that binds the human proprotein-converting enzyme subtilin / kexin type 9 (PCSK9); and (c) if the LDL-C level in the patient is less than 70 mg / dL, The patient is administered one or more of the following doses of 75 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to 70 mg / dL, one or more of the following doses of 150 mg are administered approximately every two weeks The antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 and wherein the patient Receive concomitant insulin therapy.

在另外的實施例中，本發明涉及特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段用於治療患有2型糖尿病(T2DM)和動脈粥樣硬化性心血管疾病(ASCVD)的患者中的高膽固醇血症的用途。 In a further embodiment, the invention relates to an antibody or antigen-binding fragment thereof that specifically binds the human proprotein converting enzyme subtilin / kexin type 9 (PCSK9) for use in treating patients with type 2 diabetes (T2DM) and atherosclerosis Use of hypercholesterolemia in patients with sclerosing cardiovascular disease (ASCVD).

在又另外的實施例中，本發明涉及用於治療患有T2DM和ASCVD的患者中的高膽固醇血症的方法。 In yet another embodiment, the invention relates to a method for treating hypercholesterolemia in a patient with T2DM and ASCVD.

在一個實施例中，該用途和/或方法包括以下步驟：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T2DM、(ii)ASCVD和(iii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 In one embodiment, the use and / or method includes the steps of: (a) selecting a high cardiovascular risk patient for insulin therapy, who has (i) T2DM, (ii) ASCVD, and (iii) passes maximum tolerance Statins to treat insufficiently controlled hypercholesterolemia; and (b) administer to the patient 75 mg, 150 mg, or 300 mg of an antibody or antigen thereof that specifically binds the human proprotein converting enzyme subtilin / kexin type 9 (PCSK9) Binding fragment, wherein the patient is receiving concomitant insulin therapy.

在該用途和/或方法的一個實施例中，該ASCVD被限定為冠心病(CHD)、缺血性中風或外周動脈疾病。 In one embodiment of the use and / or method, the ASCVD is defined as coronary heart disease (CHD), ischemic stroke, or peripheral arterial disease.

在該用途和/或方法的一個實施例中，該CHD包括急性心肌梗死、無症狀性心肌梗死和不穩定型心絞痛。 In one embodiment of the use and / or method, the CHD includes acute myocardial infarction, asymptomatic myocardial infarction, and unstable angina.

在該用途和/或方法的一個實施例中，該抗體或其抗原結合片段包含SEQ ID NO：2、3和4中示出的三個重鏈CDR和SEQ ID NO：7、8和10中示出的三個輕鏈CDR。 In one embodiment of the use and / or method, the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs shown in SEQ ID NOs: 2, 3, and 4 and SEQ ID NOs: 7, 8, and 10 Three light chain CDRs are shown.

在該用途和/或方法的一個實施例中，該他汀類治療是最大耐受劑量的他汀類治療。 In one embodiment of the use and / or method, the statin treatment is a maximum tolerated dose of statin treatment.

在該用途和/或方法的一個實施例中，另外的抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油O-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 In one embodiment of the use and / or method, the additional anti-diabetic treatment is selected from the group consisting of: glucagon-like peptide 1 (GLP-1) treatment, gastrointestinal peptide, glucagon receptor Agents or antagonists, glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone releasing hormone antagonists or inverse agonists, xenin, xenin analogs, biguanides, sulfonylureas , Meglitinide, thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, peroxidation Proteasome Proliferator Activated Receptor (PPAR-) (α, γ or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) agonist Agents, GPR40 agonists, GPR120 agonists, GPR142 agonists, systemic or low-absorption TGR5 agonists, diabetes immunotherapy, anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, adenosine monophosphate activation Protein kinase (AMPK) stimulant, inhibitor of 11-β-hydroxysteroid dehydrogenase 1, glucokinase activator, difluorenyl Oil-O- acyl transferase (the DGAT) inhibitor, glucose transporter-4 modulators of somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

在另外的實施例中，本發明涉及用於治療患有2型糖尿病(T2DM)的患者中的高膽固醇血症的用途和/或方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，其患有(i)T2DM、(ii)ASCVD和(iii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；(b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。 In a further embodiment, the invention relates to the use and / or method for treating hypercholesterolemia in a patient with type 2 diabetes (T2DM), the method comprising: (a) selecting a high heart rate for insulin therapy Vascular risk patients with (i) T2DM, (ii) ASCVD, and (iii) inadequately controlled hypercholesterolemia with maximally tolerated statins; (b) 75 mg of specificity administered to this patient every two weeks Antibodies or antigen-binding fragments thereof that sexually bind to the human proprotein converting enzyme subtilin / kexin type 9 (PCSK9); and (c) if the LDL-C level in the patient is less than 70 mg / dL, then approximately every two weeks The patient is administered one or more of the following doses of 75 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to 70 mg / dL, one or more of the following doses are administered approximately every two weeks. 150 mg of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 and wherein Patients received concomitant insulin therapy.

實例Examples

提出以下實例以向本領域普通技術人員提供如何製備和使用本發明的方法和組合物的完整公開和描述，並且不意欲限制本發明的發明人認為是他們的發明的範圍。已經做出努力確保關於所使用的數字(例如，量、溫度等)的準確性，但是應該考慮一些實驗誤差和偏差。除非另有說明，份數是重量份數，分子量是平均分子量，溫度是攝氏度，壓力是大氣壓或接近大氣壓。 The following examples are presented to provide one of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to the numbers used (eg, amount, temperature, etc.), but some experimental errors and biases should be considered. Unless stated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

實例1：人類PCSK9的人類抗體之產生 Example 1: Production of human antibodies to human PCSK9

如美國專利號8,062,640中所述的生成人類抗PCSK9抗體。用於以下實例的例示性PCSK9抑制劑是指定為“mAb316P”的人類抗PCSK9抗體，也稱為“REGN727”或“阿利庫單抗”。mAb316P具有以下胺基酸序列特徵：包含SEQ ID NO：5的重鏈和包含SEQ ID NO：9的輕鏈；包含SEQ ID NO：1的重鏈可變區(HCVR)和包含SEQ ID NO：6的輕鏈可變區(LCVR)；包含SEQ ID NO：2的重鏈互補決定區1(HCDR1)，包含SEQ ID NO：3的HCDR2，包含SEQ ID NO：4的HCDR3，包含SEQ ID NO：7的輕鏈互補決定區1(LCDR1)，包含SEQ ID NO：8的LCDR2和包含SEQ ID NO：10的LCDR3。 Human anti-PCSK9 antibodies were generated as described in U.S. Patent No. 8,062,640. Exemplary PCSK9 inhibitors used in the following examples are human anti-PCSK9 antibodies designated as "mAb316P", also known as "REGN727" or "Aliculumab". mAb316P has the following amino acid sequence characteristics: a heavy chain comprising SEQ ID NO: 5 and a light chain comprising SEQ ID NO: 9; a heavy chain variable region (HCVR) comprising SEQ ID NO: 1 and comprising SEQ ID NO: Light chain variable region (LCVR) of 6; heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 2, HCDR2 comprising SEQ ID NO: 3, HCDR3 comprising SEQ ID NO: 4, and SEQ ID NO : 7 light chain complementarity determining region 1 (LCDR1), LCDR2 comprising SEQ ID NO: 8 and LCDR3 comprising SEQ ID NO: 10.

實例2：隨機分配、雙盲、安慰劑對照組的平行組研究以評價阿利庫單抗在患有1型或2型糖尿病並且患有在最大耐受的LDL-C降低治療時未得到充分控制的高心血管風險的高膽固醇血症的胰島素治療的患者中的效力和安全性Example 2: Parallel group study of a randomized, double-blind, placebo control group to evaluate that aliculumab is not adequately controlled in patients with type 1 or type 2 diabetes and with LDL-C reduction therapy at maximum tolerance Efficacy and safety in insulin-treated patients with high cardiovascular risk for hypercholesterolemia

介紹Introduction

全世界有超過3.8億人患有糖尿病，其中大多數會死於心血管疾病(CVD)。與不患有糖尿病的人相比，患有糖尿病的那些人處於更高的患CVD的風險，患相關的臨床併發症並且在更早的年齡，並且具有縮短約6至7年的預期壽命。除了疾病的高人花費之外，CVD對這些患者的整體醫療支出貢獻很大。 More than 380 million people worldwide have diabetes, and most of them die of cardiovascular disease (CVD). Those with diabetes are at a higher risk of CVD than those who do not have diabetes, suffer from associated clinical complications and are at an earlier age, and have a shortened life expectancy of about 6 to 7 years. In addition to the high cost of the disease, CVD contributes significantly to the overall medical expenses of these patients.

該研究，命名為Odyssey DM-胰島素，包括在胰島素治療中的患有1型或2型糖尿病的成年患者，其患有在有或沒有其他脂質修飾治療 (LMT)的情況下，在最大耐受劑量的他汀類治療時未得到充分控制的高心血管(CV)風險的高膽固醇血症。 The study, named Odyssey DM-insulin, included adult patients with type 1 or type 2 diabetes during insulin therapy, who had the greatest tolerance in the presence or absence of other lipid modification therapies (LMT) High-cholesterolemia with high cardiovascular (CV) risk is not adequately controlled when doses of statins are treated.

研究目的Research purposes

該研究的首要目的是：(a)評價阿利庫單抗與安慰劑相比在高心血管風險患者中治療24週後降低計算的低密度脂蛋白膽固醇(LDL-C)的效力，該患者患有用胰島素治療的糖尿病並且患有在最大耐受的LDL-C降低治療時未充分控制的高膽固醇血症；和(b)評價阿利庫單抗在患有用胰島素治療的糖尿病的患者中的安全性和耐受性。 The primary objectives of the study were to: (a) evaluate the efficacy of alicutumab compared to placebo in reducing the calculated low-density lipoprotein cholesterol (LDL-C) efficacy in patients with high cardiovascular risk after 24 weeks of treatment Diabetes treated with insulin and suffering from hypercholesterolemia that is not adequately controlled at the time of maximally tolerated LDL-C reduction treatment; and (b) evaluation of the safety of aliculumab in patients with diabetes treated with insulin And tolerance.

該研究的次要目的是在第12週和第24週評價阿利庫單抗與安慰劑相比對其他脂質參數的功效(例如，測量的LDL-C、非高密度脂蛋白膽固醇(非HDL-C)、載脂蛋白B(Apo B)、總膽固醇(TC)、脂蛋白a(Lp(a))、高密度脂蛋白膽固醇(HDL-C)、甘油三酯(TG)水準、富含甘油三酯的脂蛋白(TGRL)、載脂蛋白A-1(Apo A-1)、載脂蛋白C3(ApoC3)和LDL顆粒數量和尺寸)。 The secondary objective of the study was to evaluate the efficacy of alicutumab compared to placebo on other lipid parameters (e.g., measured LDL-C, non-high density lipoprotein cholesterol (non-HDL- C), apolipoprotein B (Apo B), total cholesterol (TC), lipoprotein a (Lp (a)), high density lipoprotein cholesterol (HDL-C), triglyceride (TG) level, rich in glycerol Triesters of lipoprotein (TGRL), apolipoprotein A-1 (Apo A-1), apolipoprotein C3 (ApoC3) and LDL particles (number and size).

研究設計Research design

這是3b期隨機分配、雙盲、安慰劑對照組的多國和多中心研究，以評估通過皮下(SC)注射施用的阿利庫單抗在處於高CV風險並且患有1型或2型糖尿病並且患有通過最大耐受的LDL-C降低治療未充分控制的高膽固醇血症的胰島素治療的患者中的功效和安全性。該研究由最高達3周的篩選期，24週的雙盲治療期，以及雙盲治療期結束後持續8週的安全性觀察期組成。 This is a phase 3b randomized, double-blind, placebo-controlled, multinational and multicenter study to assess that aliculumab administered by subcutaneous (SC) injection is at high CV risk and has type 1 or type 2 diabetes And the efficacy and safety in patients with insulin therapy for the treatment of under-controlled hypercholesterolemia are reduced by LDL-C with maximum tolerance. The study consisted of a screening period of up to 3 weeks, a double-blind treatment period of 24 weeks, and a safety observation period lasting 8 weeks after the end of the double-blind treatment period.

除非患者對他汀類不耐受，否則它們在使用或不使用其他脂質修飾治療(LMT)的情況下服用穩定的、最大耐受劑量的他汀類治療。他汀類劑量和劑量方案以及一種或多種其他脂質修飾治療的劑量和劑量方案(如果可適用的話)在整個研究期間(包括篩選期前的持續4週，篩選期期間和從篩選到隨機分配)都是穩定的。在從篩選到第24週拜訪(visit)的整個研究期間，患者處於葡萄糖和脂質管理的穩定飲食中。患者正在接受根據當地/區域護理標準的糖尿病治療。 Unless patients are intolerant to statins, they take stable, maximum tolerated doses of statins with or without other lipid modification therapies (LMT). Statin doses and dosing schedules and doses and dosing schedules for one or more other lipid-modifying therapies (if applicable) were used throughout the study period (including the 4 weeks before the screening period, during the screening period, and from screening to randomization) Is stable. Patients were on a stable diet for glucose and lipid management throughout the study period from screening to visits at week 24. The patient is being treated for diabetes according to local / regional care standards.

通過糖尿病類型(即，1型糖尿病對2型糖尿病)對患者進行分層。當大約400名患者被隨機分配時，完成患有2型糖尿病患者的招募。在目標招募期結束時，完成患有1型糖尿病患者的招募。 Patients are stratified by type of diabetes (ie, type 1 diabetes versus type 2 diabetes). Recruitment of patients with type 2 diabetes was completed when approximately 400 patients were randomly assigned. At the end of the target recruitment period, recruitment of patients with type 1 diabetes is completed.

如果在第8週拜訪時LDL-C70mg/dL(1.81mmol/L)，則以75mg Q2W的起始劑量皮下施用阿利庫單抗持續12周，在第12週用盲法上升滴定至阿利庫單抗150mg Q2W。在第8週拜訪時具有LDL-C<70mg/dL(1.81mmol/L)的患者繼續使用阿利庫單抗75mg Q2W直到治療期結束。 If the LDL-C was visited during week 8 At 70 mg / dL (1.81 mmol / L), alimuzumab is administered subcutaneously at a starting dose of 75 mg Q2W for 12 weeks, and in the 12th week, the titration is increased to 150 mg Q2W by blinding. Patients with LDL-C <70 mg / dL (1.81 mmol / L) at the 8th week visit continued to use Alicuzumab 75mg Q2W until the end of the treatment period.

在隨機分配後掩蓋(mask)來自血液樣品的脂質參數的數據。根據研究者的判斷，除了患者的安全性之外，研究者或患者沒有嘗試在隨機分配後直到第24週拜訪後獨立評價患者的脂質值。 Data on lipid parameters from blood samples were masked after random assignment. At the investigator's discretion, apart from the patient's safety, the investigator or patient did not attempt to independently assess the patient's lipid value after random assignment until the 24th week visit.

患者在第-3周、第0周、第8週、第12週、第20周和第24週拜訪研究地點，每次拜訪時進行實驗室工作。另外，還在第4週和第32周進行了電話拜訪。 Patients visited the study site at weeks -3, 0, 8, 8, 12, 20, and 24, and performed laboratory work during each visit. In addition, telephone interviews were conducted in the 4th and 32nd weeks.

記錄了在最後一劑研究醫藥產品(investigational medicinal product，IMP)的70天內發生的不良事件(AE)。具有嚴重不良事件(SAE)或特殊感興趣的不良事件(AESI)的患者被隨訪(follow)直到解決、穩定或死亡。 Adverse events (AE) that occurred within 70 days of the last dose of investigational medicinal product (IMP) were recorded. Patients with severe adverse events (SAE) or adverse events of special interest (AESI) are followed until they resolve, stabilize, or die.

患者選擇Patient selection

該研究登記了共517名患者，包括患有T1DM的76名患者和患有T2DM的441名患者。 The study enrolled a total of 517 patients, including 76 patients with T1DM and 441 patients with T2DM.

納入標準Inclusion criteria

在本研究中登記的患者滿足以下所有標準： The patients enrolled in this study met all of the following criteria:

(1)患有用胰島素治療的1型或2型糖尿病的患者，並且該患者具有在使用或不使用其他LMT的情況下通過穩定的、最大劑量/方案的他汀類未充分控制的70mg/dLLDL-C的水準(1.81mmol/L)，該穩定的、最大劑量/方案的他汀類是在篩選拜訪之前(第-3周)被患者耐受了至少4週。患者耐受的最大劑量/方案的他汀類是基於研究者的判斷或關注的登記的患者耐受的劑量/方案。服用較低他汀類劑量的患者的可接受原因的一些實例包括但不限於對較高劑量的不良影響、高齡、低體重指數(BMI)、區域實踐、當地處方信息或伴隨藥物。患者可能已服用替代性的日劑量的他汀類，只要一致地服用該劑量(例如，每週一、週三、週五的劑量等)。不允許使用超過1種他汀類的伴隨治療。由研究者判斷，具有記錄的不耐受性並且因此不再接受他汀類治療的患者對於該研究也是符合條件的。以病案報告的形式記錄不進行最大劑量/方案的他汀類的一個或多個原因(包括他汀類不耐受)。 (1) Patients with type 1 or type 2 diabetes treated with insulin, and the patient has insufficiently controlled statins with stable, maximum doses / schemes with or without the use of other LMTs At a level of 70 mg / dLLDL-C (1.81 mmol / L), this stable, maximum dose / protocol statin was tolerated by patients for at least 4 weeks before the screening visit (week -3). The maximum dose / protocol tolerated by a patient is a statin that is based on the investigator's judgment or the registered patient tolerated dose / protocol. Some examples of acceptable causes for patients taking lower statin doses include, but are not limited to, adverse effects on higher doses, advanced age, low body mass index (BMI), regional practice, local prescription information, or concomitant medications. Patients may have taken alternative daily doses of statins, as long as the dose is taken consistently (eg, every Monday, Wednesday, Friday, etc.). Concomitant treatment with more than 1 statin is not allowed. At the investigator's discretion, patients with documented intolerance and therefore no longer receiving statins were eligible for the study. One or more reasons (including statin intolerance) for statins not undergoing the maximum dose / protocol are recorded in the form of a medical report.

(2)篩選拜訪時18歲或具有成年法定年齡的患者，以較大者為准。 (2) When screening visits Patients who are 18 years of age or above the legal age of majority, whichever is greater.

(3)在篩選拜訪(第-3周)前至少一年診斷患有1型或2型糖尿病的患者。被診斷患有1型糖尿病的患者需要滿足以下所有標準：(a)在30歲的年齡之前進行診斷；(b)在診斷後6個月內用多次每日注射方案/基礎-膳食胰島素方案或胰島素泵方案治療；和(c)篩選拜訪時C肽<0.2pmol/mL。 (3) Patients diagnosed with type 1 or type 2 diabetes at least one year before the screening visit (week -3). Patients diagnosed with type 1 diabetes need to meet all of the following criteria: (a) diagnosis before the age of 30 years; (b) multiple daily injection regimens / basic-dietary insulin regimens within 6 months of diagnosis Or insulin pump regimen; and (c) C peptides <0.2 pmol / mL at screening visits.

(4)篩選拜訪(第-3周)時糖基化血紅蛋白(HbA1c)<10%。如果基於研究者的判斷，在研究期間沒有計劃針對較低的HbA1c，升高的HbA1c(最高達10%)的患者是符合條件的。 (4) The glycosylated hemoglobin (HbA1c) was less than 10% at the screening visit (week -3). If based on the investigator's judgment, no patients were planned for the lower HbA1c during the study period, and patients with elevated HbA1c (up to 10%) were eligible.

(5)具有記錄的CVD病史(包括CHD和/或CHD風險等同物)和/或至少一種另外的CV風險因子的患者。 (5) Patients with a recorded history of CVD (including CHD and / or CHD risk equivalents) and / or at least one additional CV risk factor.

CHD的病史包括以下至少一項：(a)急性心肌梗死(MI)；(b)無症狀性MI；(c)不穩定型心絞痛；(d)冠狀血管再生成過程(例如，經皮冠狀動脈介入(PCI)或冠狀動脈旁路移植術(CABG))；和 (e)通過侵入性或非侵入性測試(例如冠狀動脈造影術，使用跑步機的壓力測試，負荷超聲心動圖或核成像)診斷的臨床上顯著的CHD。 The history of CHD includes at least one of: (a) acute myocardial infarction (MI); (b) asymptomatic MI; (c) unstable angina pectoris; (d) coronary angiogenesis (e.g., percutaneous coronary Interventional (PCI) or coronary artery bypass grafting (CABG)); and (e) passing invasive or non-invasive tests (such as coronary angiography, stress testing using a treadmill, stress echocardiography, or nuclear imaging) Diagnosis of clinically significant CHD.

CHD風險等同物包括以下至少一種：(a)記錄的外周動脈疾病滿足以下標準的至少一種：(i)當前的間歇性跛行(下肢肌肉不適，其是可再現的並且通過運動產生和在10分鐘內通過休息緩解)(推測其起源是動脈粥樣硬化)，同時休息時任一條腿的踝臂指數(ankle-brachial index)0.90；(ii)間歇性跛行的病史(下肢肌肉不適，其是可再現的並且通過運動產生和在10分鐘內通過休息緩解)並且同時由於動脈粥樣硬化疾病導致在一條腿或兩條腿中進行了血管內程序或外科手術干預；和(iii)嚴重肢體缺血的病史，並且同時由於動脈粥樣硬化疾病導致在一條腿或兩條腿中進行了血栓溶解、血管內程序或外科手術干預；和(b)記錄的先前的缺血性中風，其具有持續超過24小時的局灶性缺血性神經缺陷，其起源被認為是動脈粥樣硬化。必須進行計算機斷層攝影術或磁性無線電成像，以排除出血和非缺血性神經疾病。 CHD risk equivalents include at least one of the following: (a) Recorded peripheral arterial disease meets at least one of the following criteria: (i) Current intermittent claudication (lower limb muscle discomfort, which is reproducible and generated by exercise and within 10 minutes Relieved by rest) (presumably its origin is atherosclerosis), and ankle-brachial index of any leg during rest 0.90; (ii) history of intermittent claudication (lower limb muscle discomfort that is reproducible and produced by exercise and relieved by rest within 10 minutes) and at the same time caused by atherosclerotic disease in one or both legs Performed endovascular procedures or surgical interventions; and (iii) a history of severe limb ischemia and at the same time thrombolysis, endovascular procedures or surgical interventions in one or both legs due to atherosclerotic disease ; And (b) a previous ischemic stroke documented with focal ischemic neurological deficits that lasted more than 24 hours and whose origin is thought to be atherosclerosis. Computed tomography or magnetic radiography must be performed to rule out bleeding and non-ischemic neurological diseases.

心血管風險因素包括以下至少一種：(a)高血壓(建立在抗高血壓藥物上的)；(b)當前的吸煙者；(c)45歲的男性，55歲的女性；(d)微量/大量白蛋白尿的病史；(e)糖尿病視網膜病變的病史(前增生性或增生性)；(f)早發CHD的家族病史(55歲的年齡以前的父親或兄弟；65歲的年齡以前的母親或姐妹)；(g)低HDL-C(男性<40mg/dL(1.0mmol/L)，女性<50mg/dL(1.3mmol/L))；和(h)記錄的持續3個月或更久(包括篩選拜訪)的由15eGFR<60mL/min/1.73m²限定的慢性腎病(CKD)。 Cardiovascular risk factors include at least one of: (a) hypertension (based on antihypertensive drugs); (b) current smokers; (c) 45 year old male, 55-year-old female; (d) history of micro / large albuminuria; (e) history of diabetic retinopathy (pre-proliferative or proliferative); (f) family history of early-onset CHD (pre-55 years old Father or brother; mother or sister before 65 years of age); (g) low HDL-C (<40 mg / dL (1.0 mmol / L) for males, <50 mg / dL (1.3 mmol / L) for females); and ( h) Records lasting 3 months or more (including screening visits) from 15 eGFR <60mL / min / 1.73m ² -defined chronic kidney disease (CKD).

(6)簽名的書面知情同意。 (6) Signed written informed consent.

排除標準Exclusion criteria

篩選滿足所有上述納入標準的患者的以下排除標準： The following exclusions screened patients who met all of the above inclusion criteria:

(1)與研究方法有關的排除標準：(a)計劃在研究過程中開始新的LMT或修改當前LMT的劑量；(b)否者在篩選拜訪(第-3周)前持續至少4週或從篩選到隨機分配期間，未進行穩定劑量的LMT(包括他汀類或其他LMT)，除非他汀類不耐受，在這種情況下在篩選拜訪持續前4週/在篩選期間沒有進行他汀類治療；(c)在篩選拜訪前(第-3周)持續至少4週或在篩選和隨機分配拜訪之間未以穩定劑量使用可能影響脂質的營養保健品或非處方藥治療；(d)在篩選拜訪(第-3周)的4週內或篩選和隨機分配拜訪之間使用紅麴米產品；(e)使用全身性皮質類固醇，除非在隨機分配前持續至少6周用穩定方案被用作垂體/腎上腺疾病的替代治療。局部、關節內、鼻、吸入和眼科類固醇治療不被認為是“全身性的”並被允許；(f)使用連續的激素替代治療，除非該方案在篩選拜訪(第-3周)前6周中已經是穩定的，並且沒有計劃在研究期間改變方案；(g)近期(在篩選拜訪(第-3周)前3個月內或篩選和隨機分配拜訪之間)的MI、導致住院治療的不穩定性心絞痛、不受控制的心律失常、CABG、PCI、頸動脈手術或支架術、中風、短暫性缺血發作(TIA)、用於外周血管疾病的血管內程序或外科手術介入；(h)計劃在研究期間進行已排程的PCI、CABG、頸動脈或外周血管再生術；(i)過去12個月內紐約心臟協會(NYHA)III類或IV類心力衰竭(見表1)的病史；(j)篩選或隨機分配拜訪時收縮壓>180mmHg或舒張壓>110mmHg；(k)在篩選拜訪(第-3周)前2個月內、篩選和隨機分配之間已經接受血漿置換術治療或有計劃接受血漿置換術治療的患者；(l)出血性中風的已知病史； (m)PCSK9功能喪失(即基因突變或序列變異)的已知病史或純合家族性高膽固醇血症的已知病史；(n)過去5年內新發癌症或癌症的積極進展，除了充分治療的基底細胞皮膚癌、鱗狀細胞皮膚癌或原位宮頸癌之外；(o)陽性HIV測試的已知病史；(p)在1個月或5個半衰期內(以較長者為准)已經服用任何有效的研究性藥物的患者，；(q)在篩選拜訪(第-3周)前，事先沒有接受降膽固醇飲食指導的患者；(r)在篩選期間撤回同意的患者(從簽名的ICF開始)；(s)在篩選拜訪前2個月內，如研究者所判斷的定義為>5kg的變化的不穩定的體重；(t)BMI>45kg/m2或計劃在研究過程中進行減肥外科手術、減肥計劃或開始減肥藥物；(u)近期開始減肥藥物(即，在篩選拜訪前3個月內或篩選和隨機分配之間)或近期的減肥外科手術(在過去的6個月內)和如研究者所判斷的處於有效的減肥階段內；(v)在篩選拜訪前持續至少6個月未接受胰島素治療的或篩選拜訪前持續至少3個月未進行穩定的胰島素方案(即胰島素類型的變化，注射的一般時間選擇/頻率，施用模式或方式諸如僅基本(2型糖尿病)，基本-膳食等)的患者，或在研究期間需要改變胰島素類型/頻率或注射方式的可能性；(w)在篩選前持續至少3個月沒有穩定的胰島素劑量(即如研究者所判斷的，總每日胰島素劑量的變化超過30%)，或者如研究人員所判斷的研究過程中需要強化胰島素/抗高血糖藥方案的可能性(例如，添加新藥劑，滴定胰島素劑量的計劃等)；(x)患者服用的其他抗高血糖藥物在篩選拜訪前持續至少3個月不穩定；(y)在篩選拜訪前2個月內近期糖尿病代償失調的病史(即糖尿病酮酸血症或高滲性高血糖狀態(HHS))； (z)接受或計劃在研究期間接受腎臟替代治療(例如，血液透析，腎臟移植等)；(aa)存在任何已知影響血清脂質或脂蛋白的臨床上顯著的不受控制的內分泌疾病。如果甲狀腺素的劑量在篩選前持續至少3個月是穩定的並且在篩選拜訪時患者的敏感性促甲狀腺激素(s-TSH)水準在實驗室的正常範圍的±10%以內，則可以包括進行甲狀腺替代治療的患者；(bb)篩選期間的實驗室發現(不包括隨機分配實驗室，妊娠測試除外)：(i)血清TG>400mg/dL(4.52mmol/L)(允許1個重複實驗室)；(ii)有生育潛力的婦女中的陽性血清或尿妊娠測試；(iii)乙型肝炎表面抗原或丙型肝炎抗體的陽性測試；(iv)根據4變量腎臟疾病飲食改變(MDRD)等式eGFR<15mL/min/1.73m2；(v)ALT或AST>3 x ULN(允許1個重複實驗室)；或(vi)肌酸磷酸激酶(CPK)>3 x ULN(允許1個重複實驗室)；或(cc)條件/情況，諸如：(i)預期短壽命的患者；(ii)對可偏離原始評估的伴隨治療的需求；(iii)無法滿足特定的方案要求(例如，需要住院，進行研究拜訪的能力等)；(iv)患者是直接參與執行方案的研究者或任何副研究者、研究助理、藥劑師、研究協調員、其他工作人員或它們的親屬；(v)不合作或任何可能使患者可能不遵守研究程序的情況；(vi)使研究中的患者不能隨機分配的任何技術/行政原因；或(vii)在篩選時鑒定的任何臨床上顯著的異常，其在研究者或副研究者的判斷中會排除安全完成研究或限制終點評估，諸如主要的全身性疾病，預期短壽命的患者。 (1) Exclusion criteria related to the research method: (a) plan to start a new LMT or modify the current LMT dose during the study; (b) no for at least 4 weeks before the screening visit (week -3) or During the period from screening to random assignment, no stable dose of LMT (including statins or other LMTs) was performed, unless the statins were intolerant, in which case 4 weeks before the screening visit / no statin treatment during the screening period (C) not use a stable dose of nutritional supplements or over-the-counter medications that may affect lipids for at least 4 weeks before the screening visit (week -3) or between the screening and randomized visits; (d) during the screening visit ( Use of red rice products within 4 weeks of 4 weeks or between screening and random assignment visits; (e) use of systemic corticosteroids, unless used as a pituitary / adrenal gland with a stable regimen for at least 6 weeks before random assignment Alternative treatment for the disease. Local, intra-articular, nasal, inhalation, and ophthalmic steroid treatments are not considered "systemic" and allowed; (f) use of continuous hormone replacement therapy, unless the regimen is 6 weeks before the screening visit (week -3) Is already stable and there are no plans to change the protocol during the study period; (g) recent MI (within 3 months before the screening visit (week -3) or between screening and random allocation visits) Unstable angina pectoris, uncontrolled arrhythmia, CABG, PCI, carotid surgery or stenting, stroke, transient ischemic attack (TIA), intravascular procedures or surgical interventions for peripheral vascular disease; (h ) Scheduled PCI, CABG, carotid artery, or peripheral vascular regeneration during the study period; (i) History of New York Heart Association (NYHA) Class III or IV heart failure (see Table 1) in the past 12 months (J) systolic blood pressure> 180mmHg or diastolic blood pressure> 110mmHg at screening or random allocation visit; (k) plasma exchange surgery has been received between screening and random allocation within 2 months before screening visit (week -3) Contingent patients scheduled for plasmapheresis; (l) hemorrhagic Known medical history of stroke; (m) known medical history of PCSK9 loss of function (ie, gene mutation or sequence variation) or known history of homozygous familial hypercholesterolemia; (n) new cancer or cancer within the past 5 years Positive progress in addition to adequately treated basal cell skin cancer, squamous cell skin cancer, or cervical carcinoma in situ; (o) known history of positive HIV tests; (p) within 1 month or 5 half-lives ( Whichever is longer) Patients who have taken any effective research drug; (q) Patients who did not receive prior cholesterol-lowering diet guidance before screening visits (week -3); (r) Withdrawal of consent during screening Of patients (starting with a signed ICF); (s) within 2 months prior to the screening visit, as defined by the investigator as a variable unstable body weight defined as> 5kg; (t) BMI> 45kg / m2 or plan Perform bariatric surgery, weight-loss programs, or start weight-loss medications during the study; (u) recently started weight-loss medications (that is, within 3 months before the screening visit or between screening and randomization) or recent weight-loss surgery (in (In the last 6 months) and as judged by the researchers at an effective weight loss stage (V) no insulin regimen for at least 6 months before screening visits or no stable insulin regimen for at least 3 months before screening visits (ie changes in insulin type, general timing / frequency of injections, administration Patients with a pattern or pattern such as only basic (type 2 diabetes), basic-diet, etc., or the possibility of needing to change insulin type / frequency or injection pattern during the study period; (w) not stable for at least 3 months before screening The insulin dose (i.e., the total daily insulin dose changes by more than 30% as judged by the investigator), or the possibility of intensifying the insulin / antihyperglycemic regimen during the study as judged by the investigator (e.g., adding New agents, plans to titrate insulin doses, etc.); (x) other antihyperglycemic drugs taken by patients that were unstable for at least 3 months before the screening visit; (y) recent diabetes decompensation disorders within 2 months before the screening visit Medical history (i.e. diabetic ketoacidemia or hypertonic hyperglycemia (HHS)); (z) receiving or planning to undergo kidney replacement therapy during the study (e.g., hemodialysis, kidney transplantation Etc.); (aa) the presence of any clinically significant uncontrolled endocrine disease known to affect serum lipids or lipoproteins. If the dose of thyroxine is stable for at least 3 months before screening and the patient's sensitivity to thyroid stimulating hormone (s-TSH) is within ± 10% of the laboratory's normal range at the screening visit, this can include Patients with thyroid replacement therapy; (bb) Laboratory findings during screening (excluding randomized laboratories, except pregnancy tests): (i) serum TG> 400mg / dL (4.52mmol / L) (1 replicate laboratory allowed ); (Ii) positive serum or urine pregnancy tests in women with fertility potential; (iii) positive tests for hepatitis B surface antigen or hepatitis C antibodies; (iv) dietary changes based on 4-variable kidney disease (MDRD), etc. EGFR <15mL / min / 1.73m2; (v) ALT or AST> 3 x ULN (1 repeat laboratory allowed); or (vi) Creatine Phosphokinase (CPK)> 3 x ULN (1 replicate allowed) Room); or (cc) conditions / situations such as: (i) patients with short life expectancy; (ii) need for concomitant treatments that deviate from the original assessment; (iii) inability to meet specific protocol requirements (e.g., need to be hospital , Ability to conduct research visits, etc.); (iv) the patient is the investigator or any associate researcher directly involved in the implementation of the protocol Investigators, research assistants, pharmacists, research coordinators, other staff members or their relatives; (v) non-cooperation or any situation that may make patients likely not to follow the research procedures; (vi) prevent randomization of patients in the study Any technical / administrative cause; or (vii) any clinically significant abnormality identified at the time of screening that, in the judgment of the investigator or associate investigator, will preclude the safe completion of the study or limit endpoint assessments, such as major systemic diseases Patients with short life expectancy.

(2)與活性比較物(active comparator)和/或強制性背景治療相關的排除標準：在相應的國家產品標簽中顯示的背景治療的所有禁忌症或使用警告/預防措施(適當時)。 (2) Exclusion criteria related to active comparator and / or compulsory background therapy: all contraindications or use of warnings / precautions (where appropriate) of background therapy shown in the corresponding national product label.

(3)與阿利庫單抗的當前知識相關的排除標準：(a)對阿利庫單抗或對阿利庫單抗的任何成分過敏；(b)妊娠或母乳餵養的婦女；(c)未受高效生育控制方法保護的有生育潛力的婦女(在有特定的當地要求的情況下，如ICF和/或當地協議附錄中所限定的)和/或不願或不能進行妊娠測試的婦女。有生育潛力的婦女必須在篩選和納入拜訪時具有確認的陰性妊娠測試。她們必須在整個研究治療期間和在最後一次注射IMP後持續至少10周使用有效的避孕方法。所採用的避孕方法必須符合根據“International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.M3(R2)：Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals.ICH.2009 Jun：1-25”的高效生育控制方法的標準。絕經後婦女必須閉經至少12個月。 (3) Exclusion criteria related to current knowledge of Alicuzumab: (a) Allergic to Alicuzumab or any component of Alicuzumab; (b) Women who are pregnant or breastfeeding; (c) Not affected Efficient fertility control methods protect women of reproductive potential (when specific local requirements, as defined in the ICF and / or local agreement appendix) and / or women who are unwilling or unable to conduct pregnancy tests. Women with reproductive potential must have a confirmed negative pregnancy test at the time of screening and inclusion. They must use effective contraception throughout the study treatment period and for at least 10 weeks after the last IMP injection. The method used must be in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. M3 (R2): Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals.ICH.2009 Jun: 1-25 "standard for efficient fertility control methods. Postmenopausal women must have amenorrhea for at least 12 months.

研究治療Research treatment

研究用醫藥產品Research pharmaceutical products

在自動注射器(也稱為預填充筆)中，在含有蔗糖、組胺酸和聚山梨醇酯20的水性緩衝液(pH6.0)中，以75mg/mL和150mg/mL的濃度提供無菌阿利庫單抗藥物產品，兩者均為1mL體積。在預填充筆中，以1mL體積，在不添加蛋白質的情況下在與阿利庫單抗相同的製劑中製備阿利庫單抗的無菌安慰劑，用於患者以進行注射訓練，以及用於安慰劑治療組(arm)中的那些患者。在篩選期間，患者(或另一個指定的人)必須在第一次施用IMP之前使用預填充筆進行安慰劑自我注射訓練。 In an autoinjector (also known as a pre-filled pen), sterile Alligen is provided at 75 mg / mL and 150 mg / mL in an aqueous buffer (pH 6.0) containing sucrose, histidine, and polysorbate 20 Culinumab drug products, both are 1 mL volumes. In a pre-filled pen, a sterile placebo of aliculumab was prepared in the same formulation as aliculumab without the addition of protein in a volume of 1 mL for patients for injection training and for placebo Those patients in the arm. During the screening, the patient (or another designated person) must undergo a placebo self-injection training with a pre-filled pen before the first IMP administration.

對於隨機分配到阿利庫單抗的患者，初始劑量是Q2W皮下施用75mg一次。如果第8週LDL-C值70mg/dL(1.81mmol/L)，則對於隨機分配到阿利庫單抗的患者，在第12週時以盲法方式增加劑量至150mg Q2W。隨機分配到安慰劑的患者在整個24週治療期間Q2W皮下被施用他們的注射。 For patients randomized to aliculumab, the initial dose is Q2W administered subcutaneously once. If the LDL-C value at week 8 70mg / dL (1.81mmol / L), for patients randomly assigned to aliculumab, the dose was increased to 150mg Q2W in a blinded manner at week 12. Patients randomized to placebo were administered their injections subcutaneously throughout Q2W throughout the 24 week treatment period.

施用途徑和方法Route and method of administration

向地點提供預填充筆訓練指南(自動注射器訓練指南)，並向患者提供使用(使用自動注射器)說明。IMP的每次施用由在腹部、大腿或上臂的外部區域(即，三角肌區)中的1mL皮下注射組成。如果在計劃用於IMP注射的相同部位注射另外的伴隨藥物，則建議患者使用替代位置來施用IMP。 Provide a pre-filled pen training guide (autoinjector training guide) to the location, and provide patients with instructions for using (using an autoinjector). Each administration of the IMP consists of a 1 mL subcutaneous injection in the outer area of the abdomen, thighs or upper arms (ie, deltoid muscle area). If additional concomitant medications are injected at the same site that is planned for IMP injections, patients are advised to use alternative locations to administer IMP.

IMP可以通過自我注射或通過另一個指定的人(例如配偶、親屬等)施用。如果指定的人應該在研究期間向患者注射阿利庫單抗，則應確保該人在施用注射之前已經過充分的訓練。計劃施用IMP的任何人都由研究人員進行培訓。 The IMP can be administered by self-injection or by another designated person (e.g., spouse, relative, etc.). If the designated person should inject the patient with aliculumab during the study, then make sure that person is adequately trained before the injection is administered. Anyone planning to administer IMP is trained by researchers.

在訓練期間以及根據需要在研究過程中向患者(或將施用注射的另一指定人(例如配偶、親屬等))提供說明。第一次拜訪時以及根據需要在其它拜訪時給予了密切的監督和反饋。 Instructions are provided to the patient (or another designated person (e.g., spouse, relative, etc.) to whom the injection will be administered) during training and as needed during the study. Close supervision and feedback were given at the first visit and at other visits as needed.

將使用過的預填充筆丟棄在提供給患者的銳器盒中。推薦在解剖區域內輪流進行皮下IMP注射(例如，右大腿，然後左大腿或右腹，然後左腹)。在研究期間，患者還具有在不同的解剖區域(例如，大腿然後腹部，或上臂的外部區域等)注射的選擇。 Discard the used pre-filled pen in the sharps box provided to the patient. It is recommended to take subcutaneous IMP injections alternately in the anatomical area (eg, right thigh, then left thigh or right abdomen, then left abdomen). During the study, patients also had the option of injecting in different anatomical areas (eg, the thighs then the abdomen, or the outer area of the upper arms, etc.).

要求患者將IMP儲存在冰箱中。在施用之前，IMP應置於外部的安全位置的室溫下約30至40分鐘。此後，應該儘快施用IMP。 Ask the patient to store the IMP in the refrigerator. Prior to application, the IMP should be placed in an external, secure location at room temperature for approximately 30 to 40 minutes. Thereafter, IMP should be administered as soon as possible.

施用的時間選擇Timing of application

在篩選期間，患者或指定的人必須在第一次IMP注射之前進行使用預填充筆的安慰劑自我注射訓練。 During the screening period, the patient or designated person must undergo a placebo self-injection training using a pre-filled pen prior to the first IMP injection.

在隨機分配拜訪時，患者或另外的指定人(諸如配偶、親屬等)在直接的現場工作人員監督下在現場進行第一次IMP注射。在該研究中第一次注射後，在研究現場監控患者至少30分鐘。如果在研究過程中改變指定的人，將使用安慰劑培訓新指定的人。 At random assignment visits, patients or other designees (such as spouses, relatives, etc.) perform the first IMP injections on-site under the supervision of direct field staff. Patients were monitored at the study site for at least 30 minutes after the first injection in the study. If the designated person is changed during the study, the newly designated person will be trained using a placebo.

然後在臨床以外進行IMP皮下注射，Q2W直至最後一次注射。如果注射被安排發生在現場拜訪的同一天，則在血液採樣完成後進行IMP。在例外的情況下，如果患者優選在研究現場進行注射並且能夠做出規定以適應在現場施用注射，則這也是被允許的。 IMP was then injected subcutaneously outside the clinic, Q2W until the last injection. If the injection is scheduled to occur on the same day as the site visit, the IMP is performed after the blood sampling is complete. In exceptional cases, this is also permissible if the patient prefers injections at the study site and can be prescribed to accommodate injections administered at the site.

IMP應當皮下施用Q2W，理想地在一天的大致相同的時間。但是，可以接受具有±3天的窗口期。一天中的時間基於患者的偏好。 The IMP should be administered subcutaneously with Q2W, ideally at approximately the same time of day. However, it is acceptable to have a window period of ± 3 days. The time of day is based on the patient's preferences.

如果由於錯誤或由於其他情況，注射從錯過的日期延遲超過7天或完全錯過，則要求患者在不施用延遲注射的情況下返回IMP施用的原始時間表。如果由於錯誤或由於其他情況，注射從錯過日期延遲少於或等於7天，則要求患者施用延遲注射，然後重新開始IMP施用的原始時間表。 If the injection is delayed more than 7 days from the missed date or completely missed due to errors or other circumstances, the patient is required to return to the original schedule of IMP administration without the delayed injection. If the injection is delayed by less than or equal to 7 days from the missed date due to error or other circumstances, the patient is required to administer the delayed injection and then restart the original schedule of IMP administration.

非研究性藥物Non-research drug

以下類別的藥物被鑒定為非IMP，因為該藥物是背景治療或潛在的救護藥品：(a)他汀類；(b)膽固醇吸收抑制劑(依折麥布)；(c)膽汁酸結合螯合劑(如消膽胺、考來替泊(colestipol)、考來維侖(colesevelam))；(d)菸鹼酸類；(e)纖維酸類(諸如非諾貝特)；(f)ω-3脂肪酸(每日1000mg)；和(g)胰島素。 The following classes of drugs are identified as non-IMP because they are background therapy or potential rescue medications: (a) statins; (b) cholesterol absorption inhibitors (ezetimibe); (c) bile acid binding chelator (Such as cholestyramine, colestipol, colesevelam); (d) nicotinic acids; (e) fibric acids (such as fenofibrate); (f) omega-3 fatty acids (daily 1000 mg); and (g) insulin.

對於包括他汀類在內的背景LMT，現場遵循國家產品標簽用於患者的安全性監控和管理。在研究期間，患者在接受或不接受其它LMT的情況下接受穩定的、患者耐受的最大劑量/方案的他汀類治療。脂質譜值是從在隨機分配後獲得的樣品中通過盲法獲得的。然而，為了安全性的原因，現場被製成告知TG警報，目的是對患者的背景LMT做出決定。 For background LMT, including statins, the national product label is used on site for patient safety monitoring and management. During the study, patients received statins with a stable, patient-tolerated maximum dose / protocol with or without other LMT. Lipid mass spectrometry values were obtained blindly from samples obtained after random distribution. However, for safety reasons, the scene was made to inform the TG alert with the goal of making a decision on the patient's background LMT.

從篩選拜訪(第-3周)直到第24週拜訪，背景LMT都不改變。在此期間，不進行劑量調整、停止或啟動其他他汀類或其他LMT，除非根據研究者的判斷由此壓倒一切的擔憂(包括但不限於中央實驗室發佈的TG警報)保證了這樣的變化的例外的情況下。對於已經通過重複測試確認的TG警報，研究者進行調查，管理患者，並根據他/她的醫學判斷修改背景LMT。 From the screening visit (week -3) to the week 24 visit, the background LMT did not change. During this period, no dose adjustments, cessation or activation of other statins or other LMTs will be made unless such overwhelming concerns (including, but not limited to, TG alerts issued by the central laboratory) warrant such changes in the investigator's judgment. Exceptions. For TG alerts that have been confirmed through repeated testing, the investigator investigates, manages the patient, and modifies the background LMT based on his / her medical judgment.

如果患者已經耐受藥物並且保持穩定劑量，則允許所有纖維酸進入。如果患者在研究過程中需要引入纖維酸(即，作為響應TG警報的救護治療)，則僅允許添加非諾貝特。背景LMT和胰島素由贊助者提供。患者按照當地法規獲得這些藥物。 If the patient has tolerated the drug and maintains a stable dose, all the fibric acid is allowed to enter. If the patient needs to introduce fibric acid during the study (ie, as a rescue treatment in response to a TG alert), only fenofibrate is allowed to be added. Background LMT and insulin were provided by sponsors. Patients receive these drugs in accordance with local regulations.

盲法程序Blind procedure

阿利庫單抗和阿利庫單抗的安慰劑在相同匹配的預填充筆中提供並相同地包裝，其包括標記以保護盲法。每個治療試劑盒都標有編號，該編號由贊助者的計算機程序生成。治療試劑盒編號是由研究者在患者隨機分配和隨後經由IVRS/IWRS安排的患者拜訪時獲得的，該 IVRS/IWRS每天24小時每週7天可用。 Aliculumab and placebo for Aliculumab are provided in the same matching pre-filled pens and are packaged identically, which includes markers to protect the blind method. Each treatment kit is labeled with a number, which is generated by the sponsor's computer program. The treatment kit number was obtained by the investigator upon randomization of patients and subsequent patient visits scheduled via IVRS / IWRS, which is available 24 hours a day, 7 days a week.

根據雙盲設計，研究患者、研究者和研究現場人員保持對研究治療的盲目並且除了以下描述的情況之外無法獲得隨機分配(治療代碼)。 According to the double-blind design, study patients, researchers, and study site personnel remain blind to study treatments and are unable to obtain random assignments (treatment codes) except as described below.

不良事件Adverse event

治療代碼由藥物警戒部門揭盲，用於向衛生當局(the Health Authority)報告任何可疑的預料之外的嚴重不良反應(SUSAR)，即根據研究者和/或贊助者的判斷預料之外(CIB的每個特定部門)並且與IMP的使用合理相關的嚴重不良事件。 The treatment code is unblinded by the pharmacovigilance department and is used to report any suspicious unanticipated severe adverse reactions (SUSAR) to the Health Authority, which is unanticipated at the discretion of the investigator and / or sponsor (CIB Serious adverse events that are reasonably related to the use of IMP.

脂質參數Lipid parameter

從由中心實驗室進行的隨機分配拜訪後獲得的血液樣品的脂質參數值沒有被傳達到現場，使得他們不能基於所獲得的LDL-C水準推斷出其患者的治療組。，贊助者的運營團隊不能獲得與患者識別相關的脂質參數直至最終數據庫鎖定發生。為了安全性的目的，隨機分配後任何時間將TG值500mg/dL的TG警報發送給研究者。 Lipid parameter values for blood samples obtained from random allocation visits performed by the central laboratory were not communicated to the site, making them unable to infer their patient's treatment group based on the obtained LDL-C levels. The sponsor's operations team was unable to obtain lipid parameters related to patient identification until the final database lockup occurred. For security purposes, set the TG value at any time after random assignment A 500 mg / dL TG alert was sent to the investigator.

在雙盲治療期結束時(第24週拜訪)，研究者繼續根據標準實踐管理患者的脂質。隨機分配後的任何脂質值都編寫在源文件中，並且不與贊助者共享。 At the end of the double-blind treatment period (visited at Week 24), researchers continued to manage patients' lipids in accordance with standard practice. Any lipid values after random assignment are written in the source file and are not shared with the sponsor.

抗阿利庫單抗抗體Anti-aliculumab antibody

當研究正在進行時，不將患者抗阿利庫單抗抗體結果傳達到現場。直到最終數據庫鎖定發生後，贊助者的運營團隊不能獲得與患者識別編號相關的抗阿利庫單抗抗體結果。參與確定患者抗阿利庫單抗抗體效價的實驗室技術人員被排除在操作團隊之外，並建立了一個方法以防止任何潛在的揭盲。 While the study is ongoing, patient anti-aliculumab antibody results are not communicated to the site. Until the final database lock-in occurs, the sponsor's operations team is unable to obtain anti-aliculumab antibody results related to the patient identification number. Laboratory technicians involved in determining the patient's anti-aliculumab antibody titers were excluded from the operations team and a method was established to prevent any potential unblinding.

研究期間隨機分配代碼破壞Randomly assigned code breaks during the study

在AE的情況下，在需要IMP的知識以治療患者的情況下，破壞密碼。如果可能，在破壞代碼之前，開始與監控團隊/研究醫師聯繫。在適當時，所有電話均由監控團隊記錄，以包括電話的日期和時間，監控團隊內部聯繫的人的姓名、患者ID、請求的文檔以及是否揭盲的決定。 In the case of AE, where knowledge of IMP is needed to treat a patient, the password is broken. If possible, start contacting the monitoring team / research physician before breaking the code. When appropriate, all calls are recorded by the monitoring team to include the date and time of the call, the name of the person contacted within the monitoring team, the patient ID, the requested document, and the decision to unblind.

可以通過使用交互式語音響應系統(IVRS)/交互式網絡響應系統(IWRS)的適當模塊在任何時間執行代碼破壞，這取決於哪個系統用於現場，和/或為了該目的通過撥打由贊助者提供的任何其它電話號碼。但是，在揭盲病例之前，最好聯繫研究醫師討論病例。如果盲法被破壞，則要求研究者記錄日期、時間和代碼破壞的原因，並在e-CRF的適當頁面上報告該信息。當記錄揭盲的原因時，研究者沒有提供有關IMP性質的任何細節。研究者不向贊助者的代表或任何工作人員洩露IMP細節直到數據庫關閉。此外，當完成表格(例如，AE、SAE)時，研究處理沒有在表格上公開。 Code disruption can be performed at any time by using the appropriate modules of the Interactive Voice Response System (IVRS) / Interactive Network Response System (IWRS), depending on which system is used in the field, and / or for this purpose by calling a sponsor Any other phone numbers provided. However, it is best to contact the research physician to discuss the case before unblinding the case. If the blind method is breached, the researcher is required to record the date, time, and cause of the code breach and report this information on the appropriate page of the e-CRF. The researchers did not provide any details about the nature of the IMP when documenting the reasons for the illiteracy. Researchers do not disclose IMP details to sponsor representatives or any staff members until the database is closed. In addition, when the forms (eg, AE, SAE) were completed, the research process was not disclosed on the forms.

代碼破壞材料也保存在負責“24小時警報系統”的實體處；但該系統應該僅用於非常例外的情況(即IVR/IWR系統不能使用或不能聯繫研究者和/或現場工作人員)。但是，優選的選擇是使用IVRS揭盲。由臨床監控團隊向研究者報告了當地代碼破壞材料的可用性。向參與該研究的每位患者提供患者卡，包括相關的“24小時警報系統”電話號碼。還允許贊助者對於一些SAE進行揭盲，以符合監管報告要求(即，對於既相關又預料不到的一些SAE)。 Code-breaking material is also kept at the entity responsible for the "24-hour alarm system"; however, the system should be used only in very exceptional cases (ie, the IVR / IWR system cannot be used or the researcher and / or field staff cannot be contacted). However, the preferred option is to use IVRS to unblind. The clinical monitoring team reported to investigators the availability of local code disruption materials. Provide a patient card to each patient participating in the study, including the relevant 24-hour alert system phone number. Sponsors are also allowed to unblind some SAEs to meet regulatory reporting requirements (ie, for some SAEs that are both relevant and unexpected).

如果代碼被破壞，則患者永久地停止IMP施用。 If the code is broken, the patient permanently stops IMP administration.

將患者分配到治療組的方法Methods for assigning patients to treatment groups

治療試劑盒編號的隨機分配列表由贊助者集中生成。根據該列表包裝IMP(阿利庫單抗75或150mg試劑盒，或安慰劑試劑盒)。 A randomly assigned list of treatment kit numbers is generated centrally by the sponsor. IMP is packaged according to this list (Aliximab 75 or 150 mg kit, or placebo kit).

試驗供應操作管理者提供治療試劑盒編號的隨機分配列表，並且研究生物統計學家向集中治療分配系統提供者提供隨機分配方案。然後，該集中治療分配系統提供者生成患者隨機分配列表，根據該列表向患者分配治療。 The trial supply operations manager provided a random allocation list of treatment kit numbers, and the research biostatistician provided a random allocation plan to the centralized treatment allocation system provider. Then, the centralized treatment allocation system provider generates a random allocation list of patients, and allocates treatments to the patients according to the list.

在雙盲治療期間，患者被隨機分配以接受安慰劑或阿利庫單抗。隨機分配比率阿利庫單抗：安慰劑為2：1。對於每個隨機分配的患者，有幾個相應的治療試劑盒編號(再提供拜訪)，其通過集中治療分配系統分配。按糖尿病類型(即1型與2型)將隨機分配分層。 During double-blind treatment, patients were randomly assigned to receive placebo or aliculumab. Random allocation ratio of aliculumab: placebo was 2: 1. For each randomly assigned patient, there are several corresponding treatment kit numbers (revisited visits), which are assigned through a centralized treatment allocation system. Random allocation was stratified by type of diabetes (ie type 1 and type 2).

在隨機分配拜訪(第1天，第0周)、然後在第12週作為再提供拜訪、以及如果需要在事先未安排的拜訪時，使用集中治療分配系統分配治療試劑盒編號。 The treatment kit number is assigned using a centralized treatment allocation system at random assignment visits (day 1, week 0), then as a resupply visit at week 12, and if a prior unscheduled visit is required.

對於阿利庫單抗治療組中的患者，在第12週分配的治療試劑盒遵循上升滴定規則基於患者的第8週LDL-C水準。計劃在中心實驗室和集中治療分配系統提供者之間的定期數據轉移，目的是對於研究現場和贊助者以盲法方式進行。 For patients in the ariculumab-treated group, the treatment kit dispensed at week 12 followed the ascending titration rule based on the patient's weekly LDL-C level. Periodic data transfers are planned between the central laboratory and the provider of the centralized treatment distribution system, with the aim of conducting the study site and sponsors blindly.

在隨機分配患者之前，研究者或被指派者必須聯繫集中治療分配系統。 Prior to randomizing patients, the investigator or assignee must contact a centralized treatment allocation system.

將隨機分配的患者定義為使用來自集中治療分配系統的治療試劑盒編號登記並分配的患者，如其日誌文件所記錄的。在研究中，患者不能被隨機分配多於一次。如果在不聯繫集中治療分配系統的情況下使用治療，則認為患者未被隨機分配並退出研究。 Randomly assigned patients are defined as patients registered and assigned using a treatment kit number from a centralized treatment distribution system, as recorded in their log files. In the study, patients could not be randomized more than once. If treatment is used without contacting a centralized treatment allocation system, the patient is considered to have not been randomly assigned and is withdrawn from the study.

根據現場的選擇，使用兩種類型的集中治療分配系統，IVRS和IWRS。 Depending on the site selection, two types of centralized treatment distribution systems are used, IVRS and IWRS.

包裝和標簽Packaging and labeling

對於雙盲治療期，製備每種雙盲治療試劑盒(阿利庫單抗或阿利庫單抗的安慰劑)以在兒童不能打開的包裝中含有6個預填充筆。為了保護盲法，所有用於注射的雙盲治療試劑盒的箱子都具有相同的外觀和感覺，並且因此會標有雙盲標簽。 For the double-blind treatment period, each double-blind treatment kit (aliculumab or placebo for aliculumab) was prepared to contain 6 pre-filled pens in a package that children cannot open. In order to protect the blind method, all the boxes of the double-blind treatment kit for injection have the same look and feel and are therefore marked with a double-blind label.

除了用於注射的雙盲治療試劑盒之外，還製備了含有1個阿利庫單抗的安慰劑預填充筆的訓練試劑盒，用於指導患者進行注射施用的目的，其在篩選拜訪(第-3周，第一次拜訪)時隨機分配前進行。如果認為有必要，在隨機分配之前，使用另外的訓練試劑盒進行用阿利庫單抗的安慰劑的第二次注射訓練。進行使用安慰劑的注射訓練並且記錄在CRF中，這包括如果在研究過程中向患者施用IMP的指定的人改變的情況。 In addition to the double-blind treatment kit for injection, a training kit containing a placebo pre-filled pen for aliculumab was also prepared to guide patients for the purpose of injection administration. -3 weeks, first visit) before random allocation. If deemed necessary, a second training session with placebo for aliculumab was performed using an additional training kit before randomization. Injection training with placebo was performed and recorded in the CRF, which included changes if the designated person who administered IMP to the patient during the study changed.

包裝符合施用預定計劃。標簽的內容符合當地監管規範和要求。 The packaging conforms to the application schedule. The content of the label complies with local regulatory norms and requirements.

儲存條件和儲存期Storage conditions and shelf life

研究者或其他被授權人員(例如，藥劑師)負責根據當地法規、標簽規格、政策和程序將IMP存儲在保險且安全的地方。根據贊助者提供的規則管理IMP存儲條件的控制，尤其是溫度控制(例如，冷藏存儲)和關於使用中的穩定性的信息以及處理IMP的說明。 The researcher or other authorized person (for example, a pharmacist) is responsible for storing the IMP in an insured and secure place in accordance with local regulations, label specifications, policies, and procedures. Control of IMP storage conditions is governed by rules provided by the sponsor, especially temperature control (eg, refrigerated storage) and information on stability in use and instructions for handling the IMP.

IMP在現場儲存在+2℃至+8℃(36℉至46℉)之間的冰箱中。每天檢查現場冰箱的溫度並記錄在日誌表上。存儲在研究現場的IMP被保存在恰當鎖好的房間，由研究者或指定人員或其他被授權人員根據標簽上標明的儲存條件負責。 The IMP is stored on-site in a refrigerator between + 2 ° C and + 8 ° C (36 ° F to 46 ° F). Check the temperature of the on-site refrigerator daily and record it on the log sheet. The IMPs stored at the research site are kept in properly locked rooms, and are the responsibility of the researcher or designated personnel or other authorized personnel based on the storage conditions indicated on the label.

在研究現場拜訪時向患者供應IMP試劑盒之後，安排了適當的規定以將IMP試劑盒從研究現場轉輸到患者的冰箱。 After the IMP kit was supplied to the patient at the study site visit, appropriate regulations were arranged to transfer the IMP kit from the study site to the patient's refrigerator.

研究終點Study endpoint

基線特徵包括每個患者的標準人口統計(例如，年齡、種族、體重、身高等)、疾病特徵(包括病史)以及藥物歷史。 Baseline characteristics include standard demographics (eg, age, race, weight, height, etc.), disease characteristics (including medical history), and drug history for each patient.

主要功效終點Primary efficacy endpoint

主要功效終點是意向治療(intent-to-treat；ITT)群體中從基線到第24週的LDL-C的百分比變化，使用所有LDL-C值而不管是否遵守治療(ITT被估量)。百分比變化定義為100x(在第24週計算的LDL-C值-在基線計算的LDL-C值)/在基線計算的LDL-C值。 The primary efficacy endpoint was the percentage change in LDL-C from baseline to week 24 in the intent-to-treat (ITT) population, using all LDL-C values regardless of adherence to treatment (ITT estimated). Percent change is defined as 100x (LDL-C value calculated at Week 24-LDL-C value calculated at baseline) / LDL-C value calculated at baseline.

基線計算的LDL-C值是在第一次雙盲IMP注射之前獲得的最後LDL-C水準。在第24週計算的LDL-C是在第24週分析窗口內獲得的LDL-C水準。根據上述定義，如果合適的話，允許使用在第8週至第24週之間的所有計算的LDL-C值(計劃的或未計劃的，禁食的或沒有禁食的)提供主要功效終點的值。 The baseline calculated LDL-C value is the last LDL-C level obtained before the first double-blind IMP injection. The LDL-C calculated at week 24 is the LDL-C level obtained during the analysis window at week 24. According to the definition above, if applicable, all calculated LDL-C values (planned or unplanned, fasted or not fasted) between week 8 and week 24 are used to provide values for the primary efficacy endpoint .

主要安全性終點Primary safety endpoint

在整個研究中評估安全性參數(AE，實驗室參數，生命體征)。安全性數據的觀察如下：(a)治療前的時期定義為從簽名的知情同意書直至第一劑量的雙盲IMP注射；(b)治療緊急不良事件(TEAE)期定義為從第一劑量的雙盲IMP注射到最後劑量的IMP注射+70天(10周)的時間，因為治療的殘餘效應預計直到停止雙盲IMP後10周；和(c)治療後的時期定義為從TEAE期結束後的那天開始直到解決/穩定所有SAE和AESI的時間，以後到者為准。 Safety parameters (AE, laboratory parameters, vital signs) were evaluated throughout the study. Observation of safety data is as follows: (a) the pre-treatment period is defined as the double-blind IMP injection from the signed informed consent to the first dose; (b) the treatment emergency adverse event (TEAE) period is defined as the Double-blind IMP injection to the last dose of IMP injection + 70 days (10 weeks) because the residual effects of treatment are expected until 10 weeks after stopping double-blind IMP; and (c) the period after treatment is defined as after the end of the TEAE period The day starts until the time to resolve / stabilize all SAE and AESI, whichever comes later.

AE是在施用藥物產品的患者或臨床研究患者中的任何不幸的醫學事件，並且其不一定必須與該治療具有因果關係。 AE is any unfortunate medical event in a patient who is administered a drug product or a clinical study patient, and it does not necessarily have to be causally related to the treatment.

SAE是具有以下特徵的任何不幸醫學事件，其在任何劑量下：(a)導致死亡；(b)威脅生命。“嚴重”的定義中的術語“威脅生命”指在事件發生時患者有死亡風險的事件；如果它更嚴重，它不是指假設可能導致死亡的事件；(c)需要住院患者住院治療或延長現有住院時間；(d)導致持續或顯著殘疾/無行為能力；(e)是先天性異常/出生缺陷；或(f)是醫學上重要的事件。 SAE is any unfortunate medical event with the following characteristics at any dose: (a) causing death; (b) life threatening. The term "life-threatening" in the definition of "serious" refers to an event in which the patient is at risk of death at the time of the event; if it is more severe, it does not refer to an event that is assumed to lead to death; (c) requires hospitalization of the patient or extends the Length of hospital stay; (d) causes persistent or significant disability / disability; (e) is a congenital anomaly / birth defect; or (f) is a medically significant event.

在決定在其它情況下是否適合加急報告時，實行醫學和科學判斷，該情況諸如可能不會立即危脅生命或導致死亡或住院治療但可能危害患者或可能需要醫學介入或外科手術介入(即特定措施或矯正治療)的重要醫學事件，以防止上述定義中列出的其他結果之一。 In determining the suitability of expedited reporting in other circumstances, medical and scientific judgment is exercised, such as those that may not immediately threaten life or cause death or hospitalization but may harm patients or may require medical or surgical intervention (i.e. Specific medical measures or corrective treatments) to prevent one of the other results listed in the definition above.

以下醫學重要事件列表意欲用作確定哪種情況必須被視為醫學重要事件的指南。該列表並不是詳盡的： (a)在急診室或家中的強化治療用於過敏性支氣管痙攣、惡血質(即粒細胞缺乏症、再生障礙性貧血、骨髓發育不良、脊髓發育不良、各類血細胞減少等)，或驚厥(癲癇發作(seizures)，癲癇(epilepsy)，癲癇發作(epileptic fit)，失神等))；(b)發生藥物依賴或藥物濫用；(c)ALT>3 x ULN+總膽紅素>2 x ULN或無症狀ALT增加>10 x ULN；(d)自殺未遂或任何暗示自殺的事件；(e)暈厥、意識喪失(除非記錄為血液採樣的結果)；(f)大皰性皮疹；(g)在研究期間診斷或在研究期間加重的癌症；(h)研究期間慢性神經退行性疾病(新診斷的)或加重的；和(i)懷疑傳播傳染性病原體，如果經由藥物產品(例如產品污染)的任何懷疑傳播傳染性病原體。 The following list of medically significant events is intended to be used as a guide to determine which conditions must be considered medically significant. The list is not exhaustive: (a) Intensive treatment in the emergency room or home is used for allergic bronchospasm, cachexia (i.e. agranulocytosis, aplastic anemia, bone marrow dysplasia, spinal dysplasia, various types of Blood cell loss, etc.), or convulsions (seizures, epilepsy, epileptic fit, absence, etc.)); (b) drug dependence or drug abuse; (c) ALT> 3 x ULN + total Bilirubin> 2 x ULN or asymptomatic ALT increase> 10 x ULN; (d) attempted suicide or any event that suggests suicide; (e) syncope, loss of consciousness (unless recorded as a result of blood sampling); (f) large Herpes rash; (g) cancer diagnosed during the study or exacerbated during the study; (h) chronic neurodegenerative disease (newly diagnosed) or exacerbated during the study; and (i) suspected transmission of infectious pathogens, if Any suspected transmission of infectious pathogens from pharmaceutical products (eg product contamination).

特別感興趣的不良事件(AESI)是需要以預先指定的方式監控、記錄和管理的AE(嚴重的或非嚴重的)。對於該研究，AESI是：(a)ALT的增加：ALT3×ULN(如果基線ALT<ULN)或ALT基線值的2倍(如果基線ALTULN)；(b)過敏事件：過敏性藥物反應和/或局部注射部位反應被研究者視為過敏(或有過敏成分)，這需要與另一位醫生會診，以根據研究者的醫學判斷進一步評價超敏反應/過敏應該被報告為AESI；(c)妊娠：在研究期間或最後一劑研究藥物後70天內，女性患者或男性患者的伴侶(如果女性伴侶和當地監管機構允許)發生妊娠。在所有情況下，妊娠記錄為AESI。只有當其滿足一個或多個SAE標準，妊娠才被認定為SAE。在研究中包括的女性患者妊娠的情況下，停止研究產品。妊娠的隨訪是強制性的，直到已經確定結果；(d)有症狀的使用IMP的過度劑量。過度劑量(意外的或有意的)是由研究者懷疑或由患者自發通知的事件(不基於系統注射計數)，並且被定義為在預期治療間隔內至少兩次預期劑量(即，在<7個日曆日內施用2次或更多次注射)，使用術語“有症狀的過度劑量(意外的或有意的)”來報告，表明括號中的情況(例如，“有症狀的過度劑量(意外的)”或“有症狀的過度劑量(有意的)”)。監控患者並建立合適的對症治療。過度劑量的情況在逐字記錄中明確規定，並且如果有的話，症狀在單獨的AE/SAE表格中輸入。要求無症狀的過度劑量作為標準AE報告；(e)神經病學事件：要求需要進行額外檢查/程序和/或轉診給專家的神經病學事件作為AESI報告。如果該事件不需要額外的檢查/程序和/或轉診給專家，則要求將其作為標準AE報告；和(f)神經認知事件：所有神經認知事件都認為是AESI。 Of particular interest are adverse events (AESI) that are AEs (serious or non-serious) that need to be monitored, recorded, and managed in a pre-specified manner. For this study, AESI was: (a) Increase in ALT: ALT 3 × ULN (if baseline ALT <ULN) or ALT 2 times the baseline value (if baseline ALT ULN); (b) Allergic events: Allergic drug reactions and / or local injection site reactions are considered by the researcher to be allergic (or have allergic components), which requires consultation with another doctor to further based on the medical judgment of the researcher Assessing hypersensitivity / allergy should be reported as AESI; (c) Pregnancy: during the study or within 70 days after the last dose of the study drug, a female patient or a male patient's partner (if allowed by the female partner and local regulatory agency) has a pregnancy . In all cases, pregnancy was recorded as AESI. A pregnancy is considered SAE only if it meets one or more SAE criteria. In the case of pregnant women included in the study, the study product was discontinued. Follow-up of pregnancy is mandatory until results have been established; (d) symptomatic overdose of IMP. Excessive dose (accidental or intentional) is an event that is suspected by the investigator or spontaneously notified by the patient (not based on a systemic injection count) and is defined as the expected dose of at least two (i.e., <7 2 or more injections given over calendar days), reported using the term "symptomatic overdose (accidental or intentional)", indicating the condition in brackets (eg, "symptomatic overdose (accidental)" Or "symptomatic overdose (intentional)"). Monitor patients and establish appropriate symptomatic treatment. Overdose situations are clearly specified in the verbatim records and, if any, symptoms are entered on a separate AE / SAE form. Asymptomatic overdose is required to be reported as a standard AE; (e) Neurological events: Neurological events requiring additional tests / procedures and / or referrals to specialists are reported as AESI. If the event does not require additional tests / procedures and / or referrals to a specialist, it is required to be reported as a standard AE; and (f) neurocognitive events: all neurocognitive events are considered AESI.

次要功效終點Secondary efficacy endpoint

本研究的關鍵次要終點如下：(a)從基線到第24週的計算的LDL-C的百分比變化，使用功效治療期間的所有LDL-C值(治療中的被估量(on-treatment estimand))；(b)從基線到第24週的測量的LDL-C的百分比變化(ITT被估量(ITT estimand))；(c)從基線到第12週的計算的LDL-C的百分比變化(ITT被估量)；(d)從基線到第12週的測量的LDL-C的百分比變化(ITT被估量)；(e)從基線到第24週的非HDL-C的百分比變化(ITT被估量)；(f)從基線到第24週的Apo B的百分比變化(ITT被估量)；(g)從基線到第24週的總膽固醇的百分比變化(ITT被估量)；(h)在第24週達到LDL-C<70mg/dL的患者比例(治療中的被估量)；(i)在第24週達到LDL-C<50mg/dL的患者比例(治療中的被估量)；(j)在第24週達到非HDL-C<100mg/dL的患者比例(治療中的被估量)；(k)第24週達到非HDL-C<80mg/dL的患者比例(治療中的被估量)；(l)從基線到第24週的Lp(a)的百分比變化(ITT被估量)；(m)從基線到第24週的HDL-C的百分比變化(ITT被估量)；(n)從基線到第24週的TG的百分比變化(ITT被估量)；(o)從基線到第24週的LDL-C顆粒數的百分比變化(ITT被估量)；和 (p)從基線到第24週的LDL-C顆粒尺寸的百分比變化(ITT被估量)。 The key secondary endpoints for this study are as follows: (a) Calculated percentage change in LDL-C from baseline to week 24, using all LDL-C values during on-treatment treatment (on-treatment estimand) ); (B) measured percentage change in LDL-C from baseline to week 24 (ITT estimand); (c) calculated percentage change in LDL-C from baseline to week 12 (ITT (Estimated); (d) measured percentage change in LDL-C from baseline to week 12 (ITT estimated); (e) percentage change in non-HDL-C from baseline to week 24 (ITT estimated) (F) Percent change in Apo B from baseline to week 24 (estimated ITT); (g) Percent change in total cholesterol from baseline to week 24 (estimated ITT); (h) at week 24 Proportion of patients achieving LDL-C <70mg / dL (estimated during treatment); (i) Proportion of patients achieving LDL-C <50mg / dL at week 24 (estimated during treatment); (j) Proportion of patients achieving non-HDL-C <100mg / dL at 24 weeks (estimated during treatment); (k) Proportion of patients achieving non-HDL-C <80mg / dL at week 24 (estimated during treatment); (l Percent change in Lp (a) from baseline to week 24 (ITT estimated) (M) Percent change in HDL-C from baseline to Week 24 (ITT estimated); (n) Percent change in TG from baseline to Week 24 (ITT estimated); (o) From baseline to Week 24 Percent change in LDL-C particle number at 24 weeks (ITT estimated); and (p) Percent change in LDL-C particle size from baseline to week 24 (ITT estimated).

在該研究中還測量了以下與糖尿病相關的終點：(a)從基線到第12週和第24週的HbA1c的絕對變化(ITT被估量和治療中的被估量)；(b)從基線到第12週和第24週的FPG的絕對變化(ITT被估量和治療中的被估量)；(c)從基線到第12週和第24週的總每日胰島素劑量的絕對變化(ITT被估量和治療中的被估量)；和(d)從基線到第12週和第24週的葡萄糖降低治療次數的絕對變化(ITT被估量和治療中的被估量)。 The following diabetes-related endpoints were also measured in this study: (a) absolute change in HbA1c from baseline to weeks 12 and 24 (measured in ITT and estimated in treatment); (b) from baseline to Absolute changes in FPG at week 12 and week 24 (measured at ITT and at treatment); (c) Absolute changes in total daily insulin dose from baseline to weeks 12 and 24 (measured at ITT) And estimates in treatment); and (d) absolute changes in the number of glucose reduction treatments from baseline to weeks 12 and 24 (measured in ITT and estimated in treatment).

該研究的其他功效終點包括：(a)從基線到第12週的計算的LDL-C的百分比變化(治療中的被估量)；(b)從基線到第12週和第24週的測量的LDL-C的百分比變化(治療中的被估量)；(c)從基線到第12週的(ITT和治療中的被估量)和到第24週的(治療中的被估量)非HDL、ApoB、總膽固醇、Lp(a)、HDL-C和TG的百分比變化；(d)在第12週(ITT被估量和治療中的被估量)和第24週(ITT被估量)達到計算的LDL-C<50並且還<70mg/dL的患者的比例；(e)第12週和第24週計算的LDL-C與基線相比減少50%或更多的患者的比例(ITT被估量)；(f)在第12週(ITT被估量和治療中的被估量)和第24週(ITT被估量)達到非HDL-C<80mg/dL並且還<100mg/dL的患者的比例；(g)在第12週和第24週達到Apo B<80mg/dL的患者的比例(ITT被估量和治療中的被估量)；(h)從基線到第12週(ITT被估量和治療中的被估量)和第24週(治療中的被估量)的LDL-C顆粒數量和尺寸的百分比變化；(i)從基線到第12週和到第24週的TGRL、Apo A-1和Apo C-III的百分比變化(ITT被估量和治療被估量)； (j)從基線到第12週和到第24週的比率ApoB/ApoA-1和TC/HDL-C的絕對變化(ITT被估量和治療中的被估量)；(k)根據基線A1c<8%或8%，第12週和第24週達到計算的LDL-C<70和<50mg/dL的患者的比例(ITT被估量和治療中的被估量)；和(l)根據基線A1c<中值A1c或中值A1c，在第12週和第24週達到計算的LDL-C<70mg/dL和<50mg/dL的患者的比例(ITT被估量和治療中的被估量)。 Other efficacy endpoints of the study include: (a) calculated percentage change in LDL-C from baseline to week 12 (estimated during treatment); and (b) measured from baseline to week 12 and week 24 Percent change in LDL-C (estimated in treatment); (c) Non-HDL, ApoB (estimated in treatment) from baseline to week 12 (ITT and treatment) , Percentage change in total cholesterol, Lp (a), HDL-C, and TG; (d) reached calculated LDL- at week 12 (ITT estimated and treatment estimated) and at week 24 (ITT estimated) Proportion of patients with C <50 and also <70mg / dL; (e) Proportion of patients with 50% or more reduction in LDL-C from baseline calculated at weeks 12 and 24 (ITT estimated); f) Proportion of patients who achieved non-HDL-C <80mg / dL and also <100mg / dL at week 12 (measured ITT and estimated in treatment) and week 24 (measured ITT); (g) at Proportion of patients who achieved Apo B <80mg / dL at weeks 12 and 24 (ITT estimated and estimated during treatment); (h) From baseline to week 12 (ITT estimated and estimated during treatment) And percentage of LDL-C particles number and size at week 24 (estimated during treatment) (I) Percent change in TGRL, Apo A-1, and Apo C-III from baseline to week 12 and week 24 (ITT estimated and treatment estimated); (j) from baseline to week 12 And ratios to week 24 absolute changes in ApoB / ApoA-1 and TC / HDL-C (measured in ITT and measured in treatment); (k) based on baseline A1c <8% or 8%, the proportion of patients who reached calculated LDL-C <70 and <50mg / dL at 12th and 24th week (ITT estimated and estimated during treatment); and (l) based on baseline A1c <median A1c or Median A1c, the proportion of patients who reached calculated LDL-C <70 mg / dL and <50 mg / dL at 12 and 24 weeks (ITT estimated and estimated during treatment).

研究程序Research Procedure

第0周的窗口期為+3天。第8週、第12週和第24週的窗口期為±3天。第4週、第20周和第32周的窗口期為±7天。對於第1天/納入拜訪後的所有拜訪，如果一個拜訪日期改變，則根據圖1中概述的原始計劃表進行下一次拜訪。 The window period of week 0 is +3 days. The window period for weeks 8, 12, and 24 was ± 3 days. The window periods for weeks 4, 20, and 32 were ± 7 days. For all visits on Day 1 / after inclusion, if the date of one visit changes, the next visit is made according to the original schedule outlined in Figure 1.

血液取樣Blood sampling

所有血液取樣，包括用於確定脂質參數(例如，TC、LDL-C、HDL-C、TG、非HDL-C、Apo A、Apo B、Apo C-III、Lp(a)、LDL顆粒尺寸和數量)的血液取樣以及用於確定血糖的血液取樣，對於整個研究的所有現場拜訪在早晨、空腹條件下(即過夜，禁食至少10至12小時，和禁止吸煙)，並IMP注射前進行。阻止血液取樣前48小時內飲酒和24小時內強烈體育鍛煉。如果患者沒有處於空腹狀態，則不採集血液樣本，並在給予患者第二天(或盡可能接近該日期)的新的預約，同時指示禁食(見上述條件)。 All blood samples, including those used to determine lipid parameters (e.g., TC, LDL-C, HDL-C, TG, non-HDL-C, Apo A, Apo B, Apo C-III, Lp (a), LDL particle size, and (Quantity) blood sampling and blood sampling for blood glucose determination were performed for all site visits throughout the study under morning, fasting conditions (ie overnight, fasting for at least 10 to 12 hours, and no smoking), and before IMP injection. Stop drinking alcohol within 48 hours and intense physical exercise within 24 hours before blood sampling. If the patient is not on a fasting state, no blood sample is taken and a new appointment is given to the patient the next day (or as close as possible to that date) while fasting is indicated (see conditions above).

實驗室測試lab testing

根據圖1中概述的研究計劃表和以下指南收集實驗室數據：(a)血液學：除第4週和第20週外的所有拜訪；如果適用的話可以在第0周進行，並且可基於研究者的臨床判斷進行； (b)化學：除第3和6次拜訪外的所有拜訪；如果適用的話可在第0週進行，並且可基於研究者的臨床判斷進行，除了應在第0週對所有患者進行的血糖之外；(c)HbA1c：篩選和第0週、第12週和第24週；(d)脂質組(lipid panal)：篩選和第0、8、12、20和24週；(e)經由β量化的測量的LDL-C：第0、12和24週；(f)其他脂質評估(Apo B、Apo A-1、Apo C-III、LDL顆粒尺寸和數量、Lp[a])：第0、12和24週；(g)肝組(liver panel)：除第3次和第6次拜訪外的所有拜訪；如果適用的話可在第0週進行，並且可基於研究者的臨床判斷進行。在總膽紅素值高於正常範圍的情況下，會自動發生分化成結合的膽紅素和非結合的膽紅素；(h)肌酸磷酸激酶(CPK)：除第3次和第6次拜訪外的所有拜訪；如果適用的話可在第0週進行，並且可基於研究者的臨床判斷進行；(i)乙型肝炎表面抗原：僅篩選；(j)丙型肝炎抗體：篩選時和第24週；在研究期間ALT增加的情況下，應該確定丙型肝炎抗體。如果在研究期間丙型肝炎抗體為陽性，則進行反射性測試；(k)妊娠測試(僅在有生育潛力的婦女中)：僅篩選時的血清妊娠測試，第0週和第24週的尿妊娠測試；(l)促甲狀腺激素：對正在服用甲狀腺激素替代物的患者，僅篩選；(m)C肽：僅篩選；(n)PCSK9水準：僅在第0週；和(o)抗阿利庫單抗抗體(第0週、第12週和第24週)。 Collect laboratory data according to the research plan outlined in Figure 1 and the following guidelines: (a) Hematology: all visits except week 4 and week 20; if applicable can be performed at week 0 and can be based on research (B) Chemistry: all visits except for the 3rd and 6th visits; if applicable, can be performed at week 0, and can be based on the investigator's clinical judgment, except that In addition to blood glucose performed by all patients; (c) HbA1c: screening and weeks 0, 12, and 24; (d) lipid panal: screening and weeks 0, 8, 12, 20, and 24 ; (E) Measured LDL-C via β quantification: Weeks 0, 12, and 24; (f) Other lipid assessments (Apo B, Apo A-1, Apo C-III, LDL particle size and number, Lp [ a]): Weeks 0, 12 and 24; (g) Liver panel: all visits except 3rd and 6th visits; if applicable can be performed at week 0 and can be based on research Clinical judgment. When the total bilirubin value is higher than the normal range, it will automatically differentiate into bound bilirubin and unbound bilirubin; (h) Creatine phosphate kinase (CPK): except for the third and sixth All visits except visits; if applicable, can be performed at week 0 and based on the investigator's clinical judgment; (i) Hepatitis B surface antigen: screening only; (j) Hepatitis C antibody: during screening and Week 24; In case of increased ALT during the study period, hepatitis C antibodies should be identified. If the hepatitis C antibody is positive during the study, a reflex test is performed; (k) Pregnancy test (only in women with fertility potential): serum pregnancy test at screening only, urine at weeks 0 and 24 Pregnancy test; (l) thyroid stimulating hormone: screening only for patients taking thyroid hormone replacement; (m) C peptide: screening only; (n) PCSK9 level: only at week 0; and (o) anti-Ari Culumumab antibodies (weeks 0, 12 and 24).

尿液取樣Urine sampling

在篩選和第24週拜訪時進行尿分析。進行試紙條(Dipstick)測試並評估pH、比重以及是否存在血液、蛋白質、葡萄糖、酮、硝酸鹽、白細胞酯酶、尿膽素原和膽紅素。如果試紙條異常，則進行標準顯微鏡檢查。顯微鏡評價是否存在紅細胞(RBC)、紅細胞團塊、白細胞(WBC)、WBC團塊、上皮細胞(移行上皮細胞、腎小管上皮細胞和鱗狀上皮細胞)、管型(透明管型、上皮管型、WBC管型、RBC管型、顆粒管型、脂肪管型、細胞管型、寬幅管型、蠟樣管型)、晶體(三磷酸結晶、草酸鈣結晶、磷酸鈣結晶、碳酸鈣結晶、尿酸結晶、無定形結晶、重尿酸銨結晶、膽紅素結晶、亮胺酸結晶、酪胺酸結晶、胱胺酸結晶)、細菌、酵母芽、酵母菌絲、滴蟲、卵圓脂肪體、脂肪、粘液和***。 Urinalysis was performed at screening and week 24 visits. A dipstick test was performed and evaluated for pH, specific gravity, and the presence of blood, protein, glucose, ketones, nitrates, leukocyte esterase, urobilinogen, and bilirubin. If the test strip is abnormal, perform a standard microscope inspection. Microscopically evaluate the presence of red blood cells (RBC), red blood cell clumps, white blood cells (WBC), WBC clumps, epithelial cells (transitional epithelial cells, renal tubular epithelial cells, and squamous epithelial cells), casts (clear cast, epithelial cast , WBC cast, RBC cast, granular cast, fat cast, cell cast, wide cast, waxy cast), crystal (triphosphate crystal, calcium oxalate crystal, calcium phosphate crystal, calcium carbonate crystal, Uric acid crystals, amorphous crystals, ammonium biurate crystals, bilirubin crystals, leucine crystals, tyrosine crystals, cystine crystals), bacteria, yeast buds, yeast hyphae, trichomonas, oval fat bodies, Fat, mucus and sperm.

對白蛋白和肌酸酐進行斑點尿液測試以計算篩選和第24週拜訪時的白蛋白：肌酸酐比率。在對相關患者做出任何決定之前，立即重新檢查任何臨床相關的異常實驗室值。 A spot urine test was performed on albumin and creatinine to calculate the albumin: creatinine ratio at screening and week 24 visits. Recheck any clinically relevant abnormal laboratory values immediately before making any decision on the patient.

體檢Checkup

進行一般體檢。如果在納入後檢測到新的臨床顯著異常或從基線的惡化，則報告AE並根據研究者的醫學判斷考慮患者進行進一步的臨床研究和/或專家會診。 Have a general medical examination. If a new clinically significant abnormality or deterioration from baseline is detected after enrollment, the AE is reported and the patient is considered for further clinical studies and / or expert consultation based on the investigator's medical judgment.

血壓和心率Blood pressure and heart rate

在標準條件下，大約在一天的同一時間，在相同的手臂上，使用相同的設備(在患者以坐式體位舒適地休息至少5分鐘之後)以坐式體位測量血壓(BP)。數值記錄在e-CRF中；記錄收縮壓和舒張壓。在第一次篩選拜訪時，測量雙臂BP。在該次拜訪時確定具有最高舒張壓的手臂，並在整個研究過程中測量該手臂上的BP。該最高值記錄在e-CRF中。 Under standard conditions, blood pressure (BP) is measured in a sitting position using the same equipment on the same arm at about the same time of day (after the patient has rested comfortably for at least 5 minutes in a sitting position). Values are recorded in e-CRF; systolic and diastolic blood pressure are recorded. At the first screening visit, the two-arm BP was measured. The arm with the highest diastolic blood pressure was identified at this visit, and the BP on that arm was measured throughout the study. This highest value is recorded in e-CRF.

在測量BP時測量心率。 Heart rate is measured while measuring BP.

體重和身高Weight and height

在患者穿著內衣或非常輕的衣服且不穿鞋子並且在膀胱排空的情況下獲得體重。整個研究中使用相同的量表。 The patient gains weight while wearing underwear or very light clothing without shoes and with emptying of the bladder. The same scale was used throughout the study.

測量高度，因為自我報告的高度是不可接受的。 Measure height because self-reported height is unacceptable.

iTAQ調查問卷iTAQ questionnaire

iTAQ是患者報告的結果(PRO)測量，以評估在問卷完成之前的4週時間內的治療可接受性。要求患者在第8週和第24週拜訪時完成。 iTAQ is a Patient Reported Outcome (PRO) measurement to assess the acceptability of treatment during the 4 weeks before the questionnaire is completed. Patients were asked to complete at week 8 and week 24 visits.

胰島素日誌Insulin log

指導患者完成胰島素記錄，目的是在每次拜訪之前持續至少7天記錄他/她的每日胰島素劑量(基礎胰島素和餐時胰島素，如果適用)，並且將該信息帶到下次研究拜訪。在研究拜訪之前持續超過7天，患者可以記錄每日胰島素劑量，但是僅將每次拜訪之前最後7天收集的信息輸入CRF。 Instruct the patient to complete an insulin record with the goal of recording his / her daily insulin dose (basal and meal insulin, if applicable) for at least 7 days before each visit, and bring this information to the next study visit. Patients can record daily insulin doses that last more than 7 days before study visits, but only enter information collected in the last 7 days before each visit into the CRF.

結果result

共登記了76名患有T1DM的患者和441名患有T2DM的患者。 A total of 76 patients with T1DM and 441 patients with T2DM were enrolled.

所有76名患有T1DM的隨機分配的患者都被治療，因此這些患者包括在安全性群體中。2名隨機分配的患有T1DM的患者(均在阿利庫單抗組中)不包括在意向治療(ITT)群體中。 All 76 randomly assigned patients with T1DM were treated, so these patients were included in the safety population. Two randomly assigned patients with T1DM (both in the Aliculumab group) were not included in the intention-to-treat (ITT) population.

在441名T2DM患者中，3名未治療(阿利庫單抗組1名、安慰劑組2名)，並且因此不包括在安全性群體中。12名隨機分配的患有T2DM患者(阿利庫單抗組7名，安慰劑組5名)不包括在ITT群體中。 Of the 441 T2DM patients, 3 were untreated (1 in the aliculumab group and 2 in the placebo group) and were therefore not included in the safety group. Twelve randomly assigned patients with T2DM (7 in the aliculumab group and 5 in the placebo group) were not included in the ITT population.

如果在基線或在直到第24週的分析窗口之一內沒有可用的計算的LDL-C值，則患者不包括在ITT群體中。 Patients are not included in the ITT population if there are no calculated LDL-C values available at baseline or within one of the analysis windows up to Week 24.

研究患者Study patient

六名(7.9%)患有T1DM的患者過早停止研究治療(阿利庫單抗組中3例[5.9%](2名患者由於AE終止)和安慰劑組中3例[12.0%](2名患者由於AE終止)。阿利庫單抗組中的所有3名患者也沒有完成研究期，而在安慰劑組中，2名患者也沒有完成研究期，並且1名患者保持在研究中直到研究期完成。 Six (7.9%) patients with T1DM discontinued study treatment prematurely (3 [5.9%] in the alicusumab group (2 patients discontinued due to AE) and 3 [12.0%] in the placebo group (2 Patients discontinued due to AE). All 3 patients in the aliculumab group also did not complete the study period, while in the placebo group, 2 patients did not complete the study period, and 1 patient remained in the study until the study Period is complete.

39名(8.8%)患有T2DM的患者過早停止研究治療(阿利庫單抗組中29名(9.9%)，安慰劑組10名(6.8%)。在阿利庫單抗組的29名患者中，18名患者也沒有完成研究，11名患者仍在研究中，直到研究期完成。在安慰劑組中，在10名患者中，7名患者也沒有完成研究期，3名患者仍在研究中，直到研究期完成。 39 (8.8%) patients with T2DM discontinued study treatment prematurely (29 (9.9%) in the ariculizumab group and 10 (6.8%) in the placebo group. 29 patients in the ariculumab group Of the 18 patients, the study was not completed, and 11 patients were still in the study until the study period was completed. In the placebo group, of the 10 patients, 7 patients did not complete the study period and 3 patients were still studying Medium until the completion of the study period.

人口統計和基線特徵Demographics and baseline characteristics

在阿利庫單抗和安慰劑組中基線特徵通常相似。60.5%的隨機分配的患有T1DM的患者為男性，而54.2%的隨機分配的患有T2DM的患者為男性。患有T1DM的患者更年輕，平均年齡為56.1(SD=9.5)，而患有T2DM的患者的平均年齡為64.0(SD=9.1)。患有T1DM的患者的平均BMI為30.0kg/m²(SD=5.9)，而觀察到患有T2DM的患者的平均BMI為32.6kg/m²(SD=5.06)。 Baseline characteristics were usually similar in the aliquotumab and placebo groups. 60.5% of the randomly assigned patients with T1DM were men, and 54.2% of the randomly assigned patients with T2DM were men. Patients with T1DM were younger, with an average age of 56.1 (SD = 9.5), while patients with T2DM had an average age of 64.0 (SD = 9.1). The average BMI of patients with T1DM was 30.0 kg / m ² (SD = 5.9), while the average BMI of patients with T2DM was observed to be 32.6 kg / m ² (SD = 5.06).

患有T1DM的患者(平均值=121.0mg/dL,SD=51.2)的基線的計算的LDL-C高於患有T2DM的患者(平均值=110.4mg/dL,SD=37.3)。患有T1DM的患者的基線的甘油三酯中位數(Q1：Q3)=102.0mg/dL(76.5：135.0)低於患有T2DM的患者的中位數(Q1：Q3)=147.0mg/dL(105.0：212.0)。 Baseline calculated LDL-C was higher in patients with T1DM (mean = 121.0 mg / dL, SD = 51.2) than in patients with T2DM (mean = 110.4 mg / dL, SD = 37.3). Baseline median triglyceride (Q1: Q3) = 102.0 mg / dL (76.5: 135.0) in patients with T1DM is lower than the median (Q1: Q3) = 147.0 mg / dL in patients with T2DM (105.0: 212.0).

關於其他脂質參數，T1DM患者表現出從基線的LDL-C顆粒數(LS平均值)的百分比減少，在第12週為40.7%，在第24週為44.4%，以及LDL-C顆粒尺寸的百分比減少，在第12週為2.3%，在第24週為2.3%。這些患者的ApoC3在第12週減少6.9%和在第24週減少7.5%。 Regarding other lipid parameters, T1DM patients showed a percentage reduction in the number of LDL-C particles (mean LS average) from baseline, 40.7% at week 12, 44.4% at week 24, and the percentage of LDL-C particle size The decrease was 2.3% at week 12 and 2.3% at week 24. These patients had ApoC3 reductions of 6.9% at week 12 and 7.5% at week 24.

關於其他脂質參數，T2DM患者表現出從基線的LDL-C顆粒數(LS平均值)的百分比減少，在第12週為37.6%，在第24週為38.3%，以及LDL-C顆粒尺寸的百分比減少，在第12週為2.6%，第24週為2.8%。這些患者的ApoC3在第12週減少6.3%，在第24週減少5.8%。 Regarding other lipid parameters, T2DM patients showed a percentage decrease in the number of LDL-C particles (mean LS mean) from baseline, 37.6% at week 12, 38.3% at week 24, and percentage of LDL-C particle size The decrease was 2.6% at Week 12, and 2.8% at Week 24. These patients had a 6.3% reduction in ApoC3 at week 12 and a 5.8% reduction at week 24.

在患有T1DM的患者中，治療組之間的糖尿病的平均持續時間和胰島素使用的平均持續時間相似。糖尿病的平均持續時間為34.92年(SD=12.67)，胰島素使用的平均持續時間為34.81年(SD=12.77)。在患有T2DM的患者中，治療組之間的糖尿病的平均持續時間和胰島素使用的平均持續時間相似。在T2DM中，糖尿病的平均持續時間為16.75年(SD=8.13)，胰島素使用的平均持續時間為8.01年(SD=6.90)。 In patients with T1DM, the average duration of diabetes and the average duration of insulin use were similar between treatment groups. The average duration of diabetes was 34.92 years (SD = 12.67), and the average duration of insulin use was 34.81 years (SD = 12.77). In patients with T2DM, the average duration of diabetes and the average duration of insulin use were similar between treatment groups. In T2DM, the average duration of diabetes was 16.75 years (SD = 8.13), and the average duration of insulin use was 8.01 years (SD = 6.90).

治療組之間以及患有T1DM和T2DM的患者之間高膽固醇血症的持續時間通常相似。 The duration of hypercholesterolemia is usually similar between treatment groups and between patients with T1DM and T2DM.

如研究者報告的，具有他汀類不耐受的患者的比例在患有T1DM的患者中為31.6%，在患有T2DM的患者中為23.8%。 As reported by researchers, the proportion of patients with statin intolerance was 31.6% in patients with T1DM and 23.8% in patients with T2DM.

在隨機分配時接受纖維酸的患者的比例在患有T1DM的患者中為2.6%，在患有T2DM的患者中為8.8%。 The proportion of patients who received fibric acid at the time of random allocation was 2.6% in patients with T1DM and 8.8% in patients with T2DM.

在隨機分配時接受膽固醇吸收抑制劑(包括依折麥布)的患者的比例在阿利庫單抗組(13.6%)高於安慰劑組(7.6%)，特別是在患有T2DM的患者中：45名患者(15.3%)相對10名患者(6.8%)。 The proportion of patients receiving cholesterol absorption inhibitors (including ezetimibe) at the time of random allocation was higher in the alicusumab group (13.6%) than in the placebo group (7.6%), especially among patients with T2DM: Forty-five patients (15.3%) were compared with 10 patients (6.8%).

治療組之間的心血管病史和風險因素通常相似。在患有T1DM的患者和患有T2DM的患者之間觀察到以下差異： Cardiovascular history and risk factors are usually similar between treatment groups. The following differences were observed between patients with T1DM and patients with T2DM:

(1)ASCVD在患有T2DM的患者中比在患有T1DM的患者中頻率更高(40.1%相對21.1%)，冠心病(34.7%相對15.8%)和卒中(8.2%相對2.6%)也頻率更高，而在T2DM相對T1DM患者中PAD(4.3%相對9.2%)頻率更低。 (1) ASCVD is more frequent in patients with T2DM than in patients with T1DM (40.1% vs. 21.1%), and coronary heart disease (34.7% vs. 15.8%) and stroke (8.2% vs. 2.6%). Higher, and less frequent PAD (4.3% vs. 9.2%) in T2DM vs. T1DM patients.

(2)在不患ASCVD的患者中，相對於39.4%的患有T2DM的患者，56.7%的患有T1DM的患者具有靶器官損傷(微量白蛋白尿，大量白蛋白尿)和/或CKD和/或視網膜病變。仍然在不患ASCVD的患者中，觀察到以下額外的心血管風險因素： (2) Among patients without ASCVD, 56.7% of patients with T1DM have target organ damage (microalbuminuria, large albuminuria) and / or CKD and / Or retinopathy. Still in patients without ASCVD, the following additional cardiovascular risk factors were observed:

(a)T1DM患者比T2DM患者頻率更高：當前吸煙者(20.0%相對14.0%)，增殖前期糖尿病性視網膜病變(36.7%相對12.9%)和增殖期糖尿病視網膜病變(20.0%相對5.7%)。 (a) T1DM patients are more frequent than T2DM patients: current smokers (20.0% vs. 14.0%), preproliferative diabetic retinopathy (36.7% vs. 12.9%), and proliferative diabetic retinopathy (20.0% vs. 5.7%).

(b)T1DM患者比T2DM患者頻率更低：高血壓(55.0%相對84.8%)，微量白蛋白尿(10.0%相對19.7%)，低HDL-C(16.7%相對28.0%)。 (b) T1DM patients are less frequent than T2DM patients: hypertension (55.0% vs. 84.8%), microalbuminuria (10.0% vs. 19.7%), and low HDL-C (16.7% vs. 28.0%).

(3)在45%的T1DM患者和55.7%的T2DM患者中，觀察到未患ASCVD的患者中存在3個或更多的CV危險因素。 (3) In 45% of T1DM patients and 55.7% of T2DM patients, 3 or more CV risk factors were observed in patients without ASCVD.

總體而言，在兩個治療組中用高強度和中等強度他汀類治療T1DM和T2DM患者，其中較高比例的患者用中等強度他汀類治療(58.9%)。總體而言，59.0%的T1DM和T2DM患者僅接受他汀類治療。 Overall, T1DM and T2DM patients were treated with high- and moderate-intensity statins in two treatment groups, with a higher proportion of patients treated with moderate-intensity statins (58.9%). Overall, 59.0% of T1DM and T2DM patients received only statin therapy.

注釋： Notes:

^a僅針對目前服用他汀類的患者。 ^a Only for patients currently taking statins.

^b與他汀類組合或不與他汀類組合。 ^{b in} combination with or without statins.

^c高強度他汀類相當於每日40至80mg的阿托伐他汀或每日20至40mg的瑞舒伐他汀或每日80mg的辛伐他汀。 ^c High-intensity statins are equivalent to 40 to 80 mg of atorvastatin daily or 20 to 40 mg of rosuvastatin or 80 mg of simvastatin per day.

中等強度他汀類相當於每日10至20mg的阿托伐他汀或每日5至10mg的瑞舒伐他汀或每日20至40mg的辛伐他汀或每日40至80mg的普伐他汀或每日40mg的洛伐他汀或每日80mg的氟伐他汀或每日2至4mg的匹伐他汀。 Medium-intensity statins are equivalent to 10 to 20 mg of atorvastatin daily or 5 to 10 mg of rosuvastatin daily or 20 to 40 mg of simvastatin daily or 40 to 80 mg of pravastatin daily or 40 mg of lovastatin or 80 mg of fluvastatin per day or 2 to 4 mg of pitavastatin per day.

低強度他汀類相當於每日10mg的辛伐他汀或每日10至20mg的普伐他汀或每日20mg的洛伐他汀或每日20至40mg的氟伐他汀或每日1mg的匹伐他汀。 Low-intensity statins are equivalent to 10 mg of simvastatin per day or 10 to 20 mg of pravastatin per day or 20 mg of lovastatin per day or 20 to 40 mg of fluvastatin per day or 1 mg of pravastatin per day.

接受多於一個強度水準的他汀類的患者以最高強度水準計算。 Patients who received more than one level of statin were calculated at the highest level.

除了他汀類的每種強度(其中%是使用他汀類的患者的人數作為分母計算的)和每個日劑量類別(其中%是使用服用該特定他汀類的患者的人數作為分母計算的)之外，使用隨機分配的患者的人數作為分母計算%。 Except for each intensity of a statin (where% is calculated as the denominator of the number of patients using statins) and each daily dose category (where% is calculated as the denominator of the number of patients taking that particular statin) Calculate% using the number of randomly assigned patients as the denominator.

表10中總結了安全性群體暴露於研究藥物產品。 Table 10 summarizes the safety population's exposure to study drug products.

^a根據IVRS在第12週上升滴定的患者，此後用至少一次注射150mg的阿利庫單抗處理(transaction)。分母對應於具有至少一次注射第12週後IVRS處理的患者。 ^a Patients who were titrated according to IVRS at week 12 were then treated with at least one injection of 150 mg of aliculumab transaction. The denominator corresponds to patients with IVRS treatment after Week 12 of at least one injection.

患者被認為是他們實際接受的治療組中。 Patients are considered to be in the treatment group they are actually receiving.

以周計的IMP注射暴露的持續時間定義為：(最後IMP注射日期+14天-第一次IMP注射日期)/7，而不管間歇性停藥。 The duration of weekly IMP injection exposure is defined as: (last IMP injection date + 14 days-first IMP injection date) / 7 regardless of intermittent discontinuation.

功效efficacy

主要功效終點Primary efficacy endpoint

在患有T1DM的患者和患有T2DM的患者的ITT群體中，對於從基線到第24週的計算的LDL-C的變化百分比阿利庫單抗優於安慰劑(如表11和12以及圖2和3中所示)。在T1DM患者中，達到LDL-C<70mg/dL(<1.8mmol/L)的個體的比例在阿利庫單抗組為70.2%，在安慰劑組為5.1%(P<0.0001)，達到LDL-C<50mg/dL(1.3mmol/L)的個體的比例在阿利庫單抗組中為55.1%，在安慰劑組中為0%(P值不可計算)。在T2DM患者中，達到LDL-C<70mg/dL(<1.8mmol/L)的個體的比例在阿利庫單抗組中為76.4%，在安慰劑組中為7.4%(P<0.0001)，達到LDL-C<50mg/dL(1.3mmol/L)的個體的比例在阿利庫單抗組中為50.7%，在安慰劑組中為2.4%(P<0.0001)。對主要療效終點的靈敏度分析在兩個群體中顯示相似的結果(數據未顯示)。 In the ITT population of patients with T1DM and patients with T2DM, the calculated percentage of change in LDL-C from baseline to week 24 was better than placebo (as shown in Tables 11 and 12 and Figure 2). And 3). Among T1DM patients, the proportion of individuals who achieved LDL-C <70mg / dL (<1.8mmol / L) was 70.2% in the ariculumab group and 5.1% (P <0.0001) in the placebo group, reaching LDL- The proportion of individuals with C <50 mg / dL (1.3 mmol / L) was 55.1% in the aliculumab group and 0% in the placebo group (the P value was uncalculable). Among T2DM patients, the proportion of individuals achieving LDL-C <70mg / dL (<1.8mmol / L) was 76.4% in the aliculumab group and 7.4% (P <0.0001) in the placebo group, reaching The proportion of individuals with LDL-C <50 mg / dL (1.3 mmol / L) was 50.7% in the aliculumab group and 2.4% in the placebo group (P <0.0001). A sensitivity analysis of the primary efficacy endpoint showed similar results in both populations (data not shown).

注釋：最小二乘(LS)平均值、標準誤差(SE)和p值從MMRM(重複測量的混合效應模型)分析獲得。 Note: Least squares (LS) mean, standard error (SE), and p-values were obtained from MMRM (Mixed Effect Model of Repeated Measurement) analysis.

該模型包括治療組的固定分類效應(fixed categorical effects)、根據IVRS的隨機化層(strata)、時間點、治療組與時間點的交互作用、層與時間點的交互作用、治療組與層的交互作用、治療組與層與時間點的交互作用、以及基線計算的LDL-C值和基線值與時間點交互作用的連續性固定協變量。 The model includes fixed categorical effects in the treatment group, strata based on IVRS, time point, interaction between treatment group and time point, interaction between layer and time point, and treatment group and layer. The interaction, the interaction between the treatment group and the stratum and the time point, and the LDL-C value calculated at baseline and the continuity of the interaction between the baseline value and the time point were fixed covariates.

MMRM模型對ITT群體中的所有患者(即1型和2型糖尿病患者)進行。 The MMRM model is performed on all patients in the ITT population (ie, patients with type 1 and type 2 diabetes).

MMRM模型和基線描述使用基線值和模型中使用的至少一個分析窗口中的基線後的值(post-baseline value)對患者進行。 The MMRM model and baseline description are performed on patients using baseline values and post-baseline values in at least one analysis window used in the model.

根據用於確保強有力地將整體I型錯誤率控制在0.05水準的固定分層方法，如果統計學上是顯著的，則p值之後有'*'。 According to a fixed stratification method used to ensure that the overall type I error rate is controlled to a level of 0.05, if statistically significant, there is a '*' after the p-value.

該模型包括治療組的固定分類效應、根據IVRS的隨機化層、時間點、以及處理組與時間點的交互作用、層與時間點的交互作用、治療組與層的交互作用、和治療組與層與時間點的交互作用、以及基線計算的LDL-C值和基線值與時間點交互作用的連續性固定協變量。 The model includes the fixed classification effect of the treatment group, the randomization layer according to the IVRS, the time point, and the interaction between the treatment group and the time point, the interaction between the layer and the time point, the interaction between the treatment group and the layer, and the treatment group and the The interaction between the layer and the time point, and the LDL-C value of the baseline calculation and the continuity of the interaction between the baseline value and the time point are fixed covariates.

MMRM模型和基線描述使用基線值和模型中使用的至少一個分析窗口中的基線後的值對患者進行。 The MMRM model and baseline description are performed on patients using baseline values and post-baseline values in at least one analysis window used in the model.

次要功效終點Secondary efficacy endpoint

阿利庫單抗導致從基線到第24週的非HDL-C、ApoB、總膽固醇和Lp(a)水準的顯著降低(相對安慰劑的差異)，以及患有T1DM的患者和患有T2DM的患者的ITT群體中HDL-C的增加(分別如表13和14所示)。 Aliculumab caused significant reductions in non-HDL-C, ApoB, total cholesterol, and Lp (a) levels (differences from placebo) from baseline to week 24, as well as patients with T1DM and patients with T2DM Increase in HDL-C in the ITT population (shown in Tables 13 and 14, respectively).

^†在患有T2D的參與者的終點甘油三酯和患有T1D的參與者的終點HDL-C，分層測試終止，因此所有後續統計比較均未考慮統計學顯著性。 ^† At the endpoint of triglycerides in participants with T2D and HDL-C in participants with T1D, the stratification test was terminated, so all subsequent statistical comparisons did not consider statistical significance.

‡ P值僅用於描述目的。 ‡ P values are for descriptive purposes only.

Apo、載脂蛋白；ITT，意向治療；LDL-C，低密度脂蛋白膽固醇；Lp(a)，脂蛋白(a)；LS，最小二乘；非HDL-C，非高密度脂蛋白膽固醇；TRL-C，富含甘油三酯的脂蛋白膽固醇；SE，標準誤差；SD，標准偏差。 Apo, apolipoprotein; ITT, intention-to-treat; LDL-C, low-density lipoprotein cholesterol; Lp (a), lipoprotein (a); LS, least squares; non-HDL-C, non-high-density lipoprotein cholesterol; TRL-C, triglyceride-rich lipoprotein cholesterol; SE, standard error; SD, standard deviation.

與糖尿病相關的終點End points related to diabetes

總體而言，患有T1DM的患者和患有T2DM的患者中兩個治療組中FPG和HbA1c以及葡萄糖降低治療隨時間保持穩定。 Overall, FPG and HbA1c and glucose-lowering treatments remained stable over time in the two treatment groups in patients with T1DM and patients with T2DM.

關於HbA1c，在T1DM隊列中，在阿利庫單抗組中，平均HbA1c%為在基線處的7.84%(SD=0.94)，平均絕對變化=-0.03%(0.6)，而在安慰劑組中，平均HbA1c為基線處的7.68%(0.78)，平均絕對變化=-0.23%(0.36)。在T2DM隊列中，在阿利庫單抗組中，平均HbA1c為基線處的7.52%(0.96)，平均絕對變化=0.18%(0.74)，而在安慰劑組中，平均HbA1c為基線處的7.54%(1.02)，平均絕對變化=0.06%(0.66)。 Regarding HbA1c, in the T1DM cohort, the average HbA1c% was 7.84% (SD = 0.94) at baseline, and the mean absolute change was -0.03% (0.6) in the aliculumab group, while in the placebo group, The average HbA1c was 7.68% (0.78) at baseline, and the average absolute change = -0.23% (0.36). In the T2DM cohort, the mean HbA1c was 7.52% (0.96) at baseline and the mean absolute change was 0.18% (0.74) in the aliculumab group, while the mean HbA1c was 7.54% at baseline in the placebo group (1.02), mean absolute change = 0.06% (0.66).

關於FPG，在T1DM隊列中，在阿利庫單抗組中，平均FPG為基線處的173mg/dL(SD=70.6)，平均絕對變化=-0.03mg/dL(0.6)，而在安慰劑組中，平均FPG為基線處的166.5mg/dL(75.6)，平均絕對變化=14.6mg/dL(75.9)。在T2DM隊列中，在阿利庫單抗組中，平均FPG為基線處的154.1mg/dL(50.1)，平均絕對變化=9.5mg/dL(61.8)，而在安慰劑組中，平均FPG為基線處的153.5mg/dL(52.5)，平均絕對變化=10.0mg/dL(47.0)。 Regarding FPG, in the T1DM cohort, the mean FPG was 173 mg / dL (SD = 70.6) at baseline and the mean absolute change was -0.03 mg / dL (0.6) in the aliculumab group, while in the placebo group The average FPG was 166.5 mg / dL (75.6) at baseline, and the average absolute change was 14.6 mg / dL (75.9). In the T2DM cohort, the mean FPG was 154.1 mg / dL (50.1) at baseline and the mean absolute change = 9.5 mg / dL (61.8) in the aliculumab group, while the mean FPG was at baseline in the placebo group The average absolute change was 153.5 mg / dL (52.5) = 10.0 mg / dL (47.0).

安全性safety

將總共344名患者(51名T1DM和293名T2DM)暴露于阿利庫單抗，將170名患者(25名T1DM和145名T2DM)暴露於安慰劑。 A total of 344 patients (51 T1DM and 293 T2DM) were exposed to aliculumab, and 170 patients (25 T1DM and 145 T2DM) were exposed to placebo.

總體而言，具有任何治療緊急不良事件(TEAE)的患者的比率橫跨患有T1DM或T2DM的患者的安全性群體中的治療組是相似的(參見表15)。 Overall, the rate of patients with any treatment emergency adverse event (TEAE) was similar across treatment groups in the safety group of patients with T1DM or T2DM (see Table 15).

注釋：TEAE：治療緊急不良事件；SAE：嚴重不良事件。 Notes: TEAE: treatment of emergency adverse events; SAE: serious adverse events.

n(%)=至少一個TEAE的患者的人數和百分比。 n (%) = number and percentage of patients with at least one TEAE.

TEAE更高頻率(10%)地在以下系統器官分類(SOC)中報告：(a)傳染病和感染(阿利庫單抗中的21.8%相對安慰劑中的21.8%)；(b)胃腸道病症(阿利庫單抗中的13.1%相對安慰劑中的12.4%)；(c)肌肉骨骼和結締組織疾病(阿利庫單抗中的21.5%相對安慰劑中的15.9%)；和(d)全身性疾病和施用部位的情況(阿利庫單抗中的11.0%相對安慰劑中的8.8%)。 TEAE higher frequency ( 10%) are reported in the following System Organ Class (SOC): (a) infectious diseases and infections (21.8% in alicusumab vs. 21.8% in placebo); (b) gastrointestinal disorders (alicustan 13.1% in resistance versus 12.4% in placebo); (c) musculoskeletal and connective tissue disease (21.5% in alicusumab vs. 15.9% in placebo); and (d) systemic disease and administration Site conditions (11.0% in alicusumab vs. 8.8% in placebo).

在PT水準，阿利庫單抗組中最頻繁報告的並且與安慰劑組相比具有0.5%的發生率差異的TEAE(2%)是(以阿利庫單抗組中頻率降低的順序)：肌痛(4.4%相對1.8%)，關節痛(2.9%相對1.8%)，支氣管炎(2.6%相對0.6%)，頭暈(2.6%相對1.2%)和外周性水腫(2.0%相對0.6%)。相比之下，安慰劑組中最頻繁報告的並且與阿利庫單抗組相比具有0.5%的發生率差異的TEAE(2%)是：流感(2.3%相對2.9%)，肢體疼痛(1.7%相對2.9%)，低血糖症(1.7%相對2.4%)，咳嗽(1.5%相對2.9%)，肌肉骨骼疼痛(1.2%相對2.4%)，上呼吸道感染(0.9%相對2.4%)，高血糖症(0.9%相對2.4%)，和肺炎(0.6%相對2.4%)。 At the PT level, the most frequently reported in the aliculumab group and compared to the placebo group TEAE (0.5% incidence difference 2%) Yes (in order of decreasing frequency in the Alicuzumab group): myalgia (4.4% vs. 1.8%), arthralgia (2.9% vs. 1.8%), bronchitis (2.6% vs. 0.6%), dizziness ( 2.6% vs. 1.2%) and peripheral edema (2.0% vs. 0.6%). In contrast, it was most frequently reported in the placebo group and had TEAE (0.5% incidence difference 2%) are: influenza (2.3% vs. 2.9%), limb pain (1.7% vs. 2.9%), hypoglycemia (1.7% vs. 2.4%), cough (1.5% vs. 2.9%), musculoskeletal pain (1.2% 2.4%), upper respiratory infections (0.9% vs. 2.4%), hyperglycemia (0.9% vs. 2.4%), and pneumonia (0.6% vs. 2.4%).

總體而言，阿利庫單抗組的25名患者(7.3%)和安慰劑組的14名患者(8.2%)報告了治療緊急SAE。任何一個治療組中在多於1名患者中報告的SAE(在PT水準)為肺炎(阿利庫單抗組中的1名患者(0.3%)相對安慰劑組中的2名患者(1.2%)，椎間孔狹窄(阿利庫單抗組中的2名患者(0.6%)相對安慰劑組中無患者)，和尿道感染(2名患者(0.6%)相對安慰劑組中無患者)。在第一IMP劑量施用(第3次拜訪)後1個月，在安慰劑組的T2DM患者中報告了一例由於心肌梗塞導致的死亡。總體而言，阿利庫單抗組中的17名患者(4.9%)和安慰劑組中的4名患者(2.4%)經歷了導致永久性治療停止的TEAE。在PT水準，在治療組的多於一名患者中具有導致永久性治療停止的TEAE的患者的比例為：頭痛(阿利庫單抗組中的2名患者(0.6%)相對安慰劑組中無患者)，認知障礙(2名患者(0.6%)相對無患者)，過敏性皮炎(2名患者(0.6%)相對無患者)和肌痛(3名患者(0.9%)相對2名患者(1.2%))。 Overall, 25 patients (7.3%) in the alicuzumab group and 14 patients (8.2%) in the placebo group reported treatment for emergency SAE. SAE (at the PT level) reported in more than 1 patient in any treatment group was pneumonia (1 patient (0.3%) in the alicusumab group versus 2 patients (1.2%) in the placebo group) Foraminal stenosis (2 patients (0.6%) in the alicusumab group versus no patients in the placebo group), and urinary tract infections (2 patients (0.6%) versus no patients in the placebo group). One month after the first IMP dose (3rd visit), a death due to myocardial infarction was reported among T2DM patients in the placebo group. Overall, 17 patients (4.9 %) And 4 patients (2.4%) in the placebo group experienced a TEAE that caused a permanent discontinuation of treatment. At the PT level, more than one patient in the treatment group had a TEAE that caused a permanent discontinuation of treatment. The proportions were: headache (2 patients in the alicusumab group (0.6%) vs. no patients in the placebo group), cognitive impairment (2 patients (0.6%) vs. no patients), allergic dermatitis (2 patients (0.6%) compared with no patients) and myalgia (3 patients (0.9%) versus 2 patients (1.2%)).

關於特殊感興趣的不良事件(AESI)，符合AESI標準的ALT 的增加被定義為ALT3xULN(如果基線ALT<ULN)或ALT基線值的2倍(如果基線ALTULN)。相對安慰劑組的1名患者(0.6%)，在阿利庫單抗組的2名患者(0.6%)中報告了這些事件。 Regarding Adverse Events of Special Interest (AESI), the increase in AESI-compliant ALT is defined as ALT 3xULN (if baseline ALT <ULN) or ALT 2 times the baseline value (if baseline ALT ULN). These events were reported in 2 patients (0.6%) in the alicusumab group compared to 1 patient (0.6%) in the placebo group.

符合AESI標準的過敏性藥物反應被定義為過敏事件，其需要與另外的醫生會診以進一步評價。相對安慰劑組的4名患者(2.4%)，在阿利庫單抗組的5名患者(1.5%)中報告了這些事件。這些反應主要是皮膚和皮下組織病症，在阿利庫單抗組中的3名患者(0.9%)(1例過敏性皮炎、1例濕疹和1例光敏反應)和安慰劑組中的2名患者(1.2%)(1例皮炎、1例藥皮疹)中報告。阿利庫單抗組中的兩種其他AESI過敏性藥物反應是藥物超敏性和嗜酸性粒細胞增多。 An AESI-compliant allergic drug response is defined as an allergic event that requires consultation with another physician for further evaluation. These events were reported in 5 patients (1.5%) in the alicusumab group compared to 4 patients (2.4%) in the placebo group. These reactions were mainly skin and subcutaneous tissue disorders, with 3 patients (0.9%) in the ariculumab group (1 allergic dermatitis, 1 eczema, and 1 photosensitivity reaction) and 2 in the placebo group Reported in patients (1.2%) (1 dermatitis, 1 drug rash). The two other AESI allergic drug reactions in the alicusumab group were drug hypersensitivity and eosinophilia.

符合AESI標準的神經病學事件被定義為需要額外的檢查/程序和/或轉診給專家的神經病學事件。相對在安慰劑組的1名患者(吞咽困難)(0.6%)，在阿利庫單抗組(感覺異常)的1名患者(0.3%)中報告了這樣的事件。在T2DM患者中均報告了兩個事件。 AESI-compliant neurological events are defined as neurological events that require additional tests / procedures and / or referrals to specialists. Such an event was reported in 1 patient (0.3%) in the aliculumab group (paresthesia) compared to 1 patient (dysphagia) (0.6%) in the placebo group. Two events were reported in both T2DM patients.

所有神經認知事件都被認為是AESI。相對安慰劑組中沒有患者，在阿利庫單抗組的4名患者(1.2%)中報告了根據贊助者或FDA分組的神經認知事件。在T2DM患者中均報告了所有事件：在2名患者(0.6%)中報告了認知障礙，各在1名患者(0.3%)中報告了記憶障礙和遺忘。值得注意的是，2種認知障礙也導致永久性治療停止。 All neurocognitive events are considered AESI. Relative to no patients in the placebo group, neurocognitive events grouped by sponsor or FDA were reported in 4 patients (1.2%) in the aliculumab group. All events were reported in T2DM patients: cognitive impairment was reported in 2 patients (0.6%), and memory impairment and amnesia were reported in 1 patient (0.3%) each. It is worth noting that 2 cognitive impairments also lead to the discontinuation of permanent treatment.

符合AESI標準的局部注射部位反應被定義為過敏性的並且需要另一醫生會診的局部注射部位反應，或者被定義為具有臨床顯著性的非過敏性的局部注射部位反應(例如直徑>2.5cm的腫脹或紅斑的反應；干擾活動的反應)。相對安慰劑組的8名患者(4.7%)，在阿利庫單抗組的6名患者(1.7%)中報告了每個研究者確認的與IMP('eCRF')有關的LISR(安慰劑對阿利庫單抗的注射部位反應)。沒有報告符合AESI標準的局部注射部位反應(LISR)，其被定義為需要與另一位醫生會診以進行進一步評價的反應。 AESI-compliant local injection site reactions are defined as allergic local injection site reactions that require another doctor's consultation, or are defined as clinically significant non-allergic local injection site reactions (e.g.,> 2.5 cm diameter Swelling or erythema; reactions that interfere with activity). Relative to 8 patients (4.7%) in the placebo group, 6 (1.7%) in the aliquotumab group reported each investigator's confirmed LISR (placebo pair) related to IMP ('eCRF') Injection site response of aliculumab). No local injection site response (LISR) meeting AESI criteria has been reported, which is defined as a response that requires consultation with another doctor for further evaluation.

沒有關於有症狀的過度劑量或妊娠的報告。 There are no reports of symptomatic overdose or pregnancy.

肝功能測試(ALT、AST、ALP、總膽紅素)，CPK和腎功能測試(肌酸酐、eGFR、BUN)的分析未顯示治療組之間任何研究參數隨時間變化的差異。在研究期間，PCSA分析未鑒定任何治療組中ALT增加的PCSA。在在基線處具有正常CPK值的患者中，相對安慰劑組中的1名患者(0.6%)，在阿利庫單抗組的7名患者(2.1%)中報告了增加>3ULN(並且10ULN)。所有患者均患有T2DM。沒有報告CPK增加>10ULN。 Analysis of liver function tests (ALT, AST, ALP, total bilirubin), CPK, and renal function tests (creatinine, eGFR, BUN) did not show any changes in study parameters between treatment groups over time. During the study, PCSA analysis did not identify PCSA with increased ALT in any of the treatment groups. Among patients with normal CPK values at baseline, an increase of> 3ULN was reported in 7 patients (2.1%) in the aliculumab group relative to 1 patient (0.6%) in the placebo group (and 10ULN). All patients have T2DM. No increase in CPK was reported> 10ULN.

無論基線狀態如何，觀察到在治療期間腎小球濾過率(GFR)的輕度、中度或嚴重降低的患者的比例的數值的微小差異：GFR的輕度、中度和嚴重降低在阿利庫單抗組中分別為49.7%、28.1%和3.8%的患者，在安慰劑組中分別為50.6%、24.4%和3.6%的患者。類似地，相對安慰劑組中的5名患者(3.0%)，在阿利庫單抗組的13名(3.8%)患者中測量了血肌酐增加(30%且<100%)。沒有患者血肌酐增加>=100%。在腎功能方面沒有有意義的差異。 Regardless of baseline status, slight differences in the proportion of patients with mild, moderate, or severely reduced glomerular filtration rate (GFR) during treatment were observed: Mild, moderate, and severely reduced GFR in Alicou There were 49.7%, 28.1%, and 3.8% of patients in the monoclonal antibody group and 50.6%, 24.4%, and 3.6% of patients in the placebo group, respectively. Similarly, an increase in serum creatinine was measured in 13 (3.8%) patients in the aliculumab group relative to 5 patients (3.0%) in the placebo group ( 30% and <100%). No patient had an increase in blood creatinine> = 100%. There are no meaningful differences in renal function.

在治療組之間未觀察到生命體徵的有意義的差異。 No significant difference in vital signs was observed between the treatment groups.

實例3：來自Odyssey DM-胰島素臨床試驗的患有2型糖尿病和ASCVD的個體的分析Example 3: Analysis of individuals with type 2 diabetes and ASCVD from the Odyssey DM-insulin clinical trial

患有糖尿病的個體通常具有高水準的致動脈粥樣硬化的脂蛋白和膽固醇，其由低密度脂蛋白膽固醇(LDL-C)、非高密度脂蛋白膽固醇(非HDL-C)、載脂蛋白B(ApoB)和低密度脂蛋白顆粒數(LDL-PN)反映。動脈粥樣硬化性心血管疾病(ASCVD)的存在增加了未來心血管事件的風險。 Individuals with diabetes typically have high levels of atherogenic lipoproteins and cholesterol, which are composed of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB) and the number of low-density lipoprotein particles (LDL-PN) are reflected. The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events.

在該分析中，我們評估了阿利庫單抗在患有T2DM、高LDL-C或非HDL-C的個體中的功效和安全性，並且在DM-胰島素研究中確定了接受最大耐受的他汀類的ASCVD。患有ASCVD和T1DM的DM-胰島素研究參與者未包括在該分析中，因為該組中的低個體數量(阿利庫單抗：n=11；安慰劑：n=5)。如本實例中所使用的，ASCVD限定為冠心病(CHD；急性和無症狀性心肌梗塞(MI)和不穩定型心絞痛)、缺血性中風或外周動脈疾病。 In this analysis, we evaluated the efficacy and safety of aliculumab in individuals with T2DM, high LDL-C, or non-HDL-C, and identified statins that received maximum tolerance in the DM-insulin study ASCVD. Participants in the DM-insulin study with ASCVD and T1DM were not included in this analysis because of the low number of individuals in this group (aliculumab: n = 11; placebo: n = 5). As used in this example, ASCVD is defined as coronary heart disease (CHD; acute and asymptomatic myocardial infarction (MI) and unstable angina), ischemic stroke, or peripheral arterial disease.

根據研究分析基線和功效數據。功效分析包括非HDL-C、LDL-C、ApoB和LDL-PN的第24週從基線的百分比降低，以及在第24週達到非HDL-C<100mg/dL(<2.59mmol/L)、LDL-C<70mg/dL(<1.81mmol/L) 和ApoB<80mg/dL的個體的百分比。意向治療(ITT)分析包括具有基線LDL-C值和直至第24週的至少一個LDL-C值的所有隨機分配的個體。 Baseline and efficacy data were analyzed based on the study. Efficacy analysis included non-HDL-C, LDL-C, ApoB, and LDL-PN percentage reduction from baseline at week 24, and non-HDL-C <100mg / dL (<2.59mmol / L), LDL reached at week 24 -Percent of individuals with C <70 mg / dL (<1.81 mmol / L) and ApoB <80 mg / dL. An intention-to-treat (ITT) analysis included all randomly assigned individuals with a baseline LDL-C value and at least one LDL-C value through week 24.

該分析包括患有已確定的ASCVD和T2DM的177名DM-胰島素個體(表16)。 The analysis included 177 DM-insulin individuals with identified ASCVD and T2DM (Table 16).

^†通過侵入性/非侵入性測試進行診斷。^‡包括在抗HTN藥物治療中患有確定的HTN的患者。^§定義為估計的腎小球濾過率15-60mL/min/1.73m²。義為微量白蛋白尿、大量白蛋白尿、視網膜病變和/或CKD。^¶安慰劑組中的一個個體在隨機分配時未接受胰島素，並且在研究期間 ^† Diagnosed by invasive / non-invasive tests. ^‡ Includes patients with established HTN in anti-HTN medications. ^{§ is} defined as an estimated glomerular filtration rate of 15-60 mL / min / 1.73 m ² . Meaning microalbuminuria, massive albuminuria, retinopathy and / or CKD. ^¶ One individual in the placebo group did not receive insulin at the time of random assignment, and during the study period

保持沒有進行胰島素治療。 Keep no insulin treatment.

BMI，體重指數；DPP4，二肽基肽酶4；GLP-1，胰高血糖素樣肽1；GLT，葡萄糖降低治療；FPG，空腹血糖，HbA1c，糖化血紅蛋白；HTN，高血壓；SGLT2，鈉/葡萄糖協同轉運蛋白2。 BMI, body mass index; DPP4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; GLT, glucose reduction therapy; FPG, fasting blood glucose, HbA1c, glycated hemoglobin; HTN, hypertension; SGLT2, sodium / Glucose cotransporter 2.

無論治療分配如何，除了ASCVD之外，89.3%的被分析的個體還具有高血壓病史，28.2%還具有慢性腎病(CKD)。總共，20.3%證實了缺血性中風的病史，10.7%具有為外周動脈疾病(PAD)。無論治療分配如何，在基線處，平均(標准偏差[SD])非HDL-C水準為144.2(46.2)mg/dL[3.73(1.20)mmol/L]；平均LDL-C水準為108.7(39.1)mg/dL[2.82(1.01)mmol/L]。 Regardless of treatment assignment, in addition to ASCVD, 89.3% of the individuals analyzed had a history of hypertension and 28.2% also had chronic kidney disease (CKD). In total, 20.3% confirmed a history of ischemic stroke, and 10.7% had peripheral arterial disease (PAD). Regardless of treatment allocation, at baseline, the average (standard deviation [SD]) non-HDL-C level was 144.2 (46.2) mg / dL [3.73 (1.20) mmol / L]; the average LDL-C level was 108.7 (39.1) mg / dL [2.82 (1.01) mmol / L].

功效efficacy

相對對照組，在第24週，阿利庫單抗從基線減少非HDL-C、ApoB、LDL-PN和LDL-C(圖4)。在第24週，相對對照組，顯著更高比例的個體達到非HDL-C<100mg/dL(<2.59mmol/L)、LDL-C<70mg/dL(<1.81mmol/L)和ApoB<80mg/dL(所有P<0.0001；圖5)。 Relative to the control group, at week 24, aliculumab reduced non-HDL-C, ApoB, LDL-PN, and LDL-C from baseline (Figure 4). At week 24, a significantly higher percentage of individuals achieved non-HDL-C <100mg / dL (<2.59mmol / L), LDL-C <70mg / dL (<1.81mmol / L), and ApoB <80mg compared to the control group. / dL (all P <0.0001; Figure 5).

安全性safety

在DM-胰島素研究中接受最大耐受的他汀類的患有T2DM、高LDL-C或非HDL-C和確定的ASCVD的個體以及在DM-血脂異常(Dyslipidemia)研究中接受最大耐受的他汀類的患有T1DM或T2DM、高LD-C或非HDL-C和確定的ASCVD的個體的彙集群體中進行安全性分析(參見Chan et al.(2017)Ann Transl Med.5(23)：477，其通過引用整體併入本文)。總共，66.4%(阿利庫單抗)和67.0%(對照組)的個體報告了治療緊急不良事件(TEAE；表17)。兩組的不良事件模式相似。每個治療組在基線處(阿利庫單抗：7.3[0.9]%；對照組：7.3[0.9]%)和第24週(阿利庫單抗：7.6[1.2]%；對照組：7.5[1.2]%；安全性分析)的HbA1c平均(SD)水準相似。無論治療分配如何，在基線(阿利庫單抗：154.2[47.9]mg/dL,8.6[2.7]mmol/L；對照組：149.5[43.7]mg/dL,8.3[2.4]mmol/L)和第24週(阿利庫單抗：164.7[54.9]mg/dL,9.1[3.0]mmol/L；對照組：159.4[48.4]mg/dL,8.9[2.7]mmol/L；安全性分析)處的FPG水準也相似。 Individuals who received the most tolerated statins in the DM-insulin study with T2DM, high LDL-C or non-HDL-C and established ASCVD, and those who received the most tolerated statins in the DM-Dyslipidemia study Safety analysis in pooled populations of individuals with T1DM or T2DM, high LD-C or non-HDL-C and defined ASCVD (see Chan et al. (2017) Ann Transl Med. 5 (23): 477 , Which is incorporated herein by reference in its entirety). In total, 66.4% (aliculumab) and 67.0% (control group) of individuals reported treatment emergency adverse events (TEAE; Table 17). Adverse event patterns were similar in the two groups. Each treatment group was at baseline (aliculumab: 7.3 [0.9]%; control group: 7.3 [0.9]%) and at week 24 (aliculumab: 7.6 [1.2]%; control group: 7.5 [1.2 ]%; Safety analysis) HbA1c average (SD) levels are similar. Regardless of treatment allocation, at baseline (Aliculumab: 154.2 [47.9] mg / dL, 8.6 [2.7] mmol / L; control group: 149.5 [43.7] mg / dL, 8.3 [2.4] mmol / L) and FPG at 24 weeks (Aliculumab: 164.7 [54.9] mg / dL, 9.1 [3.0] mmol / L; control group: 159.4 [48.4] mg / dL, 8.9 [2.7] mmol / L; safety analysis) The level is similar.

結論in conclusion

在儘管使用最大耐受的他汀類仍具有高LDL-C水準的患有T2DM和ASCVD的個體中，相對對照組，阿利庫單抗顯著降低致動脈粥樣硬化的膽固醇的含量和LDL-PN。 In individuals with T2DM and ASCVD who have high LDL-C levels despite the use of the most tolerated statins, aliculumab significantly reduces atherogenic cholesterol and LDL-PN compared to the control group.

<110> 法商賽諾菲生物技術公司 <110> French business Sanofi biotechnology company

<120> 藉由投予PCSK9抑制劑治療糖尿病患者高脂血症之方法 <120> Method for treating hyperlipidemia in diabetic patients by administering PCSK9 inhibitor

<130> 602480：SA9-208TW <130> 602480: SA9-208TW

<150> US 62/517,672 <150> US 62 / 517,672

<151> 2017-06-09 <151> 2017-06-09

<150> US 62/532,162 <150> US 62 / 532,162

<151> 2017-07-13 <151> 2017-07-13

<150> EP 18305565.6 <150> EP 18305565.6

<151> 2018-05-04 <151> 2018-05-04

<160> 198 <160> 198

<170> PatentIn version 3.5 <170> PatentIn version 3.5

<210> 1 <210> 1

<211> 118 <211> 118

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成多肽 <223> Description of artificial sequence: synthetic peptide

<400> 1 <400> 1

<210> 2 <210> 2

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成肽 <223> Description of artificial sequence: synthetic peptide

<400> 2 <400> 2

<210> 3 <210> 3

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 3 <400> 3

<210> 4 <210> 4

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 4 <400> 4

<210> 5 <210> 5

<211> 447 <211> 447

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的REGN727重鏈多肽 <223> Description of artificial sequence: synthetic REGN727 heavy chain polypeptide

<400> 5 <400> 5

<210> 6 <210> 6

<211> 113 <211> 113

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 6 <400> 6

<210> 7 <210> 7

<211> 12 <211> 12

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 7 <400> 7

<210> 8 <210> 8

<211> 3 <211> 3

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 8 <400> 8

<210> 9 <210> 9

<211> 220 <211> 220

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的REGN727輕鏈多肽 <223> Description of artificial sequence: synthetic REGN727 light chain polypeptide

<400> 9 <400> 9

<210> 10 <210> 10

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 10 <400> 10

<210> 11 <210> 11

<211> 127 <211> 127

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 11 <400> 11

<210> 12 <210> 12

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 12 <400> 12

<210> 13 <210> 13

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 13 <400> 13

<210> 14 <210> 14

<211> 20 <211> 20

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 14 <400> 14

<210> 15 <210> 15

<211> 112 <211> 112

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 15 <400> 15

<210> 16 <210> 16

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 16 <400> 16

<210> 17 <210> 17

<211> 3 <211> 3

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 17 <400> 17

<210> 18 <210> 18

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 18 <400> 18

<210> 19 <210> 19

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 19 <400> 19

<210> 20 <210> 20

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 20 <400> 20

<210> 21 <210> 21

<211> 20 <211> 20

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 21 <400> 21

<210> 22 <210> 22

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 22 <400> 22

<210> 23 <210> 23

<211> 3 <211> 3

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 23 <400> 23

<210> 24 <210> 24

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 24 <400> 24

<210> 25 <210> 25

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 25 <400> 25

<210> 26 <210> 26

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 26 <400> 26

<210> 27 <210> 27

<211> 20 <211> 20

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 27 <400> 27

<210> 28 <210> 28

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 28 <400> 28

<210> 29 <210> 29

<211> 3 <211> 3

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 29 <400> 29

<210> 30 <210> 30

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 30 <400> 30

<210> 31 <210> 31

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 31 <400> 31

<210> 32 <210> 32

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 32 <400> 32

<210> 33 <210> 33

<211> 20 <211> 20

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 33 <400> 33

<210> 34 <210> 34

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 34 <400> 34

<210> 35 <210> 35

<211> 3 <211> 3

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 35 <400> 35

<210> 36 <210> 36

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 36 <400> 36

<210> 37 <210> 37

<211> 131 <211> 131

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VH；m2CX1D05多肽 <223> Description of artificial sequence: synthetic VH; m2CX1D05 polypeptide

<400> 37 <400> 37

<210> 38 <210> 38

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VH CDR1；m2CX1D05肽 <223> Description of artificial sequence: synthetic VH CDR1; m2CX1D05 peptide

<400> 38 <400> 38

<210> 39 <210> 39

<211> 20 <211> 20

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成VH CDR2；m2CX1D05肽 <223> Description of artificial sequence: synthetic VH CDR2; m2CX1D05 peptide

<400> 39 <400> 39

<210> 40 <210> 40

<211> 22 <211> 22

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VH CDR3；m2CX1D05肽 <223> Description of artificial sequence: synthetic VH CDR3; m2CX1D05 peptide

<400> 40 <400> 40

<210> 41 <210> 41

<211> 213 <211> 213

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的LC；m2CX1D05多肽 <223> Description of artificial sequence: synthetic LC; m2CX1D05 polypeptide

<400> 41 <400> 41

<210> 42 <210> 42

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VL CDR 1；m2CX1D05肽 <223> Description of artificial sequence: synthetic VL CDR 1; m2CX1D05 peptide

<400> 42 <400> 42

<210> 43 <210> 43

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VL CDR2；m2CX1D05肽 <223> Description of artificial sequence: synthetic VL CDR2; m2CX1D05 peptide

<400> 43 <400> 43

<210> 44 <210> 44

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VL CDR3；m2CX1D05肽 <223> Description of artificial sequence: synthetic VL CDR3; m2CX1D05 peptide

<400> 44 <400> 44

<210> 45 <210> 45

<211> 119 <211> 119

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VH；1B20多肽 <223> Description of artificial sequence: synthetic VH; 1B20 polypeptide

<400> 45 <400> 45

<210> 46 <210> 46

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VH CDR1；1B20肽 <223> Description of artificial sequence: synthetic VH CDR1; 1B20 peptide

<400> 46 <400> 46

<210> 47 <210> 47

<211> 20 <211> 20

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VH CDR2；1B20肽 <223> Description of artificial sequence: synthetic VH CDR2; 1B20 peptide

<400> 47 <400> 47

<210> 48 <210> 48

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VH CDR3；1B20肽 <223> Description of artificial sequence: synthetic VH CDR3; 1B20 peptide

<400> 48 <400> 48

<210> 49 <210> 49

<211> 220 <211> 220

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的LC；1B20多肽 <223> Description of artificial sequence: synthetic LC; 1B20 polypeptide

<400> 49 <400> 49

<210> 50 <210> 50

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VL CDR1；1B20肽 <223> Description of artificial sequence: synthetic VL CDR1; 1B20 peptide

<400> 50 <400> 50

<210> 51 <210> 51

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VL CDR2；1B20肽 <223> Description of artificial sequence: synthetic VL CDR2; 1B20 peptide

<400> 51 <400> 51

<210> 52 <210> 52

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的VL CDR3；1B20肽 <223> Description of artificial sequence: synthetic VL CDR3; 1B20 peptide

<400> 52 <400> 52

<210> 53 <210> 53

<211> 120 <211> 120

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的可變重抗體區多肽 <223> Description of artificial sequence: synthetic variable heavy antibody region polypeptide

<400> 53 <400> 53

<210> 54 <210> 54

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成AX132重鏈CDR1抗體區肽 <223> Description of artificial sequence: Synthesis of AX132 heavy chain CDR1 antibody region peptide

<400> 54 <400> 54

<210> 55 <210> 55

<211> 23 <211> 23

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX132重鏈CDR2抗體區肽 <223> Description of artificial sequence: synthetic AX132 heavy chain CDR2 antibody region peptide

<400> 55 <400> 55

<210> 56 <210> 56

<211> 15 <211> 15

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX132重鏈CDR3抗體區肽 <223> Description of artificial sequence: synthetic AX132 heavy chain CDR3 antibody region peptide

<400> 56 <400> 56

<210> 57 <210> 57

<211> 108 <211> 108

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的可變輕抗體區多肽 <223> Description of artificial sequence: synthetic variable light antibody region polypeptide

<400> 57 <400> 57

<210> 58 <210> 58

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX213和AX132輕鏈CDR1抗體區肽 <223> Description of artificial sequence: synthetic AX213 and AX132 light chain CDR1 antibody region peptides

<400> 58 <400> 58

<210> 59 <210> 59

<211> 13 <211> 13

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX213和AX132輕鏈CDR2抗體區肽 <223> Description of artificial sequence: synthetic AX213 and AX132 light chain CDR2 antibody region peptides

<400> 59 <400> 59

<210> 60 <210> 60

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX132和AX213輕鏈CDR3抗體區肽 <223> Description of artificial sequence: synthetic AX132 and AX213 light chain CDR3 antibody region peptides

<400> 60 <400> 60

<210> 61 <210> 61

<211> 120 <211> 120

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 61 <400> 61

<210> 62 <210> 62

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX213重鏈CDR1抗體區肽 <223> Description of artificial sequence: synthetic AX213 heavy chain CDR1 antibody region peptide

<400> 62 <400> 62

<210> 63 <210> 63

<211> 23 <211> 23

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX213重鏈CDR2抗體區肽 <223> Description of artificial sequence: synthetic AX213 heavy chain CDR2 antibody region peptide

<400> 63 <400> 63

<210> 64 <210> 64

<211> 15 <211> 15

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX213重鏈CDR3抗體區肽 <223> Description of artificial sequence: synthetic AX213 heavy chain CDR3 antibody region peptide

<400> 64 <400> 64

<210> 65 <210> 65

<211> 108 <211> 108

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 65 <400> 65

<210> 66 <210> 66

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 66 <400> 66

<210> 67 <210> 67

<211> 13 <211> 13

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 67 <400> 67

<210> 68 <210> 68

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 68 <400> 68

<210> 69 <210> 69

<211> 119 <211> 119

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX1 VH抗體序列多肽 <223> Description of artificial sequence: synthetic AX1 VH antibody sequence polypeptide

<400> 69 <400> 69

<210> 70 <210> 70

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX1 VH CDR1抗體序列肽 <223> Description of the artificial sequence: synthetic AX1 VH CDR1 antibody sequence peptide

<400> 70 <400> 70

<210> 71 <210> 71

<211> 23 <211> 23

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX1 VH CDR2抗體序列肽 <223> Description of artificial sequence: synthetic AX1 VH CDR2 antibody sequence peptide

<400> 71 <400> 71

<210> 72 <210> 72

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX1 VH CDR3抗體序列肽 <223> Description of the artificial sequence: synthetic AX1 VH CDR3 antibody sequence peptide

<400> 72 <400> 72

<210> 73 <210> 73

<211> 109 <211> 109

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX1 VL抗體序列多肽 <223> Description of artificial sequence: synthetic AX1 VL antibody sequence polypeptide

<400> 73 <400> 73

<210> 74 <210> 74

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX1 VL CDR1抗體序列肽 <223> Description of artificial sequence: synthetic AX1 VL CDR1 antibody sequence peptide

<400> 74 <400> 74

<210> 75 <210> 75

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX1 AX9 AX189 VL CDR2抗體序列肽 <223> Description of artificial sequence: synthetic AX1 AX9 AX189 VL CDR2 antibody sequence peptide

<400> 75 <400> 75

<210> 76 <210> 76

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX1 VL CDR3抗體序列肽 <223> Description of the artificial sequence: synthetic AX1 VL CDR3 antibody sequence peptide

<400> 76 <400> 76

<210> 77 <210> 77

<211> 121 <211> 121

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX9 AX189 VH抗體序列多肽 <223> Description of artificial sequence: synthetic AX9 AX189 VH antibody sequence polypeptide

<400> 77 <400> 77

<210> 78 <210> 78

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX9 AX189 VH CDR1抗體序列肽 <223> Description of the artificial sequence: synthetic AX9 AX189 VH CDR1 antibody sequence peptide

<400> 78 <400> 78

<210> 79 <210> 79

<211> 23 <211> 23

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX9 AX189 VH CDR2抗體序列肽 <223> Description of the artificial sequence: synthetic AX9 AX189 VH CDR2 antibody sequence peptide

<400> 79 <400> 79

<210> 80 <210> 80

<211> 18 <211> 18

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX9 AX189 VH CDR3抗體序列肽 <223> Description of the artificial sequence: synthetic AX9 AX189 VH CDR3 antibody sequence peptide

<400> 80 <400> 80

<210> 81 <210> 81

<211> 109 <211> 109

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX189 VL抗體序列多肽 <223> Description of artificial sequence: synthetic AX189 VL antibody sequence polypeptide

<400> 81 <400> 81

<210> 82 <210> 82

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX189 VL CDR1抗體序列肽 <223> Description of the artificial sequence: synthetic AX189 VL CDR1 antibody sequence peptide

<400> 82 <400> 82

<210> 83 <210> 83

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 83 <400> 83

<210> 84 <210> 84

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的AX189 VL CDR3抗體序列肽 <223> Description of artificial sequence: synthetic AX189 VL CDR3 antibody sequence peptide

<400> 84 <400> 84

<210> 85 <210> 85

<211> 115 <211> 115

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 85 <400> 85

<210> 86 <210> 86

<211> 5 <211> 5

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 86 <400> 86

<210> 87 <210> 87

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 87 <400> 87

<210> 88 <210> 88

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 88 <400> 88

<210> 89 <210> 89

<211> 109 <211> 109

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 89 <400> 89

<210> 90 <210> 90

<211> 14 <211> 14

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 90 <400> 90

<210> 91 <210> 91

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 91 <400> 91

<210> 92 <210> 92

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 92 <400> 92

<210> 93 <210> 93

<211> 123 <211> 123

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 93 <400> 93

<210> 94 <210> 94

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 94 <400> 94

<210> 95 <210> 95

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 95 <400> 95

<210> 96 <210> 96

<211> 14 <211> 14

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 96 <400> 96

<210> 97 <210> 97

<211> 111 <211> 111

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 97 <400> 97

<210> 98 <210> 98

<211> 14 <211> 14

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 98 <400> 98

<210> 99 <210> 99

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 99 <400> 99

<210> 100 <210> 100

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 100 <400> 100

<210> 101 <210> 101

<211> 114 <211> 114

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 101 <400> 101

<210> 102 <210> 102

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 102 <400> 102

<210> 103 <210> 103

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 103 <400> 103

<210> 104 <210> 104

<211> 5 <211> 5

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 104 <400> 104

<210> 105 <210> 105

<211> 113 <211> 113

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 105 <400> 105

<210> 106 <210> 106

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 106 <400> 106

<210> 107 <210> 107

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 107 <400> 107

<210> 108 <210> 108

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 108 <400> 108

<210> 109 <210> 109

<211> 118 <211> 118

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的抗PCSK9單克隆抗體pJG04(克隆LGT-209和LGT-210)Vh重鏈可變區(FR1-FR4)多肽 <223> Description of artificial sequence: synthetic anti-PCSK9 monoclonal antibody pJG04 (clones LGT-209 and LGT-210) Vh heavy chain variable region (FR1-FR4) polypeptide

<400> 109 <400> 109

<210> 110 <210> 110

<211> 5 <211> 5

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的抗PCSK9單克隆抗體克隆LGT-209,LGT-210和LGT-211重鏈CDR1肽 <223> Description of artificial sequence: synthetic anti-PCSK9 monoclonal antibody clones LGT-209, LGT-210 and LGT-211 heavy chain CDR1 peptides

<400> 110 <400> 110

<210> 111 <210> 111

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的抗PCSK9單克隆抗體克隆LGT-209,LGT-210和LGT-211重鏈CDR2肽 <223> Description of artificial sequence: synthetic anti-PCSK9 monoclonal antibody clones LGT-209, LGT-210 and LGT-211 heavy chain CDR2 peptides

<400> 111 <400> 111

<210> 112 <210> 112

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的抗PCSK9單克隆抗體pJG04(克隆LGT-209和LGT-210)Vh重鏈互補決定區3(CDR3)肽 <223> Description of artificial sequence: synthetic anti-PCSK9 monoclonal antibody pJG04 (clones LGT-209 and LGT-210) Vh heavy chain complementarity determining region 3 (CDR3) peptide

<400> 112 <400> 112

<210> 113 <210> 113

<211> 106 <211> 106

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的抗PCSK9單克隆抗體pJG10(克隆LGT-209和LGT-211)Vk輕鏈可變區(FR1-FR4)多肽 <223> Description of artificial sequence: synthetic anti-PCSK9 monoclonal antibody pJG10 (clones LGT-209 and LGT-211) Vk light chain variable region (FR1-FR4) polypeptide

<400> 113 <400> 113

<210> 114 <210> 114

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的抗PCSK9單克隆抗體克隆LGT-209,LGT-210和LGT-211輕鏈CDR1肽 <223> Description of artificial sequence: synthetic anti-PCSK9 monoclonal antibody clones LGT-209, LGT-210 and LGT-211 light chain CDR1 peptide

<400> 114 <400> 114

<210> 115 <210> 115

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 115 <400> 115

<210> 116 <210> 116

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的小鼠抗PCSK9單克隆抗體LFU720和抗PCSK9單克隆抗體克隆LGT-209,LGT-210和LGT-211輕鏈CDR3肽 <223> Description of artificial sequence: synthetic mouse anti-PCSK9 monoclonal antibody LFU720 and anti-PCSK9 monoclonal antibody clones LGT-209, LGT-210 and LGT-211 light chain CDR3 peptides

<400> 116 <400> 116

<210> 117 <210> 117

<211> 118 <211> 118

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 117 <400> 117

<210> 118 <210> 118

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 118 <400> 118

<210> 119 <210> 119

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 119 <400> 119

<210> 120 <210> 120

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的可變重鏈CDR肽 <223> Description of artificial sequence: synthetic variable heavy chain CDR peptide

<400> 120 <400> 120

<210> 121 <210> 121

<211> 107 <211> 107

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 121 <400> 121

<210> 122 <210> 122

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成的可變輕鏈CDR肽 <223> Description of artificial sequence: synthetic variable light chain CDR peptide

<400> 122 <400> 122

<210> 123 <210> 123

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 123 <400> 123

<210> 124 <210> 124

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 124 <400> 124

<210> 125 <210> 125

<211> 118 <211> 118

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 125 <400> 125

<210> 126 <210> 126

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 126 <400> 126

<210> 127 <210> 127

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 127 <400> 127

<210> 128 <210> 128

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 128 <400> 128

<210> 129 <210> 129

<211> 107 <211> 107

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 129 <400> 129

<210> 130 <210> 130

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 130 <400> 130

<210> 131 <210> 131

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 131 <400> 131

<210> 132 <210> 132

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 132 <400> 132

<210> 133 <210> 133

<211> 118 <211> 118

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 133 <400> 133

<210> 134 <210> 134

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 134 <400> 134

<210> 135 <210> 135

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 135 <400> 135

<210> 136 <210> 136

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 136 <400> 136

<210> 137 <210> 137

<211> 107 <211> 107

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 137 <400> 137

<210> 138 <210> 138

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 138 <400> 138

<210> 139 <210> 139

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 139 <400> 139

<210> 140 <210> 140

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 140 <400> 140

<210> 141 <210> 141

<211> 118 <211> 118

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 141 <400> 141

<210> 142 <210> 142

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 142 <400> 142

<210> 143 <210> 143

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 143 <400> 143

<210> 144 <210> 144

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 144 <400> 144

<210> 145 <210> 145

<211> 108 <211> 108

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 145 <400> 145

<210> 146 <210> 146

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 146 <400> 146

<210> 147 <210> 147

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 147 <400> 147

<210> 148 <210> 148

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 148 <400> 148

<210> 149 <210> 149

<211> 115 <211> 115

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 149 <400> 149

<210> 150 <210> 150

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 150 <400> 150

<210> 151 <210> 151

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 151 <400> 151

<210> 152 <210> 152

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 152 <400> 152

<210> 153 <210> 153

<211> 108 <211> 108

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 153 <400> 153

<210> 154 <210> 154

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 154 <400> 154

<210> 155 <210> 155

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 155 <400> 155

<210> 156 <210> 156

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 156 <400> 156

<210> 157 <210> 157

<211> 123 <211> 123

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 157 <400> 157

<210> 158 <210> 158

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 158 <400> 158

<210> 159 <210> 159

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 159 <400> 159

<210> 160 <210> 160

<211> 14 <211> 14

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 160 <400> 160

<210> 161 <210> 161

<211> 107 <211> 107

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 161 <400> 161

<210> 162 <210> 162

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 162 <400> 162

<210> 163 <210> 163

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 163 <400> 163

<210> 164 <210> 164

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 164 <400> 164

<210> 165 <210> 165

<211> 117 <211> 117

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 165 <400> 165

<210> 166 <210> 166

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 166 <400> 166

<210> 167 <210> 167

<211> 6 <211> 6

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 167 <400> 167

<210> 168 <210> 168

<211> 8 <211> 8

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 168 <400> 168

<210> 169 <210> 169

<211> 108 <211> 108

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 169 <400> 169

<210> 170 <210> 170

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 170 <400> 170

<210> 171 <210> 171

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 人工序列的描述：合成可變輕鏈CDR肽 <223> Description of artificial sequence: Synthesis of variable light chain CDR peptides

<400> 171 <400> 171

<210> 172 <210> 172

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 小家鼠 <213> Mus musculus

<400> 172 <400> 172

<210> 173 <210> 173

<211> 121 <211> 121

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 173 <400> 173

<210> 174 <210> 174

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 174 <400> 174

<210> 175 <210> 175

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 175 <400> 175

<210> 176 <210> 176

<211> 12 <211> 12

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 176 <400> 176

<210> 177 <210> 177

<211> 108 <211> 108

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 177 <400> 177

<210> 178 <210> 178

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 178 <400> 178

<210> 179 <210> 179

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 179 <400> 179

<210> 180 <210> 180

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 180 <400> 180

<210> 181 <210> 181

<211> 121 <211> 121

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 181 <400> 181

<210> 182 <210> 182

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 182 <400> 182

<210> 183 <210> 183

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 183 <400> 183

<210> 184 <210> 184

<211> 12 <211> 12

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 184 <400> 184

<210> 185 <210> 185

<211> 108 <211> 108

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 185 <400> 185

<210> 186 <210> 186

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 186 <400> 186

<210> 187 <210> 187

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 187 <400> 187

<210> 188 <210> 188

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 188 <400> 188

<210> 189 <210> 189

<211> 125 <211> 125

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 189 <400> 189

<210> 190 <210> 190

<211> 10 <211> 10

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 190 <400> 190

<210> 191 <210> 191

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 191 <400> 191

<210> 192 <210> 192

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 192 <400> 192

<210> 193 <210> 193

<211> 112 <211> 112

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 193 <400> 193

<210> 194 <210> 194

<211> 16 <211> 16

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 194 <400> 194

<210> 195 <210> 195

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 195 <400> 195

<210> 196 <210> 196

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<400> 196 <400> 196

<210> 197 <210> 197

<211> 2076 <211> 2076

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 197 <400> 197

<210> 198 <210> 198

<211> 692 <211> 692

<212> PRT <212> PRT

<213> 智人 <213> Homo sapiens

<400> 198 <400> 198

Claims

一種用於治療患有1型糖尿病(T1DM)的患者中高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，該患者患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 A method for treating hypercholesterolemia in a patient with type 1 diabetes (T1DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, the patient having (i) T1DM, and ( ii) treatment of insufficiently controlled hypercholesterolemia with maximally tolerated statins; and (b) administering to the patient 75 mg, 150 mg, or 300 mg of a specific binding human preprotein converting enzyme subtilin / kexin type 9 (PCSK9 ) Antibody or antigen-binding fragment thereof, wherein the patient is receiving concomitant insulin therapy.

如請求項1的方法，其中每兩週向該患者施用75mg的該抗體或抗原結合片段。 The method of claim 1, wherein the patient is administered 75 mg of the antibody or antigen-binding fragment every two weeks.

如請求項1的方法，其中每兩週向該患者施用150mg的該抗體或抗原結合片段。 The method of claim 1, wherein the patient is administered 150 mg of the antibody or antigen-binding fragment every two weeks.

如請求項1的方法，其中每四週向該患者施用300mg的該抗體或抗原結合片段。 The method of claim 1, wherein the patient is administered 300 mg of the antibody or antigen-binding fragment every four weeks.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段包含SEQ ID NO：2、3和4中示出的三個重鏈CDR，和SEQ ID NO：7、8和10中示出的三個輕鏈CDR。 The method of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs shown in SEQ ID NOs: 2, 3, and 4, and SEQ ID NOs: 7, 8, and 10 Three light chain CDRs are shown.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的重鏈可變區(HCVR)，和具有SEQ ID NO：6的胺基酸序列的輕鏈可變區(LCVR)。 The method of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1, and an amine having SEQ ID NO: 6 Light chain variable region (LCVR) of the amino acid sequence.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段選自以下組成之群組：阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab和LY3015014。 The method of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of: alicusimab, evocutumab, bococizumab, rodecizumab, ralpancizumab, and LY3015014.

如請求項7的方法，其中該抗體或其抗原結合片段是阿利庫單抗。 The method of claim 7, wherein the antibody or antigen-binding fragment thereof is aliculumab.

如前述請求項中任一項的方法，其進一步包括：(c)如果該患者中的LDL-C水準低於閾值水準，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 The method of any one of the preceding claims, further comprising: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses of 75 mg to the patient approximately every two weeks The antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

如前述請求項中任一項的方法，其進一步包括：(c)如果該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 The method of any one of the preceding claims, further comprising: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses of 300 mg of the patient to the patient approximately every four weeks The antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

如請求項9或10的方法，其中該閾值水準是70mg/dL。 The method of claim 9 or 10, wherein the threshold level is 70 mg / dL.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段皮下施用。 The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

如前述請求項中任一項的方法，其中該患者進一步接受伴隨脂質修飾治療(LMT)。 The method of any of the preceding claims, wherein the patient further receives concomitant lipid modification therapy (LMT).

如請求項13的方法，其中該LMT選自以下組成之群組：他汀類、膽固醇吸收抑制劑、纖維酸類、菸鹼酸類、ω-3脂肪酸和膽汁酸螯合劑。 The method of claim 13, wherein the LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibric acid, a nicotinic acid, an omega-3 fatty acid, and a bile acid chelator.

如請求項14的方法，其中該LMT是他汀類治療。 The method of claim 14, wherein the LMT is a statin therapy.

如請求項15的方法，其中該他汀類選自以下組成之群組：阿托伐他汀、瑞舒伐他汀、辛伐他汀、普伐他汀、洛伐他汀、氟伐他汀、匹伐他汀和西立伐他汀。 The method of claim 15, wherein the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and western Livastatin.

如請求項14-16中任一項的方法，其中該他汀類治療是最大耐受的他汀類治療。 The method of any of claims 14-16, wherein the statin treatment is a statin treatment that is most tolerated.

如請求項14的方法，其中該膽固醇吸收抑制劑是依折麥布。 The method of claim 14, wherein the cholesterol absorption inhibitor is ezetimibe.

如請求項1-14和18中任一項的方法，其中該患者對他汀類不耐受。 The method of any of claims 1-14 and 18, wherein the patient is intolerant to statins.

如前述請求項中任一項的方法，其中該胰島素治療選自以下組成之群組：人胰島素、甘精胰島素、谷賴胰島素、地特胰島素、賴脯胰島素、德穀胰島素、門冬胰島素和基礎胰島素。 The method of any one of the preceding claims, wherein the insulin treatment is selected from the group consisting of: human insulin, insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin deguer, insulin aspart, and Basal insulin.

如前述請求項中任一項的方法，其中該患者除胰島素治療之外還接受伴隨抗糖尿病治療。 The method of any of the preceding claims, wherein the patient receives concomitant anti-diabetic therapy in addition to insulin therapy.

如請求項21的方法，其中該另外的伴隨抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油O-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 The method of claim 21, wherein the additional concomitant anti-diabetic treatment is selected from the group consisting of glucagon-like peptide 1 (GLP-1) therapy, a gastrointestinal peptide, a glucagon receptor agonist, or Antagonists, glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone-releasing hormone antagonists or inverse agonists, xenin, xenin analogs, biguanides, sulfonylureas, mag Lenais, thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, peroxisomes Proliferator-activated receptor (PPAR-) (α, γ, or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) agonist, GPR40 Agonists, GPR120 agonists, GPR142 agonists, systemic or low-absorption TGR5 agonists, diabetes immunotherapy, anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, adenosine monophosphate-activated protein kinase ( AMPK) stimulant, inhibitor of 11-β-hydroxysteroid dehydrogenase 1, glucokinase activator, diglycerol O- Inhibitors of fluorenyltransferase (DGAT), modulators of glucose transporter-4, somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段將該患者的LDL-C水準降低至少40%。 The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof reduces the patient's LDL-C level by at least 40%.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段將該患者的非HDL-C水準降低至少35%。 The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof reduces the patient's non-HDL-C level by at least 35%.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段降低該患者的載脂蛋白C3(ApoC3)水準。 The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof reduces the apolipoprotein C3 (ApoC3) level of the patient.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段減少該患者中的脂蛋白顆粒的數量和/或尺寸。 The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof reduces the number and / or size of lipoprotein particles in the patient.

如前述請求項中任一項的方法，其中該抗體或其抗原結合片段：(a)不影響該患者的血紅蛋白A1c(HbA1c)水準；和/或(b)不影響該患者的空腹血糖(FPG)水準。 The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof: (a) does not affect the patient's hemoglobin A1c (HbA1c) level; and / or (b) does not affect the patient's fasting blood glucose (FPG) )level.

一種用於治療患有1型糖尿病(T1DM)的患者中高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，該患者患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和 (c)如果該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列LCVR，並且其中該患者接受伴隨胰島素治療。 A method for treating hypercholesterolemia in a patient with type 1 diabetes (T1DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, the patient having (i) T1DM, and ( ii) treatment of inadequately controlled hypercholesterolemia with the most tolerated statins; and (b) administering to the patient 75 mg of bispecific human proprotein-converting enzyme subtilin / kexin type 9 (PCSK9) every two weeks The antibody or antigen-binding fragment thereof; and (c) if the LDL-C level in the patient is below 70 mg / dL, the patient is administered one or more of the following doses of 75 mg of the antibody or antigen thereof approximately every two weeks A binding fragment, or if the LDL-C level in the patient is greater than or equal to 70 mg / dL, about one or more of the following dose of 150 mg of the antibody or antigen-binding fragment thereof is administered, wherein the antibody or antigen-binding fragment thereof The fragment comprises an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6, and wherein the patient is receiving concomitant insulin therapy.

一種用於治療患有2型糖尿病(T2DM)的患者中的高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，該患者患有(i)T1DM，和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 A method for treating hypercholesterolemia in a patient with type 2 diabetes (T2DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, the patient having (i) T1DM, And (ii) treatment of insufficiently controlled hypercholesterolemia with maximally tolerated statins; and (b) administering to the patient 75 mg, 150 mg, or 300 mg of a specific binding human preprotein converting enzyme subtilin / kexin type 9 (PCSK9) an antibody or antigen-binding fragment thereof, wherein the patient is receiving concomitant insulin therapy.

如請求項29的方法，其中每兩週向該患者施用75mg的該抗體或抗原結合片段。 The method of claim 29, wherein the patient is administered 75 mg of the antibody or antigen-binding fragment every two weeks.

如請求項29的方法，其中每兩週向該患者施用150mg的該抗體或抗原結合片段。 The method of claim 29, wherein the patient is administered 150 mg of the antibody or antigen-binding fragment every two weeks.

如請求項29的方法，其中每四週向該患者施用300mg的該抗體或抗原結合片段。 The method of claim 29, wherein the patient is administered 300 mg of the antibody or antigen-binding fragment every four weeks.

如請求項29-32中任一項的方法，其中該抗體或其抗原結合片段包含SEQ ID NO：2、3和4中示出的三個重鏈CDR和SEQ ID NO：7、8和10中示出的三個輕鏈CDR。 The method of any one of claims 29-32, wherein the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs shown in SEQ ID NOs: 2, 3, and 4 and SEQ ID NOs: 7, 8, and 10 Three light chain CDRs are shown in.

如請求項29-33中任一項的方法，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的重鏈可變區(HCVR)和具有SEQ ID NO：6的胺基酸序列的輕鏈可變區(LCVR)。 The method of any one of claims 29-33, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1 and a polypeptide having SEQ ID NO: 6 Light chain variable region (LCVR) of an amino acid sequence.

如請求項29-32中任一項的方法，其中該抗體或其抗原結合片段選自以下組成之群組：阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab和LY3015014。 The method of any one of claims 29-32, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of: alicusimab, evocutumab, bococizumab, rodecizumab, ralpancizumab and LY3015014 .

如請求項35的方法，其中該抗體或其抗原結合片段是阿利庫單抗。 The method of claim 35, wherein the antibody or antigen-binding fragment thereof is aliculumab.

如請求項29-36中任一項的方法，其進一步包括：(c)如果該患者中的LDL-C水準低於閾值水準，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 The method of any one of claims 29-36, further comprising: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses to the patient approximately every two weeks 75 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

如請求項29-36中任一項的方法，其進一步包括：(c)如果該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 The method of any one of claims 29-36, further comprising: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses of 300 mg to the patient approximately every four weeks The antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

如請求項37或38的方法，其中該閾值水準是70mg/dL。 The method of claim 37 or 38, wherein the threshold level is 70 mg / dL.

如請求項29-39中任一項的方法，其中該抗體或其抗原結合片段皮下施用。 The method of any one of claims 29-39, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

如請求項29-40中任一項的方法，其中該患者進一步接受伴隨脂質修飾治療(LMT)。 The method of any one of claims 29-40, wherein the patient further receives concomitant lipid modification therapy (LMT).

如請求項41的方法，其中該LMT選自以下組成之群組：他汀類、膽固醇吸收抑制劑、纖維酸類、菸鹼酸類、ω-3脂肪酸和膽汁酸螯合劑。 The method of claim 41, wherein the LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibric acid, a nicotinic acid, an omega-3 fatty acid, and a bile acid chelator.

如請求項42的方法，其中該LMT是他汀類治療。 The method of claim 42, wherein the LMT is a statin therapy.

如請求項43的方法，其中該他汀類選自以下組成之群組：阿托伐他汀、瑞舒伐他汀、辛伐他汀、普伐他汀、洛伐他汀、氟伐他汀、匹伐他汀和西立伐他汀。 The method of claim 43, wherein the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and westvat Livastatin.

如請求項42-44中任一項的方法，其中該他汀類治療是最大耐受劑量的他汀類治療。 The method of any of claims 42-44, wherein the statin therapy is a statin therapy at a maximum tolerated dose.

如請求項42的方法，其中該膽固醇吸收抑制劑是依折麥布。 The method of claim 42, wherein the cholesterol absorption inhibitor is ezetimibe.

如請求項29-42和46中任一項的方法，其中該患者對他汀類不耐受。 The method of any of claims 29-42 and 46, wherein the patient is intolerant to statins.

如請求項29-47中任一項的方法，其中該胰島素治療選自以下組成之群組：人胰島素、甘精胰島素、谷賴胰島素、地特胰島素、賴脯胰島素、德穀胰島素、門冬胰島素和基礎胰島素。 The method of any one of claims 29-47, wherein the insulin treatment is selected from the group consisting of: human insulin, insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin deguera, aspart Insulin and basal insulin.

如請求項29-48中任一項的方法，其中該患者除胰島素治療之外還接受伴隨抗糖尿病治療。 The method of any of claims 29-48, wherein the patient receives concomitant anti-diabetic therapy in addition to insulin therapy.

如請求項49的方法，其中該另外的抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油O-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 The method of claim 49, wherein the additional anti-diabetic treatment is selected from the group consisting of glucagon-like peptide 1 (GLP-1) therapy, a gastrointestinal peptide, a glucagon receptor agonist, or an antagonist Agents, glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone releasing hormone antagonists or inverse agonists, xenin, xenin analogs, biguanides, sulfonylureas, meglitazone Nai, thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, peroxisome proliferation Activator or receptor (PPAR-) (α, γ or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) agonist, GPR40 Agents, GPR120 agonists, GPR142 agonists, systemic or low-absorption TGR5 agonists, diabetes immunotherapy, anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, adenosine monophosphate-activated protein kinase (AMPK ) Stimulant, inhibitor of 11-β-hydroxysteroid dehydrogenase 1, glucokinase activator, diglycerol O-fluorenyl Shift enzyme (the DGAT) inhibitor, glucose transporter-4 modulators of somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

如請求項29-50中任一項的方法，其中該抗體或其抗原結合片段將該患者的LDL-C水準降低至少40%。 The method of any one of claims 29-50, wherein the antibody or antigen-binding fragment thereof reduces the patient's LDL-C level by at least 40%.

如請求項29-51中任一項的方法，其中該抗體或其抗原結合片段將該患者的非HDL-C水準降低至少35%。 The method of any one of claims 29-51, wherein the antibody or antigen-binding fragment thereof reduces the patient's non-HDL-C level by at least 35%.

如請求項29-52中任一項的方法，其中該抗體或其抗原結合片段降低該患者的ApoC3水準。 The method of any one of claims 29-52, wherein the antibody or antigen-binding fragment thereof reduces the ApoC3 level of the patient.

如請求項29-53中任一項的方法，其中該抗體或其抗原結合片段減少該患者中的脂蛋白顆粒的數量和/或尺寸。 The method of any one of claims 29-53, wherein the antibody or antigen-binding fragment thereof reduces the number and / or size of lipoprotein particles in the patient.

如請求項29-54中任一項的方法，其中該抗體或其抗原結合片段：(a)不影響該患者的血紅蛋白A1c(HbA1c)水準；和/或(b)不影響該患者的空腹血糖(FPG)水準。 The method of any one of claims 29-54, wherein the antibody or antigen-binding fragment thereof: (a) does not affect the patient's hemoglobin A1c (HbA1c) level; and / or (b) does not affect the patient's fasting blood glucose (FPG) level.

一種用於治療患有2型糖尿病(T2DM)的患者中高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，該患者患有(i)T2DM和(ii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。 A method for treating hypercholesterolemia in a patient with type 2 diabetes (T2DM), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, the patient having (i) T2DM and (ii) ) Treating insufficiently controlled hypercholesterolemia with the most tolerated statins; and (b) administering to the patient 75 mg of bisulfin / kexin type 9 (PCSK9) that specifically binds to the human proprotein converting enzyme The antibody or antigen-binding fragment thereof; and (c) if the LDL-C level in the patient is less than 70 mg / dL, the patient is administered one or more of the following doses of 75 mg of the antibody or antigen-binding agent approximately every two weeks Fragment, or if the LDL-C level in the patient is greater than or equal to 70 mg / dL, about one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered, wherein the antibody or antigen-binding fragment thereof A HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6 and wherein the patient is receiving concomitant insulin therapy.

一種用於治療患有T2DM和動脈粥樣硬化性心血管疾病(ASCVD)的患者中高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，該患者患有(i)T2DM、(ii)ASCVD和(iii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；和(b)向該患者施用75mg、150mg或300mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段，其中該患者接受伴隨胰島素治療。 A method for treating hypercholesterolemia in patients with T2DM and atherosclerotic cardiovascular disease (ASCVD), the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, the patient having (i) T2DM, (ii) ASCVD, and (iii) treatment of insufficiently controlled hypercholesterolemia with maximally tolerated statins; and (b) administering to the patient 75 mg, 150 mg, or 300 mg of specific binding human preprotein An antibody or antigen-binding fragment of the invertase subtilisin / kexin type 9 (PCSK9), wherein the patient is receiving concomitant insulin therapy.

如請求項56的方法，其中該ASCVD被定義為冠心病(CHD)、缺血性中風或外周動脈疾病。 The method of claim 56, wherein the ASCVD is defined as coronary heart disease (CHD), ischemic stroke, or peripheral arterial disease.

如請求項58的方法，其中該CHD包括急性心肌梗死、無症狀性心肌梗死和不穩定型心絞痛。 The method of claim 58, wherein the CHD includes acute myocardial infarction, asymptomatic myocardial infarction, and unstable angina.

如請求項57-59中任一項的方法，其中每兩週向該患者施用75mg的該抗體或抗原結合片段。 The method of any one of claims 57-59, wherein the patient is administered 75 mg of the antibody or antigen-binding fragment every two weeks.

如請求項57-59中任一項的方法，其中每兩週向該患者施用150mg的該抗體或抗原結合片段。 The method of any of claims 57-59, wherein the patient is administered 150 mg of the antibody or antigen-binding fragment every two weeks.

如請求項57-59中任一項的方法，其中每四週向該患者施用300mg的該抗體或抗原結合片段。 The method of any one of claims 57-59, wherein the patient is administered 300 mg of the antibody or antigen-binding fragment every four weeks.

如請求項57-62中任一項的方法，其中該抗體或其抗原結合片段包含SEQ ID NO：2、3和4中示出的三個重鏈CDR，和SEQ ID NO：7、8和10中示出的三個輕鏈CDR。 The method of any one of claims 57-62, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs shown in SEQ ID NOs: 2, 3, and 4, and SEQ ID NOs: 7, 8, and Three light chain CDRs shown in 10.

如請求項57-63中任一項的方法，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的重鏈可變區(HCVR)和具有SEQ ID NO：6的胺基酸序列的輕鏈可變區(LCVR)。 The method of any one of claims 57-63, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1 and a polypeptide having SEQ ID NO: 6 Light chain variable region (LCVR) of an amino acid sequence.

如請求項57-62中任一項的方法，其中該抗體或其抗原結合片段選自以下組成之群組：阿利庫單抗、依伏庫單抗、bococizumab、羅德希珠單抗、ralpancizumab和LY3015014。 The method of any one of claims 57-62, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of: alicusimab, evocuzumab, bococizumab, rodecizumab, ralpancizumab, and LY3015014 .

如請求項65的方法，其中該抗體或其抗原結合片段是阿利庫單抗。 The method of claim 65, wherein the antibody or antigen-binding fragment thereof is aliculumab.

如請求項57-66中任一項的方法，其進一步包括：(c)如果該患者中的LDL-C水準低於閾值水準，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 The method of any of claims 57-66, further comprising: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses to the patient about every two weeks 75 mg of the antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

如請求項57-66中任一項的方法，其進一步包括：(c)如果該患者中的LDL-C水準低於閾值水準，則約每四週向該患者施用一個或多個以下劑量的300mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於該閾值水準，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段。 The method of any of claims 57-66, further comprising: (c) if the LDL-C level in the patient is below a threshold level, administering one or more of the following doses of 300 mg to the patient approximately every four weeks The antibody or antigen-binding fragment thereof, or if the LDL-C level in the patient is greater than or equal to the threshold level, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof are administered approximately every two weeks.

如請求項67或68的方法，其中該閾值水準是70mg/dL。 The method of claim 67 or 68, wherein the threshold level is 70 mg / dL.

如請求項57-69中任一項的方法，其中該抗體或其抗原結合片段皮下施用。 The method of any one of claims 57-69, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

如請求項57-70中任一項的方法，其中該患者進一步接受伴隨脂質修飾治療(LMT)。 The method of any of claims 57-70, wherein the patient further receives concomitant lipid modification therapy (LMT).

如請求項71的方法，其中該LMT選自以下組成之群組：他汀類、膽固醇吸收抑制劑、纖維酸類、菸鹼酸類、ω-3脂肪酸和膽汁酸螯合劑。 The method of claim 71, wherein the LMT is selected from the group consisting of a statin, a cholesterol absorption inhibitor, a fibric acid, a nicotinic acid, an omega-3 fatty acid, and a bile acid chelator.

如請求項72的方法，其中該LMT是他汀類治療。 The method of claim 72, wherein the LMT is a statin therapy.

如請求項73的方法，其中該他汀類選自以下組成之群組：阿托伐他汀、瑞舒伐他汀、辛伐他汀、普伐他汀、洛伐他汀、氟伐他汀、匹伐他汀和西立伐他汀。 The method of claim 73, wherein the statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and westvat Livastatin.

如請求項72-74中任一項的方法，其中該他汀類治療是最大耐受劑量的他汀類治療。 The method of any of claims 72-74, wherein the statin treatment is a statin treatment at a maximum tolerated dose.

如請求項72的方法，其中該膽固醇吸收抑制劑是依折麥布。 The method of claim 72, wherein the cholesterol absorption inhibitor is ezetimibe.

如請求項57-72和76中任一項的方法，其中該患者對他汀類不耐受。 The method of any of claims 57-72 and 76, wherein the patient is intolerant to statins.

如請求項57-77中任一項的方法，其中該胰島素治療選自以下組成之群組：人胰島素、甘精胰島素、谷賴胰島素、地特胰島素、賴脯胰島素、德穀胰島素、門冬胰島素和基礎胰島素。 The method of any one of claims 57-77, wherein the insulin treatment is selected from the group consisting of: human insulin, insulin glargine, insulin glulisine, insulin detemir, insulin lispro, insulin deguera, aspart Insulin and basal insulin.

如請求項57-78中任一項的方法，其中該患者除胰島素治療之外還接受伴隨抗糖尿病治療。 The method of any of claims 57-78, wherein the patient receives concomitant anti-diabetic therapy in addition to insulin therapy.

如請求項79的方法，其中該另外的抗糖尿病治療選自以下組成之群組：胰高血糖素樣肽1(GLP-1)治療、胃腸肽、胰高血糖素受體促效劑或拮抗劑、葡萄糖依賴性促胰島素多肽(GIP)受體促效劑或拮抗劑、生長激素釋放激素拮抗劑或反向促效劑、xenin、xenin類似物、雙胍類、磺醯脲類、美格列奈類、噻唑烷二酮類、DPP-4抑制劑、α-葡糖苷酶抑制劑、鈉依賴性葡萄糖轉運蛋白2(SGLT-2)抑制劑、SGLT-1抑制劑、過氧化物酶體增殖物激活受體(PPAR-)(α、γ或α/γ)促效劑或調節劑、胰澱素、胰澱素類似物、G蛋白偶聯受體119(GPR119)促效劑、GPR40促效劑、GPR120促效劑、GPR142促效劑、全身性或低吸收性TGR5促效劑、糖尿病免疫治療、用於治療代謝綜合征和糖尿病的抗炎劑、腺苷單磷酸激活蛋白激酶(AMPK)刺激劑、11-β-羥基類固醇脫氫酶1的抑制劑、葡糖激酶的活化劑、二醯基甘油O-醯基轉移酶(DGAT)的抑制劑、葡萄糖轉運蛋白-4的調節劑、生長抑素受體3促效劑、降脂劑，以及它們的組合。 The method of claim 79, wherein the additional anti-diabetic treatment is selected from the group consisting of glucagon-like peptide 1 (GLP-1) treatment, gastrointestinal peptide, glucagon receptor agonist or antagonist Agents, glucose-dependent insulinotropic polypeptide (GIP) receptor agonists or antagonists, growth hormone releasing hormone antagonists or inverse agonists, xenin, xenin analogs, biguanides, sulfonylureas, meglitazone Nai, thiazolidinediones, DPP-4 inhibitors, α-glucosidase inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, SGLT-1 inhibitors, peroxisome proliferation Activator or receptor (PPAR-) (α, γ or α / γ) agonist or modulator, amylin, amylin analog, G protein coupled receptor 119 (GPR119) agonist, GPR40 Agents, GPR120 agonists, GPR142 agonists, systemic or low-absorption TGR5 agonists, diabetes immunotherapy, anti-inflammatory agents for the treatment of metabolic syndrome and diabetes, adenosine monophosphate-activated protein kinase (AMPK ) Stimulant, inhibitor of 11-β-hydroxysteroid dehydrogenase 1, glucokinase activator, diglycerol O-fluorenyl Shift enzyme (the DGAT) inhibitor, glucose transporter-4 modulators of somatostatin receptor 3 agonists, lipid lowering agents, and combinations thereof.

如請求項57-80中任一項的方法，其中該抗體或其抗原結合片段將該患者的LDL-C水準降低至少40%。 The method of any of claims 57-80, wherein the antibody or antigen-binding fragment thereof reduces the patient's LDL-C level by at least 40%.

如請求項57-81中任一項的方法，其中該抗體或其抗原結合片段將該患者的非HDL-C水準降低至少35%。 The method of any of claims 57-81, wherein the antibody or antigen-binding fragment thereof reduces the patient's non-HDL-C level by at least 35%.

如請求項57-82中任一項的方法，其中該抗體或其抗原結合片段降低該患者的ApoC3水準。 The method of any of claims 57-82, wherein the antibody or antigen-binding fragment thereof reduces the ApoC3 level of the patient.

如請求項57-83中任一項的方法，其中該抗體或其抗原結合片段減少該患者中的脂蛋白顆粒的數量和/或尺寸。 The method of any of claims 57-83, wherein the antibody or antigen-binding fragment thereof reduces the number and / or size of lipoprotein particles in the patient.

如請求項57-84中任一項的方法，其中該抗體或其抗原結合片段：(a)不影響該患者的血紅蛋白A1c(HbA1c)水準；和/或(b)不影響該患者的空腹血糖(FPG)水準。 The method of any one of claims 57-84, wherein the antibody or antigen-binding fragment thereof: (a) does not affect the patient's hemoglobin A1c (HbA1c) level; and / or (b) does not affect the patient's fasting blood glucose (FPG) level.

一種用於治療患有T2DM和ASCVD的患者中高膽固醇血症的方法，該方法包括：(a)選擇接受胰島素治療的高心血管風險患者，該患者患有(i)T2DM、(ii)ASCVD和(iii)通過最大耐受的他汀類治療未充分控制的高膽固醇血症；(b)每兩週向該患者施用75mg的特異性結合人類前蛋白轉化酶枯草菌素/kexin 9型(PCSK9)的抗體或其抗原結合片段；和(c)如果該患者中的LDL-C水準低於70mg/dL，則約每兩週向該患者施用一個或多個以下劑量的75mg的該抗體或其抗原結合片段，或如果該患者中的LDL-C水準大於或等於70mg/dL，則約每兩週施用一個或多個以下劑量的150mg的該抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含具有SEQ ID NO：1的胺基酸序列的HCVR和具有SEQ ID NO：6的胺基酸序列的LCVR，並且其中該患者接受伴隨胰島素治療。 A method for treating hypercholesterolemia in a patient with T2DM and ASCVD, the method comprising: (a) selecting a high cardiovascular risk patient for insulin therapy, the patient having (i) T2DM, (ii) ASCVD and (iii) treatment of inadequately controlled hypercholesterolemia with maximally tolerated statins; (b) administering to the patient 75 mg of bispecific human proprotein-converting enzyme subtilin / kexin type 9 (PCSK9) every two weeks The antibody or antigen-binding fragment thereof; and (c) if the LDL-C level in the patient is below 70 mg / dL, the patient is administered one or more of the following doses of 75 mg of the antibody or antigen thereof approximately every two weeks. A binding fragment, or if the LDL-C level in the patient is greater than or equal to 70 mg / dL, one or more of the following doses of 150 mg of the antibody or antigen-binding fragment thereof is administered approximately every two weeks, wherein the antibody or antigen-binding fragment thereof The fragment comprises an HCVR having an amino acid sequence of SEQ ID NO: 1 and an LCVR having an amino acid sequence of SEQ ID NO: 6, and wherein the patient is receiving concomitant insulin therapy.