WO2016159204A1 - アンチトロンビン ガンマを含む治療用組成物 - Google Patents
アンチトロンビン ガンマを含む治療用組成物 Download PDFInfo
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- WO2016159204A1 WO2016159204A1 PCT/JP2016/060599 JP2016060599W WO2016159204A1 WO 2016159204 A1 WO2016159204 A1 WO 2016159204A1 JP 2016060599 W JP2016060599 W JP 2016060599W WO 2016159204 A1 WO2016159204 A1 WO 2016159204A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the present invention relates to a composition for treatment of blood coagulation such as generalized intravascular coagulation syndrome or disseminated intravascular coagulation syndrome accompanied by a decrease in antithrombin or a thrombus formation tendency based on congenital antithrombin deficiency, including antithrombin gamma .
- Antithrombin is also referred to as antithrombin III.
- Human antithrombin which is a naturally occurring human antithrombin, is a glycoprotein consisting of 432 amino acids and having a molecular weight of about 59,000 to 65,000, and contains three disulfide bonds (Cys8-Cys128, Cys21-Cys95 and Cys247-Cys430) in the molecule. (Non-patent Document 1).
- N-glycoside-linked sugar chains are added to four positions of the 96th, 135th, 155th and 192nd asparagines (represented as N96, N135, N155 and N192, respectively) from the N-terminus. .
- Human antithrombin present in human plasma has two types of isoforms, ⁇ -type having 4 N-glycoside-linked sugar chains and ⁇ -type having no sugar chain added to Asn135 and having only 3 sugar chains. Although there is a form (Non-patent Document 2), 90 to 95% of human antithrombin present in human plasma is ⁇ -type, and the remaining 5 to 10% is ⁇ -type.
- the N-glycoside-linked complex sugar chain added to human antithrombin present in human plasma is composed of N-acetylglucosamine, sialic acid, galactose and mannose. Another feature of antithrombin present in human plasma is that the sugar chain structure is not modified with fucose.
- Human antithrombin is one of the main coagulation inhibitors in blood, and in addition to thrombin, these anticoagulant groups form a complex with factor X, factor XII, factor IX or factor XI, etc. Is inactivated.
- DIC disseminated intravascular coagulation syndrome
- DIC is an acquired syndrome characterized by extensive hypervascular coagulation caused by various causes.
- the main underlying diseases that cause DIC include infectious diseases, hematopoietic malignant tumors or solid cancers.
- Non-patent Document 3 The number of DIC patients in Japan is estimated to be 73,000 per year based on a nationwide questionnaire survey conducted in 1997 by the Ministry of Health and Welfare specific disease blood coagulation disorder research group. The prognosis of DIC was poor, and the mortality rate of 2193 people who developed DIC was 56.0% in the same survey (Non-patent Document 3).
- Non-Patent Document 4 The most common finding of DIC is bleeding, which ranges from capillary bleeding from the venipuncture site, punctate bleeding, ecchymosis to massive bleeding to the digestive tract, lungs or central nervous system.
- the hypercoagulable state observed in DIC is manifested as microcirculatory vascular occlusion, resulting in organ failure, which may cause embolization of large blood vessels and cerebral thrombosis (Non-Patent Document 4).
- the treatment target of DIC is to improve the survival rate in sepsis and to withdraw from DIC in leukemia.
- a treatment for DIC first, a treatment for an underlying disease is performed. Usually, treatment of a basic disease is performed before DIC diagnosis, but when DIC is diagnosed, more powerful treatment such as administration of an antibacterial agent and an antineoplastic agent is performed according to the basic disease (non-patented). Reference 5).
- CAD congenital antithrombin deficiency
- Non-patent Document 7 The percentage of CAD patients in Japan is estimated to be 0.16%, which is considered to be similar to that in the West (0.02 to 0.17%) (Non-patent Document 8).
- thrombosis develops by the age of 50 to 60 years, and it often occurs mainly in the venous system after 10 to 35 years, especially after the age of 14 (Non-patent Document 9). ). Thrombosis is most common in the deep veins of the lower extremities, about 40% of which are associated with pulmonary infarction. About 70% of thrombosis is caused by minor triggers that usually do not lead to the development of thrombosis, such as trauma, surgery, pregnancy or oral contraceptives.
- antithrombotic therapy is implemented as a CAD treatment together with systemic management for circulatory failure.
- a thrombolytic drug is used in combination with heparin that rapidly exhibits an anticoagulant action. Since anticoagulant action of heparin depends on the level of human antithrombin in blood, sufficient anticoagulant action of heparin cannot be expected in CAD patients, and supplementation with a human antithrombin preparation is required (Non-patent Document 9). .
- Non-patent Document 9 Non-patent Document 9
- plasma-derived human antithrombin a preparation containing human antithrombin derived from human plasma (hereinafter referred to as plasma-derived human antithrombin) is available in Japan as Neuart (registered trademark), anthrobin (registered trademark) P or blood donation nonthrone (registered trademark).
- Neuart registered trademark
- anthrobin registered trademark
- blood donation nonthrone registered trademark
- DIC generalized intravascular coagulation syndrome with reduced antithrombin III
- thrombogenic tendency based on congenital antithrombin III deficiency are approved and used as indications.
- Non-Patent Document 10 from the viewpoint of stable supply of blood products and self-sufficiency in Japan based on blood donation in Japan, “Development of blood product substitutes such as genetically modified products remains an important issue in the future. "Is clearly stated. Therefore, in order to supply human antithrombin without using human plasma as a raw material, switching to a gene recombinant is considered.
- Patent Documents 1 and 2 Recently, a recombinant human antithrombin composition in which fucose is not bound to N-acetylglucosamine on the reducing end of an N-glycoside-linked complex sugar chain that binds to a protein has been reported (Patent Documents 1 and 2). .
- antithrombin gamma As a recombinant human antithrombin composition in which fucose is not bound to N-acetylglucosamine at the reducing end of the N-glycoside-linked complex sugar chain that binds to ⁇ -type protein, antithrombin gamma [antithrombin gamma ( Also known as “genetical recombination”].
- a therapeutic composition comprising antithrombin gamma that is used in an appropriate manner and dosage in the treatment of blood clotting such as DIC or CAD-based thrombus formation tendency with antithrombin reduction.
- the inventor of the present invention uses a therapeutic composition containing antithrombin gamma with a specific usage and dose, thereby allowing blood coagulation such as a tendency to form a thrombus based on DIC or CAD with a decrease in antithrombin.
- blood coagulation such as a tendency to form a thrombus based on DIC or CAD
- the inventors have found that it exhibits effectiveness and safety, and have completed the present invention described below.
- the present invention relates to the following (1) to (7).
- (1) with a total of 36 international units / kg of isolated antithrombin gamma per day, used to be administered intravenously or intravenously, with antithrombin reduction A composition for the treatment of generalized intravascular coagulation syndrome or disseminated intravascular coagulation syndrome.
- (2) The dose contains a total of 48-72 international units / kg of isolated antithrombin gamma per day and is used to be administered urgently by intravenous or infusion
- Innate anti-thrombin wherein the dose comprises 24 to 72 international units / kg of isolated antithrombin gamma per day and is used to be administered intravenously or intravenously A therapeutic composition for the tendency of thrombus formation based on thrombin deficiency.
- the therapeutic composition according to (4) which is used to determine the dose while monitoring the antithrombin activity value.
- the therapeutic composition containing the antithrombin gamma of the present invention is used according to an appropriate usage and dose, so that in the treatment of DIC with antithrombin reduction, obstetrical or surgical DIC or CAD-based thrombus formation tendency, etc. It shows an increase in plasma antithrombin activity and has efficacy and safety.
- FIG. 1 is a diagram showing the amino acid sequence of antithrombin gamma, disulfide bonds and deduced structures of main sugar chains.
- antithrombin gamma As an embodiment of the specific structure of antithrombin gamma, the amino acid sequence, disulfide bond and deduced structures of main sugar chains are shown in FIG.
- One specific example of antithrombin gamma is the Japanese generic name of medicine (also called JAN), antithrombin gamma (genetical recombination) in Japanese name, or antithrombin Gamma (general recombination) (medicine food) in English name.
- JAN Japanese generic name of medicine
- antithrombin gamma genetical recombination
- antithrombin Gamma general recombination
- isolated antithrombin gamma is a recombinant human antithrombin, and is a Chinese lacking glycoprotein 6- ⁇ -L-fucose transferase (also referred to as ⁇ 1,6-fucosyltransferase). It is a glycoprotein consisting of 432 amino acid residues produced by hamster ovary cells (also called CHO cells) and having four N-glycoside-linked complex sugar chains.
- the isolated antithrombin gamma is added to Chinese hamster ovary cells lacking glycoprotein 6- ⁇ -L-fucose transferase by the method described in International Publication No. 2005/035563 or International Publication No. 2008/120801. It can be obtained by culturing a transformant obtained by introducing DNA encoding human antithrombin and purifying the obtained culture solution.
- the biological activity value of antithrombin gamma is expressed in International Units (IU).
- Biological activity of antithrombin gamma for example, concentrated human antithrombin international standard (The 3 rd International Standard for Antithrombin , Concentrate, Human, NIBSC code: 06/166) or on the basis of the concentrated human antithrombin international standards It can be calculated by measuring antithrombin activity using a standard substance tested in advance.
- the antithrombin activity is determined by adding heparin and thrombin to the target human antithrombin to form a complex, then adding the substrate, and the concentration of the chromogenic compound released from the substrate by thrombin remaining depending on the concentration of human antithrombin. This is a method for quantifying the specific activity of human antithrombin by measuring absorbance.
- the therapeutic composition containing antithrombin gamma may be administered once per day, or may be divided into multiple doses. When dividing into multiple times, it is preferably twice or three times per day.
- Examples of the method of administering the therapeutic composition containing antithrombin gamma in the present invention include intravenous injection (also referred to as intravenous administration or intravenous injection) or intravenous infusion (also referred to as intravenous intravenous injection or intravenous infusion).
- the therapeutic composition containing antithrombin gamma in the present invention is usually mixed with one or more pharmacologically acceptable carriers, additives, pH adjusters, etc. for use as pharmaceuticals, It is preferably provided as a composition prepared by any method well known in the pharmaceutical arts.
- the therapeutic composition containing antithrombin gamma uses a carrier, additive, pH adjuster, or the like comprising an amino acid, sugar, salt, buffer, or a mixture thereof as a composition suitable for intravenous or intravenous infusion. It can be prepared as a liquid injection.
- a therapeutic composition containing antithrombin gamma can be prepared as a powdery injection obtained by lyophilizing antithrombin gamma or a therapeutic composition containing antithrombin gamma according to a conventional method.
- administration as a powdery injection it is used after dissolving a powder containing antithrombin gamma or a therapeutic composition containing antithrombin gamma in a solution such as water for injection or physiological saline.
- the therapeutic composition containing antithrombin gamma is preferably a composition containing sodium citrate, sodium citrate hydrate, glycine, sodium L-glutamate, D-mannitol or sodium chloride in addition to antithrombin gamma. More preferably, a composition containing glycine and sodium citrate hydrate, or a composition containing glycine, sodium citrate hydrate and sodium chloride is mentioned. An example is A epicate (registered trademark).
- the rate at which a therapeutic composition containing antithrombin gamma is administered to a patient by intravenous injection or intravenous infusion in the present invention is not particularly limited, and examples thereof include slow administration.
- Examples of the time when the therapeutic composition containing antithrombin gamma in the present invention is administered to a patient include a time when the antithrombin activity value is lower than normal. Preferably, there is a time when the antithrombin activity value has decreased to 70% or less of the normal value.
- the antithrombin activity values are Trinichrome (registered trademark) ATXa (manufactured by Kyowa Medex), L-system ATIII, Verichrome anti-thrombin III auto B, L-system ATIII (above, Sysmex), Test Team (registered trademark) -Neo ATIII, Test Team (registered trademark) ATIII-2 kit, Test Team (registered trademark) S ATIII (above, manufactured by Sekisui Medical), Evatest ATIII (produced by Nissui Pharmaceutical), ATIII Liquid, STA reagent series (above Plasma such as N-assay TIA ATIII, N-assay L ATIII Nittobo (Nittobo Medical), Chromolyte ATIII (C) II (manufactured by LSI Rulece)
- a commercially available antithrombin III kit for blood tests that can be measured using whole blood or the like (Pharmaceutical Emission 0329 No. 10 “Revision of General Names
- Therapeutic composition for DIC When a therapeutic composition containing antithrombin gamma is used for the treatment of DIC with antithrombin reduction, it contains a total of 36 international units of isolated antithrombin gamma per kg body weight to be administered per day The therapeutic composition is administered intravenously or intravenously.
- a therapeutic composition containing antithrombin gamma When a therapeutic composition containing antithrombin gamma is used for the treatment of obstetrical or surgical DIC, isolated antithrombin totaling 48-72 international units per kg body weight to be administered per day
- the therapeutic composition containing gamma is administered urgently by intravenous or intravenous infusion.
- Obstetric DIC is also called obstetric DIC.
- diseases causing obstetric DIC include, for example, early placental exfoliation, hemorrhagic shock, severe infection, amniotic fluid embolism, eclampsia, severe pregnancy toxemia, dead fetal syndrome, acute pregnancy fatty liver or hydatidiform mole Etc.
- Surgical DIC is also called surgical DIC.
- Examples of the basic disease causing surgical DIC include trauma or burn.
- a therapeutic composition containing antithrombin gamma is urgently treated. Can be administered.
- continuous iv infusion of heparin may be administered simultaneously with the therapeutic composition containing antithrombin gamma in all DIC including obstetric DIC or surgical DIC.
- heparin in the present invention examples include pharmaceutical compositions containing heparin, heparin sodium, heparin calcium, or heparins such as unfractionated heparin, low molecular weight heparin or heparinoid as an active ingredient.
- the dose of heparin is usually 5000 to 20000 units, preferably 10,000 units per day.
- the dosage of heparin is preferably less than 500 units per hour.
- composition for treating thrombus formation based on CAD Composition for treating thrombus formation based on CAD
- a therapeutic composition comprising antithrombin gamma
- the therapeutic composition containing gamma is administered intravenously or intravenously.
- the present invention it is preferable to determine and administer the therapeutic composition containing antithrombin gamma while monitoring the antithrombin activity value in the treatment of thrombus formation tendency based on CAD.
- the antithrombin activity value can be measured by the method described above.
- the dose of the therapeutic composition containing antithrombin gamma should be an amount calculated based on the monitored antithrombin activity value so that the antithrombin activity value maintains the normal range of healthy subjects. Is preferred.
- an antithrombin gamma preparation is one aspect of the therapeutic composition containing the antithrombin gamma.
- Example 1 Pharmacokinetic comparison test of antithrombin gamma and plasma-derived human antithrombin when the same amount of drug is administered Among the phase I clinical trials of antithrombin gamma in Japan, the contents of the pharmacokinetic comparison test and The results are shown below.
- Target Healthy adult male
- Study design Randomized parallel group comparison study
- Exclusion criteria 1. 1. A person with an existing disease that needs treatment 2. History of drug allergy or current illness 3. History of abnormal bleeding, thrombosis, or family history 4. History or history of overt gastrointestinal bleeding (melena, vomiting, etc.) 5. alcohol or drug addict 6. Those who did not become negative in all items in the infectious disease test (HBs antigen, HCV antibody, HIV antibody, syphilis test) 7. Those who have used drugs (including over-the-counter drugs and external preparations) within 4 weeks before the start of study drug administration. 8. Patients who received other study drugs within 4 months before the start of study drug administration. 9. Those who have been hospitalized or treated within 3 months prior to the start of study drug administration, or who have taken more than 200 mL of blood (blood donation). 10. Those who have received antithrombin gamma preparations in the past. Other persons who are judged to be ineligible for this clinical trial by the investigator or the investigator.
- pAT plasma-derived human antithrombin
- Plasma antithrombin activity was measured.
- the plasma antithrombin activity value (1.08 ⁇ 0.10 IU / mL) before administration for each subject was calculated from the plasma antithrombin activity values after all administration. Subtraction and pharmacokinetic parameters were calculated.
- C max, 3rd the primary endpoint C max after the third dose
- AUC 48-t the start of the third dose
- N is the number of subjects
- C max and 3rd are the maximum plasma antithrombin activity after the third administration
- AUC 48-t is the amount of plasma activity determined from the start of the third administration (48 hours after the start of the first administration).
- AUCs up to the earliest point at which subjects who were less than the lower limit were observed, respectively, and the ratio (%) of the antithrombin gamma preparation calculated from the difference between the logarithm conversion values of C max, 3rd and AUC 48-t The ratio to the pAT formulation is shown.
- Example 2 Bioequivalence study of antithrombin gamma and plasma-derived human antithrombin when administered 1.2 times as much as plasma-derived human antithrombin Phase I clinical trial of antithrombin gamma in Japan Among the tests, the contents and results of the bioequivalence test are shown below.
- Target Healthy adult male
- Study design Randomized, open-label, parallel group comparison study
- Exclusion criteria 1. 1. A person with an existing disease that needs treatment 2. History of drug allergy or current illness 3. History of abnormal bleeding, thrombosis, heart failure, hypokalemia, prolonged QT syndrome or family history 4. History or history of overt gastrointestinal bleeding (melena, vomiting, etc.) 5. Person who has alcohol or drug dependence or who has not tested negative for all items 6. Those who did not become negative in all items in the infectious disease test (HBs antigen, HCV antibody, HIV antibody, syphilis test) 7. Those who have used drugs (including general drugs, topical drugs, vitamins and Chinese medicines) within 4 weeks before the start of study drug administration. 8. Participants who participated in clinical trials or similar studies of drugs containing new active ingredients within 4 months prior to the start of study drug administration 9.
- the plasma antithrombin activity value (1.01 ⁇ 0.09 IU / mL) before administration for each subject was calculated from all post-administration plasma antithrombin activity values. Subtraction and pharmacokinetic parameters were calculated. Table 2 shows Cmax, 3rd and AUC 48-t , which are the main evaluation items.
- N is the number of subjects
- Cmax 3rd is the highest plasma antithrombin activity after the third administration
- AUC 48-t is the plasma antithrombin activity from the start of the third administration (48 hours after the first administration).
- the AUCs up to the final detection time are shown, and the ratio (%) shows the ratio of the antithrombin gamma preparation to the pAT preparation calculated from the difference between the mean values of the logarithmic conversion values of Cmax, 3rd and AUC48 -t .
- antithrombin gamma preparation 72 IU / kg and pAT preparation 60 IU / kg is shown, and antithrombin gamma preparation is an international unit per body weight and 1.2 times the amount of pAT preparation. It was found that the administration can be expected to develop and maintain the same efficacy as that of the pAT preparation.
- Example 3 Effectiveness of antithrombin gamma and plasma-derived human antithrombin when antithrombin gamma was administered to a DIC patient directly caused by infection as a result of 1.2 times the dose of plasma-derived human antithrombin And anti-thrombin gamma phase III clinical trials in Japan, infectious disease is the direct trigger, and the DIC diagnostic criteria for acute DIC prepared by the DIC Special Committee of the Japanese Emergency Medical Association Medical journal, 16, 188-202 (2005)] (hereinafter referred to as acute phase DIC diagnostic criteria), the contents and results of the study for patients diagnosed with DIC are shown below.
- Target DIC patients who developed directly from infectious diseases
- Study design Randomized, open-label, parallel group comparison study
- Antithrombin gamma 36 IU / kg or pAT preparation 30 IU / kg once a day for 5 days
- Exclusion criteria 1. 1. Patients with a history of severe drug allergy or current illness 2. Patients with severe liver damage such as fulminant hepatitis or decompensated cirrhosis. 3. Even if DIC is recovered, early death is estimated, and it is difficult to secure sufficient study drug administration period and to acquire efficacy / safety data. 4. Pregnant, breastfeeding or possibly pregnant. 5. Patients who have participated in other clinical trials within 4 months prior to obtaining consent. 6. Patients who have received antithrombin gamma preparation in the past. 7. Patients who received concomitant prohibited drugs or concomitant prohibited therapy between consent acquisition and registration Other patients who are judged to be ineligible for this clinical trial by the investigator or the investigator.
- antithrombin gamma preparation 36 IU / kg or pAT preparation [Neuart (registered trademark)] 30 IU / kg was administered intravenously once a day for 5 days under the combined use of heparins.
- the antithrombin gamma preparation or pAT preparation was administered alone.
- the number of patients who administered heparins was 32 out of 109 cases in the antithrombin gamma group and 31 out of 112 cases in the pAT group.
- 221 cases antithrombin gamma preparation group: 108 cases, pAT preparation group: 113 cases except for one case in the antithrombin gamma preparation group, which was discontinued before the administration of the investigational drug, were included in the safety analysis. It was.
- the plasma antithrombin activity before administration was 54.2% ⁇ 11.5% in the antithrombin gamma preparation group and 53.2% ⁇ 14.1% in the pAT preparation group.
- plasma antithrombin activity on day 6 after the start of administration was 107.3% ⁇ 26.1% in the antithrombin gamma preparation group and 115.0% ⁇ 25.3% in the pAT preparation group.
- DIC withdrawal defined as having a DIC score of less than 4 calculated from the acute DIC diagnostic criteria
- the percentage of subjects with a 95% confidence interval was 56.4% [46.6 to 65.8%] (62/110 cases) in the antithrombin gamma preparation group and 52.7% in the pAT preparation group. [43.0-62.2%] (59/112 cases).
- the antithrombin gamma preparation 36 IU / kg administration group and the pAT preparation 30 IU / kg administration group have the same increase in plasma antithrombin activity, efficacy and safety regardless of the presence or absence of heparin combination. It has been shown.
- Example 4 Study on efficacy and safety of antithrombin gamma when antithrombin gamma is administered to a DIC patient in combination with heparins 1.2 times as much as plasma-derived human antithrombin (1) DIC diagnostic criteria prepared by the Ministry of Health and Welfare Specific Disease Blood Coagulation Abnormality Investigation Research Group in the Japanese phase III clinical trial of antithrombin gamma [Ministry of Health and Welfare Specific Disease Blood Coagulation Investigation Research Group 1987 Research Report, 37-41 (1988)] (hereinafter referred to as the DIC diagnostic criteria of the Ministry of Health and Welfare) The contents and results of the study under the combined use of heparins for patients diagnosed with DIC or suspected DIC are shown below.
- Target Patients diagnosed with DIC or suspected DIC according to the DIC diagnostic criteria of the Ministry of Health and Welfare Although the underlying disease is not specified, patients with hematopoietic malignant tumor as the underlying disease are included in this study.
- Clinical trial design Multicenter uncontrolled open-label study (3) Antithrombin gamma preparation 36IU / kg once a day for 5 days
- Exclusion criteria 1. Patients with a history of severe drug allergy or current illness 2. Patients with severe liver damage such as fulminant hepatitis or decompensated cirrhosis. 3. Even if DIC is recovered, early death is estimated, and it is difficult to secure sufficient study drug administration period and to acquire efficacy / safety data. 4. Pregnant, breastfeeding or possibly pregnant. 5. Patients who have participated in other clinical trials within 4 months prior to obtaining consent. 6. Patients who have received antithrombin gamma preparation in the past. 7. Patients who received concomitant prohibited drugs or concomitant prohibited therapy between consent acquisition and registration 8. Patients at risk of promoting bleeding due to combined use of heparins. Other patients who are judged to be ineligible for this clinical trial by the investigator or the investigator.
- Antithrombin gamma preparation 36 IU / kg was administered by intravenous infusion once a day for 5 days under the combined use of heparins.
- 15 patients leukemia group: 9 cases, non-leukemia group: 6 cases were administered the study drug, and all cases were included in the analysis of safety and efficacy.
- the underlying diseases are: acute myeloid leukemia, myelodysplastic syndrome, 2 non-Hodgkin lymphomas, multiple myeloma, aplastic anemia, myeloid proliferative disorder (polycythemia vera)
- non-leukemic group there were 2 non-Hodgkin lymphomas, hemophilia B, non-small cell lung cancer, autoimmune hemolytic anemia, and HIV infection.
- the plasma antithrombin activity before administration was 54.2% ⁇ 14.1%.
- the antithrombin activity in plasma on day 6 after the start of administration of the antithrombin gamma preparation was 97.5% ⁇ 19.6%.
- the main endpoint of efficacy, withdrawal from DIC on the 6th day after the start of administration (when the trial was stopped by the 6th day) (DIC score according to the DIC diagnostic criteria of the Ministry of Health and Welfare), the underlying disease is leukemia
- the ratio [95% confidence interval] of subjects who were found to be less than 3 in cases and less than 6 in non-leukemia cases was 40.0% [16.3-67.7%] (6/15 cases) Met.
- Example 5 Study on efficacy and safety of antithrombin gamma when antithrombin gamma is administered to a DIC patient in combination with heparins 1.2 times the amount of plasma-derived human antithrombin (2) Listed below are the details and results of the study of antithrombin gamma studies in Japan in combination with heparins in patients diagnosed with DIC diagnosed by DIC diagnostic criteria for acute DIC. did.
- Target Patients diagnosed with DIC according to acute DIC diagnostic criteria
- Study design Multicenter uncontrolled open-label study
- Antithrombin gamma preparation 36IU / kg once a day for 5 days
- Exclusion criteria 1. 1. Patients with a history of severe drug allergy or current illness 2. Patients with severe liver damage such as fulminant hepatitis or decompensated cirrhosis. 3. Even if DIC is recovered, early death is estimated, and it is difficult to secure sufficient study drug administration period and to acquire efficacy / safety data. 4. Pregnant, breastfeeding or possibly pregnant. 5. Patients who have participated in other clinical trials within 4 months prior to obtaining consent. 6. Patients who have received antithrombin gamma preparation in the past. 7. Patients who received concomitant prohibited drugs or concomitant prohibited therapy between consent acquisition and registration 8. Patients at risk of promoting bleeding due to combined use of heparins. Other patients who are judged to be ineligible for this clinical trial by the investigator or the investigator.
- antithrombin gamma preparation 36 IU / kg was intravenously administered once a day for 5 days under the combined use of heparins.
- antithrombin gamma preparation was administered to 5 cases, and all cases were included in the analysis of safety and efficacy.
- the breakdown of the underlying diseases was 2 cases each for infection and heat stroke, and 1 case for acute pancreatitis.
- the plasma antithrombin activity before administration was 53.4% ⁇ 11.1%.
- the antithrombin activity in plasma on day 6 after the start of administration of the antithrombin gamma preparation was 96.8% ⁇ 27.0%.
- the antithrombin gamma preparation 36 IU / kg administration is not limited to infectious diseases, but the increase in the plasma antithrombin activity and efficacy is the same as in Example 3 for DIC patients combined with heparins. And has been shown to have safety.
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Abstract
Description
(1)用量が1日当り合計36国際単位/kgの単離されたアンチトロンビン ガンマを含み、静注または点滴静注にて投与されるように用いられることを特徴とする、アンチトロンビン低下を伴う汎発性血管内凝固症候群または播種性血管内凝固症候群の治療用組成物。
(2)用量が1日当り合計48~72国際単位/kgの単離されたアンチトロンビン ガンマを含み、静注または点滴静注にて緊急処置的に投与されるように用いられることを特徴とする、産科的または外科的な汎発性血管内凝固症候群または播種性血管内凝固症候群の治療用組成物。
(3)更にヘパリンの持続点滴静注を同時に投与されるように用いられることを特徴とする、(1)または(2)に記載の治療用組成物。
(4)用量が1日当り合計24~72国際単位/kgの単離されたアンチトロンビン ガンマを含み、静注または点滴静注にて投与されるように用いられることを特徴とする、先天性アンチトロンビン欠乏に基づく血栓形成傾向の治療用組成物。
(5)アンチトロンビン活性値をモニタリングしながら投与量を決定するように用いられることを特徴とする、(4)に記載の治療用組成物。
(6)1日当り1回投与されるように用いられることを特徴とする(1)~(5)のいずれか1に記載の治療用組成物。
(7)1日当り少なくとも2回に分割して投与されるように用いられることを特徴とする(1)~(5)のいずれか1に記載の治療用組成物。
アンチトロンビン ガンマを含む治療用組成物をアンチトロンビン低下を伴うDICの治療に使用する場合には、1日当り、投与する対象の体重1kg当り、合計36国際単位の単離されたアンチトロンビン ガンマを含む治療用組成物を静注または点滴静注にて投与する。
アンチトロンビン ガンマを含む治療用組成物を、CADに基づく血栓形成傾向の治療に使用する場合には、1日当り、投与する対象の体重1kg当り、合計24~72国際単位の単離されたアンチトロンビン ガンマを含む治療用組成物を、静注または点滴静注にて投与する。
アンチトロンビン ガンマの日本における第I相臨床試験のうち、薬物動態比較試験の実施内容及び結果を以下に示す。
(1)対象:
健康成人男性
(2)治験デザイン:
無作為化並行群間比較試験
(3)用法・用量:
アンチトロンビン ガンマ製剤60IU/kg又は血漿由来ヒトアンチトロンビン製剤60IU/kgを1日1回、3日間投与
1.本治験開始前に治験薬及び本治験の目的・内容について十分な説明を受け、よく理解したうえ本治験の被験者になることについて本人から自由意思による文書同意が得られている者
2.同意取得時に20歳以上45歳未満の日本人男性
3.事前検査時にBMIが18.5以上25.0未満の者
1.治療を必要とする現病を有する者
2.薬物アレルギーの既往歴又は現病を有する者
3.異常出血、血栓症の既往歴又は家族歴を有する者
4.顕性の消化管出血(下血、吐血等)の既往歴又は現病を有する者
5.アルコール又は薬物依存者
6.感染症検査(HBs抗原、HCV抗体、HIV抗体、梅毒検査)で全項目陰性とならなかった者
7.治験薬の投与開始前4週間以内に薬剤(市販薬及び外用剤を含む)を使用した者
8.治験薬の投与開始前4ヵ月以内に他の治験薬の投与を受けた者
9.治験薬の投与開始前3ヵ月以内に入院又は手術の治療を受けた者、又は200mLを超える採血(献血)を行った者
10.過去にアンチトロンビン ガンマ製剤の投与を受けた者
11.その他、治験責任医師又は治験分担医師により本治験の対象として不適格と判断された者
20歳以上45歳未満の健康成人男性20例を対象に、アンチトロンビン ガンマ製剤又は血漿由来ヒトアンチトロンビン(以下、pATと表記する)製剤[ノイアート(登録商標)静注用][以下、ノイアート(登録商標)と表記する](各群10例)を、それぞれ60IU/kgの用量で1日1回3日間反復静脈内投与した。
アンチトロンビン ガンマの日本における第I相臨床試験のうち、生物学的同等性試験の実施内容及び結果を以下に示す。
(1)対象:
健康成人男性
(2)治験デザイン:
無作為化非盲検並行群間比較試験
(3)用法・用量:
アンチトロンビン ガンマ製剤72IU/kg又はpAT製剤60IU/kgを1日1回、3日間投与
1.本治験への参加に関し、本人からの自由意思による文書同意が得られている者
2.同意取得時に20歳以上45歳未満の日本人男性
3.事前検査時にBMIが18.5以上25.0未満の者
1.治療を必要とする現病を有する者
2.薬物アレルギーの既往歴又は現病を有する者
3.異常出血、血栓症、心不全、低カリウム血症、QT延長症候群の既往歴又は家族歴を有する者
4.顕性の消化管出血(下血、吐血等)の既往歴又は現病を有する者
5.アルコール若しくは薬物依存症の者又は乱用薬物検査で全項目陰性とならなかった者
6.感染症検査(HBs抗原、HCV抗体、HIV抗体、梅毒検査)で全項目陰性とならなかった者
7.治験薬の投与開始前4週間以内に薬剤(一般薬、外用剤、ビタミン剤及び漢方薬を含む)を使用した者
8.治験薬の投与開始前4ヵ月以内に新有効成分含有医薬品の臨床試験又はそれに準ずる試験に参加し、投与された者
9.治験薬の投与開始前3ヵ月以内に入院した者若しくは手術を受けた者、又は200mLを超える採血(献血、成分献血を含む)を行った者
10.過去にアンチトロンビン ガンマ製剤の投与を受けた者
11.その他、治験責任医師又は治験分担医師により本治験の対象として不適格と判断された者
20歳以上45歳未満の健康成人男性42例を対象に、アンチトロンビン ガンマ製剤72IU/kg又はpAT製剤[ノイアート(登録商標)]60IU/kg(各群21例)を1日1回3日間反復静脈内投与した。投与1及び2日目には、投与前と投与後1から10時間の間の3測定時点で、投与3日目には、投与前と投与後1から169時間の間の10測定時点で、血漿中アンチトロンビン活性が測定された。
アンチトロンビン ガンマの日本における第III相臨床試験のうち、感染症が直接誘因であり、日本救急医学会DIC特別委員会にて作成された急性期DIC診断基準[日救急医会誌, 16, 188-202 (2005)](以下、急性期DIC診断基準と表記する)によりDICと診断された患者を対象とした検討の実施内容及び結果を以下に示す。
感染症が直接誘因となり発症したDIC患者
(2)治験デザイン:
無作為化非盲検並行群間比較試験
(3)用法・用量:
アンチトロンビン ガンマ36IU/kg又はpAT製剤30IU/kgを1日1回、5日間投与
1.ACCP/SCCMsepsis基準(SIRS項目のうち2項目以上+Infection)を満たす患者(severe sepsis、septic shock含む)
2.登録時検査で急性期DIC診断基準のDIC スコアが4点以上の患者
3.登録時検査でアンチトロンビン活性が70%以下の患者
4.同意取得時に20歳以上の患者。性別は問わない
5.本人又は代諾者から文書による同意が得られている患者
1.重篤な薬物アレルギーの既往歴あるいは現病を有する患者
2.劇症肝炎、非代償性肝硬変等の重篤な肝障害のある患者
3.DICを回復させたとしても早期死亡が推定され、十分な治験薬投与期間の確保や有効性・安全性データの取得が困難と思われる患者
4.妊婦、授乳婦又は妊娠している可能性のある患者
5.同意取得前4ヵ月以内に、他の治験に参加したことがある患者
6.過去にアンチトロンビン ガンマ製剤の投与を受けた患者
7.同意取得から登録の間に併用禁止薬投与又は併用禁止療法を行った患者
8.その他、治験責任医師又は治験分担医師により本治験の対象として不適格と判断された患者
20歳以上、血漿中アンチトロンビン活性が70%以下で、ACCP/SCCM sepsis基準を満たし、感染症がDICの直接誘因であり、急性期DIC診断基準によりDICと診断(DICスコア4以上)された患者[目標症例数:200例(各群100例)]を対象に、アンチトロンビン ガンマ製剤の有効性及び安全性を検討することを目的とした無作為化非盲検並行群間比較試験を実施した。
アンチトロンビン ガンマの日本における第III相臨床試験のうち、旧厚生省特定疾患血液凝固異常症調査研究班より作成されたDIC診断基準[厚生省特定疾患血液凝固異常症調査研究班 昭和62年度研究報告書, 37-41 (1988)](以下、厚生省DIC診断基準と表記する)によりDIC又はDICの疑いと診断された患者を対象としたヘパリン類併用下での検討の実施内容及び結果を以下に示す。
厚生省DIC診断基準によりDIC又はDICの疑いと診断された患者
なお、基礎疾患は規定しないが、造血器悪性腫瘍を基礎疾患とする患者は本治験の対象とする。
(2)治験デザイン:
多施設共同非対照非盲検法試験
(3)用法・用量:
アンチトロンビン ガンマ製剤36IU/kgを1日1回、5日間投与
1.登録時検査で厚生省DIC診断基準によりDIC又はDICの疑いに相当する(白血病群:3点以上、非白血病群:6点以上)患者
なお、白血病群としては白血病及び類縁疾患、再生不良性貧血、抗腫瘍剤投与後等骨髄巨核球減少が顕著で、高度の血小板減少をみる患者、非白血病群としては白血病群に分類されない患者を示す。
2.登録時検査でアンチトロンビン活性が70%以下の患者
3.同意取得時に20歳以上の患者。性別は問わない
4.本人又は代諾者から文書による同意が得られている患者
1.重篤な薬物アレルギーの既往歴あるいは現病を有する患者
2.劇症肝炎、非代償性肝硬変等の重篤な肝障害のある患者
3.DICを回復させたとしても早期死亡が推定され、十分な治験薬投与期間の確保や有効性・安全性データの取得が困難と思われる患者
4.妊婦、授乳婦又は妊娠している可能性のある患者
5.同意取得前4ヵ月以内に、他の治験に参加したことがある患者
6.過去にアンチトロンビン ガンマ製剤の投与を受けた患者
7.同意取得から登録の間に併用禁止薬投与又は併用禁止療法を行った患者
8.ヘパリン類の併用により、出血を助長する危険性のある患者
9.その他、治験責任医師又は治験分担医師により本治験の対象として不適格と判断された患者
20歳以上、血漿中アンチトロンビン活性が70%以下で、厚生省DIC診断基準によりDIC又はDICの疑いと診断[DICスコアが、白血病及び類縁疾患、再生不良性貧血、抗腫瘍剤投与後等骨髄巨核球減少が顕著で、高度の血小板減少をみる場合(白血病群)は3以上、白血病群に分類されない場合(非白血病群)は6以上]された患者(目標症例数:10例以上)を対象に、ヘパリン類併用下でのアンチトロンビン ガンマ製剤の有効性及び安全性を検討することを目的とした非盲検非対照試験を実施した。
アンチトロンビン ガンマの日本における第III相臨床試験のうち、急性期DIC診断基準によりDICと診断されたDICと診断された患者を対象としたヘパリン類併用下での検討の実施内容及び結果を以下記載した。
急性期DIC診断基準によりDICと診断された患者
(2)治験デザイン:
多施設共同非対照非盲検試験
(3)用法・用量:
アンチトロンビン ガンマ製剤36IU/kgを1日1回、5日間投与
1.登録時検査で急性期DIC診断基準のDICスコアが4点以上の患者
2.登録時検査でアンチトロンビン活性が70%以下の患者
3.同意取得時に20歳以上の患者。性別は問わない
4.本人又は代諾者から文書による同意が得られている患者
1.重篤な薬物アレルギーの既往歴あるいは現病を有する患者
2.劇症肝炎、非代償性肝硬変等の重篤な肝障害のある患者
3.DICを回復させたとしても早期死亡が推定され、十分な治験薬投与期間の確保や有効性・安全性データの取得が困難と思われる患者
4.妊婦、授乳婦又は妊娠している可能性のある患者
5.同意取得前4ヵ月以内に、他の治験に参加したことがある患者
6.過去にアンチトロンビン ガンマ製剤の投与を受けた患者
7.同意取得から登録の間に併用禁止薬投与又は併用禁止療法を行った患者
8.ヘパリン類の併用により、出血を助長する危険性のある患者
9.その他、治験責任医師又は治験分担医師により本治験の対象として不適格と判断された患者
20歳以上、血漿中アンチトロンビン活性が70%以下で、急性期DIC診断基準によりDICと診断(DICスコア4以上)された患者(目標症例数:10例以上)を対象に、ヘパリン類併用下でのアンチトロンビン ガンマ製剤の有効性及び安全性を検討することを目的とした非盲検非対照試験を実施した。
Claims (7)
- 用量が1日当り合計36国際単位/kgの単離されたアンチトロンビン ガンマを含み、静注または点滴静注にて投与されるように用いられることを特徴とする、アンチトロンビン低下を伴う汎発性血管内凝固症候群または播種性血管内凝固症候群の治療用組成物。
- 用量が1日当り合計48~72国際単位/kgの単離されたアンチトロンビン ガンマを含み、静注または点滴静注にて緊急処置的に投与されるように用いられることを特徴とする、産科的または外科的な汎発性血管内凝固症候群または播種性血管内凝固症候群の治療用組成物。
- 更にヘパリンの持続点滴静注を同時に投与されるように用いられることを特徴とする、請求項1または2に記載の治療用組成物。
- 用量が1日当り合計24~72国際単位/kgの単離されたアンチトロンビン ガンマを含み、静注または点滴静注にて投与されるように用いられることを特徴とする、先天性アンチトロンビン欠乏に基づく血栓形成傾向の治療用組成物。
- アンチトロンビン活性値をモニタリングしながら投与量を決定するように用いられることを特徴とする、請求項4に記載の治療用組成物。
- 1日当り1回投与されるように用いられることを特徴とする請求項1~5のいずれか1項に記載の治療用組成物。
- 1日当り少なくとも2回に分割して投与されるように用いられることを特徴とする請求項1~5のいずれか1項に記載の治療用組成物。
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JP2017510167A JP6859255B2 (ja) | 2015-03-31 | 2016-03-31 | アンチトロンビン ガンマを含む治療用組成物 |
EP16773084.5A EP3278814B1 (en) | 2015-03-31 | 2016-03-31 | Therapeutic composition containing antithrombin gamma |
ES16773084T ES2897985T3 (es) | 2015-03-31 | 2016-03-31 | Composición terapéutica que contiene antitrombina gamma |
US15/561,690 US20180104318A1 (en) | 2015-03-31 | 2016-03-31 | Therapeutic composition containing antithrombin gamma |
US16/709,499 US20200147188A1 (en) | 2015-03-31 | 2019-12-10 | Therapeutic composition containing antithrombin gamma |
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- 2016-03-31 JP JP2017510167A patent/JP6859255B2/ja active Active
- 2016-03-31 EP EP16773084.5A patent/EP3278814B1/en active Active
- 2016-03-31 US US15/561,690 patent/US20180104318A1/en not_active Abandoned
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2019
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Patent Citations (1)
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WO2005035563A1 (ja) * | 2003-10-09 | 2005-04-21 | Kyowa Hakko Kogyo Co., Ltd. | アンチトロンビンⅲ組成物の製造方法 |
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AKIRA SATO ET AL.: "Bio Iyakuhin Kiban Seibi ni Muketa Bio Kozokuhin (Biosimilar) eno Torikumi", PHARM TECH JAPAN, vol. 30, no. 7, 2014, pages 1429 - 1434, XP009506358 * |
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TERUHIDE YAMAGUCHI: "Guideline for follow-on biologics", HUMAN SCIENCE, vol. 20, no. 3, 2009, pages 30 - 36, XP009506388 * |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020166557A1 (ja) * | 2019-02-11 | 2020-08-20 | 協和キリン株式会社 | 妊娠高血圧腎症の治療方法 |
JPWO2020166557A1 (ja) * | 2019-02-11 | 2021-12-16 | 協和キリン株式会社 | 妊娠高血圧腎症の治療方法 |
Also Published As
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ES2897985T3 (es) | 2022-03-03 |
EP3278814B1 (en) | 2021-08-18 |
EP3278814A1 (en) | 2018-02-07 |
US20180104318A1 (en) | 2018-04-19 |
JPWO2016159204A1 (ja) | 2018-02-01 |
JP6859255B2 (ja) | 2021-04-14 |
EP3278814A4 (en) | 2018-10-31 |
US20200147188A1 (en) | 2020-05-14 |
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