TW202405190A - 改良之非酒精性脂肪性肝炎檢測方法 - Google Patents
改良之非酒精性脂肪性肝炎檢測方法 Download PDFInfo
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Abstract
本發明提供用於檢測高風險非酒精性脂肪性肝炎(NASH)的改良方法。
Description
本發明係基於針對臨床試驗之重要資料集的詳細分析。本文中提供一種用於鑑別高風險NASH個體的最佳化之非侵入方法。
非酒精性脂肪性肝炎(NASH)係在組織學上以脂肪積累、肝細胞損傷及類似於酒精性肝炎之發炎為特徵的一種慢性肝病。NASH可導致肝纖維化、肝硬化、肝衰竭及/或肝細胞癌(HCC)。
由於NASH在其早期階段無明顯症狀,並且由於缺乏專門針對檢測該疾病開發之廣泛之非侵入式測試,直至最近,NASH之檢測在很大程度上被低估。高風險NASH狀態定義為患有NASH、NAS評分為4且纖維化階段為F2,代表一個需要鑑別的重要NASH亞群。實際上,此等患者有較高之疾病惡化風險,尤其是肝硬化風險以及較高的肝相關死亡及全因死亡風險。歸因於技術限制以及作為NASH及纖維化檢測之臨床參考標準之切片的風險,以血液為基礎之非侵入式測試(NIT)的開發具有重要意義。已開發出不同的NIT,主要為了纖維化階段。NIS4
®係首創以血液為基礎之NIT,專門設計成藉由複合式纖維化*NAS終點,偵測高風險NASH患者,並含有4種獨立的生物標誌物:miR-34a-5p、α-2巨球蛋白(A2M)、YKL-40 (或殼質酶3樣蛋白質1)及糖化血色素(HbA1c) (Harrison等人, The Lancet Gastroenterology & Hepatology, 5(11):970-985, 2020)。NIS4
®允許執行穩健分析。NIS4
®基於不同生物流體(全血及血清)及不同實驗室方法評估4種不同生物標誌物。在此情形中,吾人評估是否能提供相對於先前技術NIT有所改良之NIT。
因此,本發明係關於一種用於檢測高風險NASH個體的方法,其中該方法包含對該個體之生物流體樣本中miR-34a-5p及YKL-40之水平進行定量,並將經定量之水平與該個體之性別組合。
更特定言之,本發明係關於一種用於檢測、篩選、監測或預後高風險NASH個體之的方法,該方法包含:
- 對該個體之生物流體樣本中miR-34a-5p及YKL-40之水平進行定量;
- 獲得該個體之性別;
- 在數學函數中組合經定量之水平及該性別以分配評分;及
- 將該評分與截止值相比較以確定該個體是否有高風險NASH之風險。
在一個特定實施例中,本發明之方法係用於個體之高風險NASH的檢測。
在另一特定實施例中,將評分與截止值相比較以確定該個體患高風險NASH之風險高、低還是不確定。
在一個特定實施例中,該數學函數包括邏輯斯回歸函數(logistic regression function)。
在另一實施例中,生物流體樣本係血液、血清或血漿樣本,較佳地為血清樣本。
在又另一實施例中,該個體罹患肥胖症、胰島素抵抗、葡萄糖失耐、2型糖尿病(T2DM)、糖尿病前期、血脂異常或高甘油三酯血症。
根據另一態樣,本發明係關於一種電腦程式,其包含指令,該等指令當由處理器/處理裝置執行時,使該處理器/處理裝置:
- 接收miR34a-5p及YKL-40的經定量之水平;
- 接收該個體之性別;
- 根據數學函數,由此等經定量之水平及該個體之性別計算評分;及
- 基於經計算之評分與預先確定之截止值的比較,將該個體分配至高風險個體組或非高風險個體組中。
在又另一態樣中,本發明係關於一種電腦可讀取媒體,其包含本文所揭示之電腦程式。在一個特定實施例中,該電腦可讀取媒體係非暫時性媒體或儲存媒體。
此外,本發明係關於用於治療有需要個體之高風險NASH的特定抗NASH劑或抗纖維化劑,其中根據本文所揭示之方法,該個體已被歸類為患有高風險NASH。
本發明係關於一種非侵入式方法,其可用於幫助由個體之生物流體樣本辨別該個體之高風險NASH與非高風險NASH。
已開發出組織學評分/分期系統來評估NAFLD活動度水平及纖維化階段以及估計其演變為臨床肝臟結果之風險。已開發出NALFD活動度評分(NALFD-Activity-Score,NAS)來評估NAFLD之嚴重程度。NAS係由肝生檢切片確定之三個組織學評分之總和:
- S:脂肪變性評分:0:<5%;1:5-33%;2:34-66%;及3:>66%;
- LI:肝小葉發炎評分(每20*視野之病灶數):0:無;1:<2個病灶;2:2-4個病灶;及3:>4個病灶;及
- HB:氣球樣變性評分:0:無;1:極少;2:許多細胞/明顯的氣球樣變。
使用此評分系統,「NASH患者」具有NAS≥3,且脂肪變性為至少1分,肝小葉發炎為至少1分及肝細胞氣球樣變為至少1分。「非NASH」患者係具有以下中之任一者之患者:(i) NAS≥3且脂肪變性、肝小葉發炎及肝細胞氣球樣變評分中之至少一者等於0;或(ii) NAS<3。此外,在本發明的情形中,若患者患有病毒性肝炎、自體免疫肝病、酒精相關性肝病、藥物誘發之肝病或先天性慢性肝病,諸如遺傳性血色素沉著症、威爾遜氏病(Wilson's disease)、α-1-抗胰蛋白酶缺乏及多囊性卵巢症候群,則排除該患者為NASH患者。
組織學檢查時纖維化(F)之位置及程度預示NASH之嚴重程度(進展)。非酒精性脂肪性肝炎臨床研究網路(Nonalcoholic SteatoHepatitis Clinical Network,NASH-CRN)已開發出專用的纖維化分期系統(Kleiner, D.E等人, Hepatology, 2005年6月; 41(6):1313-21)。
NASH臨床研究網路評分系統定義 F評分
竇周或門靜脈周纖維化 1
輕度竇周纖維化(第3區) 1a
中度竇周纖維化(第3區) 1b
門靜脈/門靜脈周纖維化 1c
竇周及門靜脈/門靜脈周纖維化 2
橋接纖維化 3
肝硬化 4
使用此纖維化分期系統,無纖維化或具有極輕微纖維化(F=0-1)之患者一般不被視為有肝硬化、肝衰竭、肝細胞癌(HCC)或肝相關死亡之風險。具有顯著纖維化(F=2)及晚期纖維化(F=3)之患者發展肝硬化、肝衰竭、HCC及肝相關死亡之風險增加。患有代償性肝硬化之患者具有嚴重纖維化(F=4)且有較高的肝衰竭(失代償性肝硬化)、HCC及肝相關死亡風險。鑑別有發展HCC、肝硬化併發症及肝相關死亡風險的患者係肝臟評估之最終原因。根據FDA及EMA定義,應在藥理學上治療的有肝臟結果風險之患者係NAS≥4(且脂肪變性、肝小葉發炎及氣球樣變各自之評分≥ 1)且NASH-CRN纖維化評分(F)≥2的患者。
因此,在本發明的情形中,患有「高風險NASH」之患者,又稱為「高風險患者」或「具有肝臟結果風險之患者」係NAS高於或等於4、S評分高於或等於1、LI評分高於或等於1、HB評分高於或等於1且F評分高於或等於2的患者。其定義發展至少一種危及生命之肝臟結果諸如肝硬化、肝衰竭、HCC及肝相關死亡之風險較高的NASH患者亞組。
術語「個體」與「患者」在本文中可互換使用且係指人類個體。如上文所提及,NASH更常出現於罹患代謝障礙之患者。此外,已知NASH與諸如代謝障礙之類合併症相關。因此,本發明之方法可對呈現此類合併症之患者特別有益。常見的NASH合併症包括肥胖症、胰島素抵抗、葡萄糖失耐、T2DM、糖尿病前期、血脂異常、高甘油三酯血症、高血壓及心血管疾病。較大的年齡亦可能使NASH患者易患HCC。因此,在一個特定實施例中,患者罹患代謝障礙,諸如肥胖症、胰島素抵抗、葡萄糖失耐、T2DM、糖尿病前期、血脂異常及高甘油三酯血症。
如本文所使用,表述「生物流體樣本」係指血液、血清或血漿樣本,較佳地為血清樣本。
在一個特定實施例中,如本文所使用,表述「篩選」係指隊列中或臨床研究中待治療或不予治療之患者的選擇。患者之篩選可隱含檢測步驟以及接著以下各組中患者之分配:待治療組及不予治療組。
在本發明中,NASH患者中高風險NASH患者的選擇取決於利用hsa-miR34a及YKL40水平以及患者性別計算的評分。該評分與截止值之進一步比較可用於將患者分配至將接受治療之患者組中或不接受治療之患者組中。
在本發明的情形中,待治療之患者係有患NASH風險之患者且不予治療之患者係無NASH風險之患者。
如本文所使用,術語「監測」係指在兩個時間點計算之評分的比較。監測係隨著計劃或病況,如臨床研究或治療方案的進展而進行的資料之持續性、系統性收集及分析。根據本發明,該評分隨時間增加,病理學進展,而若評分降低,則病理學消退。監測因根據本發明之方法的非侵入性而成為可能。實際上,此分析之易用性允許在病理學之時間過程中進行重複量測及患者追蹤。總之,監測僅為隨著時間對患者應用檢測方法。
取決於待定量之生物標誌物的類型,可使用若干分析方法對生物流體樣本進行分析。此類分析方法包括定量RT-PCR、質譜、免疫PCR及免疫偵測。亦可引用生物晶片之使用來實施多種生物標誌物之同時分析。
在一個特定實施例中,miR-34a-5p之水平係以Cq (擴增循環數)或倍數變化,較佳地以倍數量測。熟習此項技術者易於獲得適合方法。特定RNA可在自生物流體樣本中提取出總RNA之後,使用例如市售套組定量。可監測提取效率以最大限度地減小樣本間變化。此類監測可藉由在總RNA提取之前,將內部處理對照(internal process control,IPC)添加至樣本中來進行。此類IPC可對應於已知序列之miRNA分子,該分子相對於樣本為異源的。舉例而言,可使用在不同於人類之物種中發現的miRNA分子,諸如來自秀麗隱桿線蟲(
Caenorhabditis elegans)之miRNA分子,特別是Cel-miR-40-3p (SEQ ID NO:1:UCACCGGGUGUACAUCAGCUAA)。此類IPC可包含在合成囊泡中。為了定量miR-34a-5p之水平,可使用miR-34a-5p Cq值已知之陽性對照,諸如miR-34a-5p Cq值已知之三種陽性對照。此等陽性對照可覆蓋NASH群體中miR-34a-5p水平之範圍。在使用三種陽性對照的情況下,一種對應於低miR-34a-5p水平,一種對應於中等水平且另一種對應於高水平。中等水平亦可稱為校準物(calibrator),用於分析中以計算倍數變化值。陽性對照係與個體之測試樣本同時處理。使用例如市售逆轉錄套組同時對以下各物進行逆轉錄:i)自外加有IPC之樣本提取之總RNA;及ii)來自亦外加有IPC之陽性對照的總RNA。接著,可使用例如市售定量PCR套組對cDNA實施定量。Cq確定模式可為回歸。另外,對於各患者樣本,可使用IPC及校準物Cq,根據用於將校準物針對IPC正規化、將樣本針對IPC正規化及以倍數變化定量miR-34a-5p水平的等式,以倍數變化表示轉錄本豐度。
在以下段落中,吾人描述實現miR34a-5p定量的特定但非限制性方法。簡言之,使用Promega的基於磁珠之提取Maxwell®血漿及血清套組(AS1680, Promega)及RCS48儀器(AS8500, Promega),根據製造商之說明書自患者血清樣本中提取出總RNA。為了監測提取效率並最大限度地減小樣本間變化,使用含有秀麗隱桿線蟲Cel-miR-40-3p(成熟miRNA序列UCACCGGGUGUACAUCAGCUAA-3';Integrated DNA Technologies;純化無RNA酶級HPLC)的合成囊泡作為IPC並在RNA提取之前添加至各樣本中。覆蓋NASH群體中miR-34a表現量範圍的miR-34a Cq值已知(低hsa-miR34a-5p水平[C1=32 Cq];中等hsa-miR34a-5p水平,亦稱為校準物[C2=30.7 Cq];及高hsa-miR34a-5p水平[C3=28Cq])之三種陽性對照係與測試樣本在同一時間處理,其中該中等標準亦用作該分析之校準物以計算倍數變化值。同時,使用TaqMan微小核糖核酸逆轉錄套組(4366597, Applied Biosystems, Thermo Fisher Scientific)逆轉錄含有IPC的來自血清樣本之總RNA及亦含有IPC的來自陽性對照之總RNA。逆轉錄反應係在24 μL含有3 μL TaqMan MicroRNA Assay 5*之最終混合物中進行並在熱循環器T100 (Biorad)中培育。將cDNA在-20℃儲存於低結合管中待用。使用TaqMan miRNA RT-qPCR Assay 20*及不含尿嘧啶-N-糖基酶(Uracil-N-Glycosilase,UNG)之TaqMan Universal Master Mix II (4440040, Applied Biosystems, ThermoFisher Scientific),根據製造商之說明書對成熟miRNA之表現量進行定量。使用5 μL固定體積之總cDNA作為模板,使用CFX96即時PCR偵測系統進行qPCR分析。使用miR-34a TaqMan分析(成熟hsa-miR-34a-5p之序列=UGGCAGUGUCUUAGCUGGUUGU(SEQ ID NO: 2);miR-base編號=MIMAT0000255;及成熟Cel-miR-40-3p之序列=UCACCGGGUGUACAUCAGCUAA(SEQ ID NO: 1);miR-base編號=MIMAT0000011)。Cq確定模式為回歸。對於各患者樣本,使用IPC及校準物Cq,根據以下等式,以倍數變化表示miRNA水平:
- 步驟1:針對內部處理對照將校準物C2正規化
ΔCq
C2 miR-34= Cq
C2 miR-34a- Cq
C2 中之 C2 miR-40- 步驟2:針對內部處理對照將樣本正規化
ΔCq
樣本 miR-34a= Cq
樣本 miR-34a- Cq
樣本 miR-40- 步驟3:以Cq表示的樣本miR-34a Δ表達式計算
ΔΔCq
樣本 miR-34= ΔCq
樣本- ΔCq
C2- 步驟4:以倍數表示的miR-34a之樣本Δ表達式
hsa-miR-34a倍數變化ΔFC) = 2
- ΔΔ Cq
在一個特定實施例中,YKL-40水平係以ng/ml量測。確定生物流體樣本中諸如YKL-40之類蛋白質之水平的方法係熟習此項技術者易於獲得的。舉例而言,可引用基於免疫偵測之方法,諸如ELISA。
該方法進一步包含確定該個體之性別。本文中顯示,性別對於實施miR-34a-5p及YKL-40水平之評分的輸出具有重要影響。意外地是,可使用此等生物標誌物之水平及個體之性別開發能夠準確地預測高風險NASH之機率的數學函數Δ亦即,統計演算法)。
因此,較佳地,生物標誌物水平及個體之性別可分別代入數學函數中以產生與高風險NASH狀態相關之輸出值。因此,該方法可用於將個體辨別為患有高風險NASH或未患高風險NASH。熟習此項技術者知道多種適合開發數學函數的方法,且所有此等方法皆在本發明之範圍內。在一個特定實施例中,該數學函數包括邏輯斯回歸等式。
在另一實施例中,本發明之方法實施下式:
其中
y = β0 + β1*log10ΔmiR-34a-5p Δ倍數)) + β2*log10ΔYKL-40 Δng/ml)) + β3*性別 + β4*log10ΔmiR-34a-5p ΔFold))*性別;及
其中若個體為女性,則性別為0,或若個體為男性,則性別為1。
在一個特定實施例中,β0包含在-3與3之間,特別是在-2與2之間。在一個特定實施例中,β1包含在1與5之間,特別是在2與4之間。在一個特定實施例中,β2包含在0與4.5之間,特別是在0.5與3之間。在一個特定實施例中,β3包含在-2與2之間,特別是在-1與1之間。在一個特定實施例中,β4包含在-1與2之間,特別是在0與2之間。在另一特定實施例中,β0包含在-3與3之間,β1包含在1與5之間,β2包含在0與4.5之間,β3包含在-2與2之間,且β4包含在-1與2之間。在又另一特定實施例中,β0包含在-2與2之間,β1包含在2與4之間,β2包含在0.5與3之間,β3包含在-1與1之間,且β4包含在0與2之間。
舉例而言,可使用以下等式檢測高風險NASH:
等式1:
y = -1.4539 + 2.3003*log10ΔmiR-34a-5p Δ倍數)) + 1.0598*log10ΔYKL-40 Δng/ml)) - 0.0533*性別 + 0.4514*log10ΔmiR-34a-5p Δ倍數))*性別
等式2:
y = -0.8756 + 3.3957*log10ΔmiR-34a-5p Δ倍數)) + 2.5248*log10ΔYKL-40 Δng/ml)) - 0.6496*性別 + 0.2873*log10ΔmiR-34a-5p Δ倍數))*性別
等式3:
y = 1.1543 + 2.5678*log10ΔmiR-34a-5p Δ倍數)) + 1.7859*log10ΔYKL-40 Δng/ml)) + 0.3514*性別 + 0.7264*log10ΔmiR-34aΔ5p Δ倍數))*性別
接著,可將由數學函數計算的評分與預先確定之截止值,諸如低及高截止值相比較。在此情形中,S計算值低於低截止值提示個體未患高風險NASH,且S計算值大於或等於高截止值提示個體患有高風險NASH。
在一個特定實施例中,低截止值包含在0.24與0.5之間,特別是在0.41與0.49之間。在另一特定實施例中,高截止值包含在0.6與0.95之間,特別是在0.62與0.74之間。在另一特定實施例中,低截止值等於0.4564。在另一特定實施例中,高截止值等於0.6815。在另一特定實施例中,低截止值等於0.4564且高截止值等於0.6815。
本發明亦關於一種電腦程式,其包含指令,該等指令當由處理器/處理裝置執行時,使該處理器/處理裝置:
- 接收miR-34a-5p及YKL-40的經定量之水平;
- 接收該個體之性別;
- 根據如上文所描述之數學函數,由此等經定量之水平及該個體之性別計算評分;及
- 基於經計算之評分與預先確定之截止值的比較,將該個體分配至高風險個體組或非高風險個體組中。
本發明進一步提供一種電腦可讀取媒體,其包含其中所描述之電腦程式。根據一個特定實施例中,該電腦可讀取媒體係非暫時性媒體或儲存媒體。
在一些實施例中,根據本發明之方法,可決定向個體提出生活方式建議Δ諸如食物方案或提供身體活動建議),對個體提供醫學護理Δ例如藉由安排定期向醫師問診或定期檢查,例如定期監測肝損傷標誌物),或向患者投予至少一種NASH或肝纖維化療法,以治療或預防高風險NASH。在一個特定實施例中,可決定向個體提出生活方式建議或投予至少一種NASH或肝纖維化療法。因此,本發明進一步關於一種用於治療有需要個體之NASH之方法中的抗NASH化合物或抗纖維化化合物,其中已基於根據本發明之方法對該個體進行鑑別。
如本文所使用,術語「治療」係指治療性措施及防治性或預防性措施兩者,其中目標在於預防或減慢Δ減輕)不合需要之生理變化或病症。有益或所需的臨床結果包括但不限於症狀緩解;使病理狀態穩定Δ特定言之,不惡化);減慢或停止疾病進展;改善或緩解病理病況。特定言之,出於本發明之目的,治療係針對減慢NASH及/或纖維化之進展及降低其他併發症之風險。治療亦可涉及使存活期相較於未接受治療時的預期存活期延長。
抗NASH劑或抗纖維化劑係以治療有效量投予。如本文所使用,表述「治療有效量」係指有效達成所需治療結果的藥物之量。藥物之治療有效量可根據諸如個人之疾病狀態、年齡、性別及體重以及藥物在個人中引起所需反應之能力之類因素而變化。治療有效量亦為治療有益作用超過藥劑之任何有毒或有害作用的量。藥物之有效劑量及劑量方案取決於待治療之疾病或病況且可由熟習此項技術者確定。具有此項技術中一般技術的醫師可易於確定且規定所需醫藥組成物之有效量。舉例而言,醫師可以低於達成所需治療作用所需水平的水平開始醫藥組成物中所採用之藥物劑量,且逐漸增加劑量直至達成所需作用。一般而言,本發明組成物之適合劑量將為作為根據特定劑量方案有效產生治療作用之最低劑量的化合物之量。此類有效劑量一般將取決於以上描述之因素。
在一個特定實施例中,本發明係關於一種用於治療罹患高風險NASH之個體之NASH的方法中之抗NASH化合物,其中基於根據本發明之方法,該個體已被歸類為患有高風險NASH。
示例性抗NASH化合物及抗纖維化化合物列於下:
- 式ΔI)之化合物或其醫藥學上可接受之鹽:
ΔI)
其中:
X1表示鹵素原子、R1基團或G1-R1基團;
A表示CH=CH或CH2-CH2基團;
X2表示G2-R2基團;
G1表示氧原子;
G2表示氧原子或硫原子;
R1表示氫原子、未經取代之烷基、芳基或經一或多個選自以下之取代基取代的烷基:鹵素原子、烷氧基、烷基硫基、環烷基、環烷基硫基及雜環基;
R2表示經-COOR3基團取代之烷基,其中R3表示氫原子或烷基,該烷基經或未經一或多個選自以下之取代基取代:鹵素原子、環烷基及雜環基;及
R4及R5相同或不同,表示烷基,該烷基經或未經一或多個選自以下之取代基取代:鹵素原子、環烷基及雜環基;AMP活化蛋白激酶刺激劑,諸如PXL-770、MB-11055、Debio-0930B、二甲雙胍Δmetformin)、CNX-012、O-304、芒果苷鈣鹽Δmangiferin calcium salt)、艾曲波帕Δeltrombopag)、卡羅妥昔單抗Δcarotuximab)及伊美格列明Δimeglimin);膽酸,諸如奧貝膽酸ΔOCA)、熊去氧膽酸ΔUDCA)、降熊去氧膽酸及熊去氧膽酸;CCR拮抗劑,諸如森尼韋若Δcenicriviroc) ΔCCR2/5拮抗劑)、PG-092、RAP-310、INCB-10820、RAP-103、PF-04634817及CCX-872;二肽基肽酶IVΔDPP4)抑制劑,諸如依格列汀Δevogliptin)、維格列汀Δvidagliptin)、複格列汀Δfotagliptin)、阿格列汀Δalogliptin)、沙格列汀Δsaxagliptin)、替格列汀Δtilogliptin)、阿拉格列汀Δanagliptin)、西他列汀Δsitagliptin)、瑞格列汀Δretagliptin)、美格列汀Δmelogliptin)、果格列汀Δgosogliptin)、曲格列汀Δtrelagliptin)、替格列汀Δteneligliptin)、度格列汀Δdutogliptin)、利格列汀Δlinagliptin)、吉格列汀Δgemigliptin)、優格列汀Δyogliptin)、貝格列汀Δbetagliptin)、依格列汀Δimigliptin)、奧格列汀Δomarigliptin)、維格列汀及地格列汀Δdenagliptin);法尼醇X受體ΔFarnesoid X receptor,FXR)促效劑,諸如奧貝膽酸ΔOCA)、曲匹氟索Δtropifexor)ΔLJN452)、希勒氟索Δcilofexor)ΔGS9674)、尼度氟索ΔNidufexor)ΔLMB763)、EDP-305、AKN-083、INT-767、GNF-5120、LY2562175、INV-33、NTX-023-1、EP-024297、Px-103、SR-45023、TERN-101 Δ6-{4-[5-環丙基-3-Δ2,6-二氯-苯基)-異噁唑-4-基甲氧基]-哌啶-1-基}-1-甲基-1H-吲哚-3甲酸)、TERN-201、TERN-501及TERN-301;纖維母細胞生長因子19 ΔFGF-19)受體配體或FGF-19的經工程改造之功能性變異體;纖維母細胞生長因子21 ΔFGF-21)促效劑,諸如PEG-FGF21Δ派貝複明Δpegbelfermin),先前為BMS-986036)、YH-25348、BMS-986171、YH-25723、LY-3025876及NNC-0194-0499;經工程改造之纖維母細胞生長因子19 ΔFGF-19)類似物,諸如NGM-282 Δ阿達佛明Δaldafermin));升糖素樣肽-1 ΔGLP-1)類似物,諸如索馬魯肽Δsemaglutide)、利拉魯肽Δliraglutide)、艾塞那肽Δexenatide)、阿比魯肽Δalbiglutide)、度拉糖肽Δdulaglutide)、利司那肽Δlixisenatide)、洛塞那肽Δloxenatide)、埃格納肽Δefpeglenatide)、他司魯肽Δtaspoglutide)、MKC-253、DLP-205及ORMD-0901;菸酸,諸如菸鹼酸ΔNiacin)及維生素B3;硝唑尼特Δnitazoxanide)ΔNTZ)、其活性代謝物替唑尼特Δtizoxanide)ΔTZ)或TZ之其他前藥,諸如RM-5061;PPARα促效劑,諸如非諾貝特Δfenofibrate)、環丙貝特Δciprofibrate)、培馬貝特Δpemafibrate)、吉非羅齊Δgemfibrozil)、氯貝特Δclofibrate)、比尼貝特Δbinifibrate)、克利貝特Δclinofibrate)、氯貝酸Δclofibric acid)、尼可貝特Δnicofibrate)、吡貝特Δpirifibrate)、普拉貝脲Δplafibride)、羅尼貝特Δronifibrate)、羥乙茶鹼氯貝特Δtheofibrate)、托考貝特Δtocofibrate)及SR10171;PPARγ促效劑,諸如吡格列酮Δpioglitazone)、氘化吡格列酮、羅格列酮Δrosiglitazone)、埃非他酮Δefatutazone)、ATx08-001、OMS-405、CHS-131、THR-0921、SER-150-DN、KDT-501、GED-0507-34-Levo、CLC-3001及ALL-4;PPARδ促效劑,諸如GW501516 Δ恩度拉泊ΔEndurabol)或Δ{4-[Δ{4-甲基-2-[4-Δ三氟甲基)苯基]-1,3-噻唑-5-基}甲基)硫基]-2-甲基苯氧基}乙酸))、MBX8025Δ塞拉德帕ΔSeladelpar)或{2-甲基-4-[5-甲基-2-Δ4-三氟甲基-苯基)-2H-[l,2,3]***-4-基甲基硫基]-苯氧基}-乙酸)、GW0742Δ[4-[[[2-[3-氟-4-Δ三氟甲基)苯基]-4-甲基-5-噻唑基]甲基]硫基]-2-甲基苯氧基]乙酸)、L165041、HPP-593及NCP-1046;PPAR α/γ雙重促效劑Δ又稱為格列紮類Δglitazars)),諸如沙羅格列紮Δsaroglitazar)、阿格列紮Δaleglitazar)、莫格列紮Δmuraglitazar)、替格列紮Δtesaglitazar)及DSP-8658;PPAR γ/δ雙重促效劑,諸如經結合之亞麻油酸ΔCLA)及T3D-959;PPAR α/γ/δ泛促效劑或PPAR泛促效劑,諸如IVA337、TTAΔ十四烷基硫代乙酸)、巴伐奇寧Δbavachinin)、GW4148、GW9135、苯紮貝特Δbezafibrate)、拉尼蘭諾Δlanifibranor)、洛貝格列酮Δlobeglitazone)及CS038;鈉-葡萄糖運輸蛋白ΔSGLT)2抑制劑,諸如利可格列淨Δlicoglifozin)、瑞格列淨Δremogliflozin)、達格列淨Δdapagliflozin)、恩格列淨Δempagliflozin)、埃格列淨Δertugliflozin)、索格列淨Δsotagliflozin)、伊格列淨Δipragliflozin)、泰格列淨Δtianagliflozin)、卡格列淨Δcanagliflozin)、托格列淨Δtofogliflozin)、加格列淨Δjanagliflozin)、貝沙格列淨Δbexagliflozin)、魯格列淨Δluseogliflozin)、舍格列淨Δsergliflozin)、HEC-44616、AST-1935及PLD-101;硬脂醯基CoA去飽和酶-1抑制劑/脂肪酸膽酸結合物,諸如阿雷美羅Δaramchol)、GRC-9332、斯蒂美羅Δsteamchol)、TSN-2998、GSK-1940029及XEN-801;甲狀腺受體β ΔTHRβ)促效劑,諸如VK-2809、瑞美替羅Δresmetirom)ΔMGL-3196)、MGL-3745、SKL-14763、索貝替羅Δsobetirome)、BCT-304、ZYT-1、MB-07811及伊羅替羅Δeprotirome);維生素E及同功型;維生素E與維生素C及阿托伐他汀Δatorvastatin)之組合。
在一個特定實施例中,該抗NASH劑係選自派貝複明、森尼韋若、達格列淨、度拉糖肽、恩格列淨、非諾貝特、拉尼蘭諾、利拉魯肽、奧貝膽酸、吡格列酮、瑞美替羅、沙羅格列紮鎂、塞拉德帕、索馬魯肽、西他列汀、TERN-101、TERN-201及曲匹氟索。
實例
NIS4
®係首創的基於血液之NIT,專門設計成藉由偵測高風險NASH患者來解決複合式纖維化*NAS終點,並含有4種獨立的生物標誌物:miR-34a-5p、α-2巨球蛋白ΔA2M)、YKL-40 Δ或殼質酶3樣蛋白質1)及糖化血色素ΔHbA1c) ΔHarrison等人
,The Lancet Gastroenterology & Hepatology, 5Δ11):970-985, 2020)。NIS4
®係基於針對需要不同生物流體Δ全血及血清)及不同實驗室方法之4種不同生物標誌物的評價。
因此,目的係在可能情況下,在偵測高風險NASH個體方面實現與NIS4
®同樣高之效能的同時,改善該NIT,以及藉由限制可能影響NIT效能之外部因素來改善模型之穩健性。目的亦在於以降低之成本提供測試。
由Golden-505臨床試驗ΔNCT01694849)發佈之資料集用作訓練隊列。Golden資料集僅含有至少NAS評分等於3的NASH患者。另外,此資料集中不存在肝硬化患者。最終提取之訓練資料集含有198名NASH患者,其中高風險NASH之發生率為50%。藉由保持最初存在於該資料集中之所有高風險NASH患者並對其中各者選擇最佳控制,非高風險與高風險NASH群體均如預期一般針對潛在干擾因素進行充分平衡。
由Golden資料集已計算出包括構成NIS4
®之不同生物標誌物組合的不同模型之貝葉斯資訊量準則Δbayesian information criterion,BIC)。另外,亦評價可潛在地影響測試之穩健性的不同參數,諸如患者之年齡、性別及T2DM狀態。此等模型均使用邏輯斯回歸進行訓練。接著,使用由Resolve-It臨床試驗ΔNCT02704403)得到的資料集,吾人確定簡化模型之穩健性。此資料集含有684名患者,主要為NASH患者Δ95.32%),其高風險NASH之發生率為66%。使用此資料集,吾人構建出不同的匹配亞群來分析利用該簡化模型獲得的評分之穩健性。
吾人使用4.3.2版MatchIt套裝軟體中的matchit函數,利用基因方法。在各情況下,吾人並行啟動20次執行,使得測徑器在0.005至0.1*0.005範圍內。在測試的所有測徑器之間,將進行測徑器之選擇以便實現所有變量之標準化差異小於0.1,可能的話0.05,同時保持最高的患者數目。藉由使用此方法,吾人在各情況下獲得所有因子皆充分平衡的亞群,以使得僅兩個群體之間不同的特徵為所研究之特徵。因此,吾人可以合理地假定,此特定因子係對生物標誌物之影響的來源,若存在影響的話。
值得關注的是,miR-34與YKL-40之組合使該模型在年齡及T2DM狀態方面穩定。相反地,發現性別對模型之輸出具有影響。因此,進行新穎建模以考慮性別之影響。
為了嘗試校正miR-34a-5p及YKL-40之組合中性別的影響,吾人決定利用以上描述之Golden訓練隊列訓練一個新模型,該模型亦含有「miR-34a-5p*性別」相互作用參數。
由本研究得到下式:
其中
y = β0 + β1*log10ΔmiR-34a-5p Δ倍數)) + β2*log10ΔYKL-40 Δng/ml)) + β3*性別 + β4*log10ΔmiR-34a-5p ΔFold))*性別;及
其中若個體為女性,則性別為0,或若個體為男性,則性別為1。
此模型在下文中稱為「GBM」。
實例示於表1中。
表1
miR34-a | YKL-40 | 性別 | miR34a-5p * 性別 | |
miR-34a-5p + YKL-40 | 2.3003 | 1.0598 | -0.0533 | 0.4514 |
接著,計算截止值。由此計算出低ΔLc,80%靈敏度)截止值等於0.4564且高ΔHc,90%特異性)截止值等於0.6815。
接著,使用來自Resolve-it臨床試驗之患者,將此模型之效能與NIS4
®之效能相比較。此資料集,稱為「RIt2」,係由獲自2035名患者之資訊得到。此表示相對於用作訓練資料集之Golden資料集的獨立驗證資料集。
正如預期,與非高風險NASH群體相比較,高風險NASH患者亦與T2DM、血脂異常、高血壓以及肥胖患者之較高發生率相關聯。關於組織學譜,吾人觀察到具有F3/F4纖維化評分但NAS評分為3的一組重要患者。
接著,吾人進行AUROC分析。為了開始此驗證程序,吾人先關注於不同測試在偵測高風險NASH患者方面之總體效能。吾人先以繪製NIS4
®/GBM模型之ROC曲線以及纖維化-4指數ΔFIB-4)及丙胺酸轉胺酶ΔALT)模型之ROC曲線開始。實際上,FIB-4通常被用作纖維化之參考/替代標誌物,而ALT可視為NASH之替代標誌物。吾人接著使用Delong測試比較不同GBM、FIB-4與ALT AUROC與NIS4
®AUROC,且結果報導於表2中。
表2:相對於NIS4
®的AUROC比較-高風險NASH終點
數量 | 高風險數量 | AUROC Δ95% CI) | P值 | |
NIS4 ® | 2035 | 929 | 0.7919 Δ0.7722, 0.8107) | NA |
GBM | 2035 | 929 | 0.8133 Δ0.7951, 0.8318) | 2e-04 |
FIB-4 | 2035 | 929 | 0.6528 Δ0.6287, 0.6763) | <0.0001 |
ALT | 2035 | 929 | 0.6986 Δ0.6766, 0.721) | <0.0001 |
對於偵測AUROC回到0.81的高風險NASH患者,GBM總體上勝過其他NIT,包括NIS4
®。
遵循NIMBLE方法,比較GBM針對與高風險NASH不同之終點的總體效能。為此,吾人決定分析主要關注於NASH之3個不同終點Δ高風險NASH F3、NASH、NAS4)及僅3個纖維化終點ΔF2、F3、F4)。對於第一者,吾人在比較器中包括ALT作為參考,且對於第二組,包括FIB-4作為參考。結果分別彙總於表3及表4中。
表3:相對於NIS4之AUROC比較-不同NASH相關性終點
表4:相對於NIS4之AUROC比較-不同纖維化終點
高風險F3 Δ26.1%) | NASH Δ66.0%) | NAS4 Δ64.5%) | ||||
AUROC Δ95% CI) | P值 | AUROC Δ95% CI) | P值 | AUROC Δ95% CI) | P值 | |
NIS4 ® | 0.8 Δ0.79, 0.83) | NA | 0.74 Δ0.71, 0.76) | NA | 0.72 Δ0.7, 0.75) | NA |
GBM | 0.79 Δ0.77, 0.81) | 0.0113 | 0.78 Δ0.76, 0.8) | <0.0001 | 0.78 Δ0.76, 0.8) | <0.0001 |
ALT | 0.66 Δ0.64, 0.69) | <0.0001 | 0.7 Δ0.68, 0.72) | 0.0054 | 0.73 Δ0.71, 0.76) | 0.3689 |
F2 Δ59.1%) | F3 Δ35.2%) | F4 Δ6.5%) | ||||
AUROC Δ95% CI) | P值 | AUROC Δ95% CI) | P值 | AUROC Δ95% CI) | P值 | |
NIS4 ® | 0.82 Δ0.8, 0.84) | NA | 0.79 Δ0.77, 0.81) | NA | 0.77 Δ0.74, 0.81) | NA |
GBM | 0.81 Δ0.79, 0.83) | 0.037 | 0.74 Δ0.72, 0.77) | <0.0001 | 0.69 Δ0.65, 0.73) | <0.0001 |
FIB-4 | 0.72 Δ0.69, 0.74) | <0.0001 | 0.74 Δ0.72, 0.77) | 1e-04 | 0.78 Δ0.75, 0.82) | 0.6882 |
GBM在不同NASH定向之終點中保持高效能,由此亦改善NIS4
®針對NAS4終點之效能。
接著,吾人關注於比較NIS4
®與GBM對於排除及納入具有以上確定之各別Lc及Hc之高風險NASH患者的臨床效能。結果彙總於表5中。
表5:NIS4
®相對於GBM臨床效能比較
NIS4 ® | GBM | P值 | |
AUC | 0.7919 Δ0.7722, 0.8107) | 0.8133 Δ0.7951, 0.8318) | 2e-04 |
排除 | |||
Lc | 0.3614 | 0.4564 | 0.2695 |
SenLc | 86.11 Δ83.68, 88.24) | 85.04 Δ82.54, 87.24) | <0.0001 |
SpeLc | 53.07 Δ50.08, 56.04) | 61.21 Δ58.26, 64.08) | 0.3437 |
NPV | 81.98 Δ78.93, 84.69) | 82.97 Δ80.17, 85.45) | 1e-04 |
不確定 | 566 Δ27.81) | 474 Δ23.29) | |
納入 | |||
Hc | 0.6282 | 0.6815 | |
SenHc | 58.77 Δ55.52, 61.95) | 62.11 Δ58.89, 65.23) | 0.0134 |
SpeHc | 81.28 Δ78.83, 83.52) | 84.81 Δ82.53, 86.85) | 8e-04 |
PPV | 72.51 Δ69.14, 75.64) | 77.45 Δ74.24, 80.37) | 1e-04 |
關於排除效能,對於使兩種NIT達成類似靈敏度Δ85-86%)及NPVΔ82-83%)的Lc,吾人觀察到相對於NIS4
®,GBM之特異性顯著增加。
關於納入效能,GBM實現相較於NIS4
®明顯較高的特異性值Δ85%相對於81%)、PPV值Δ77%相對於73%)。GBM相較於NIS4
®亦回到明顯較高之靈敏度Δ62%相對於59%)。
最後,當關注於不確定區時,結果亦有利於GBM。
亦執行亞群分析並在NIS4
®與GBM之間進行比較。參見下表6。
表6:NIS4
®及GBM之組間平均值比較
NIS4® | GBM | ||||
Prev | 平均值 ± sd | P值 | 平均值± sd | P值 | |
性別 Δn=1318) | |||||
女性 | 52.2 | 0.509 ± 0.26 | NA | 0.564 ± 0.27 | NA |
男性 | 52.2 | 0.541 ± 0.26 | 0.0235 | 0.564 ± 0.27 | 0.9755 |
年齡Δn=738) | |||||
≤50 | 46.1 | 0.463 ± 0.27 | NA | 0.54 ± 0.28 | NA |
≥60 | 46.1 | 0.557 ± 0.25 | <0.0001 | 0.554 ± 0.26 | 0.4921 |
T2DM Δn=1284) | |||||
N | 47.7 | 0.493 ± 0.25 | NA | 0.556 ± 0.27 | NA |
Y | 47.7 | 0.577 ± 0.24 | <0.0001 | 0.562 ± 0.26 | 0.7051 |
NIS4
®受年齡及T2DM狀態影響,而GBM評分不再受年齡及T2DM狀態明顯影響。因此,吾人獲得在此等因子方面穩健的GBM建模。
GBM亦高效減少性別對評分之影響。吾人觀察到,GBM評分之校正主要係針對低值執行,對應於觀察到性別對miR-34a-5p之影響主要存在於高風險NASH患者。
因此,吾人已鑑別出相較於NIS4
®簡化且更穩健的NIT。此新模型係基於減少數目之生物標誌物,其中兩者之定量係在血清中執行。
值得關注的是,此新模型僅需要一個生物流體樣本來執行標誌物分析。出於此原因,此NIT亦更便宜且更易於實施。另外,吾人已證實,相較於NIS4
®,此新NIT受性別、年齡及T2DM狀態之影響較小。此提供用於檢測高風險NASH個體的新穎有用工具。
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TW202405190A_112113147_SEQL.xml
Claims (9)
- 一種用於檢測、篩選、監測或預後高風險非酒精性脂肪性肝炎ΔNASH)個體的方法,該方法包含: 對該個體之生物流體樣本中miR-34a-5p及YKL-40之水平進行定量; 獲得該個體之性別; 在數學函數中組合經定量之水平及該性別以分配評分;及 將該評分與截止值相比較以確定該個體是否為高風險NASH個體。
- 如請求項1之方法,其中該數學函數包括邏輯斯回歸函數Δlogistic regression function)。
- 如請求項1或2之方法,其中該生物流體樣本係血液、血清或血漿樣本。
- 如請求項1至3中任一項之方法,其中該生物流體樣本係血清樣本。
- 如請求項1至4中任一項之方法,其中該個體罹患肥胖症、胰島素抵抗、葡萄糖失耐、T2DM、糖尿病前期、血脂異常或高甘油三酯血症。
- 一種電腦程式,其包含指令,該等指令當由處理器/處理裝置執行時,使該處理器/處理裝置: 接收miR-34a-5p及YKL-40的經定量之水平; 接收該個體之性別; 根據數學函數,由此等經定量之水平及該個體之性別計算評分;及 基於經計算之評分與預先確定之截止值的比較,將該個體分配至高風險個體組或非高風險個體組中。
- 一種電腦可讀取媒體,其包含如請求項6之電腦程式。
- 如請求項7之電腦可讀取媒體,其係非暫時性媒體或儲存媒體。
- 一種用於治療高風險NASH個體的抗NASH劑或抗纖維化劑,其中 該抗NASH劑係選自派貝複明Δpegbelfermin)、森尼韋若Δcenicriviroc)、達格列淨Δdapagliflozin)、度拉糖肽Δdulaglutide)、恩格列淨Δempagliflozin)、非諾貝特Δfenofibrate)、拉尼蘭諾Δlanifibranor)、利拉魯肽Δliraglutide)、奧貝膽酸Δobeticholic acid)、吡格列酮Δpioglitazone)、瑞美替羅Δresmetirom)、沙羅格列紮鎂Δsaroglitazar magnesium)、塞拉德帕Δseladelpar)、索馬魯肽Δsemaglutide)、西他列汀Δsitagliptin)、TERN-101、TERN-201及曲匹氟索Δtropifexor),及 其中根據如請求項1至5中任一項之方法,該個體已被歸類為患有高風險NASH。
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