歌禮制藥-B(01672.HK)：甘萊宣佈其NASH候選藥物FXR激動劑ASC42在美國I期臨牀試驗中取得良好頂線數據
格隆匯6月16日丨歌禮制藥-B(01672.HK)公吿，公司全資附屬公司甘萊製藥有限公司("甘萊")的非酒精性脂肪性肝炎(NASH)候選藥物法尼醇X受體(FXR)激動劑ASC42在美國I期臨牀試驗中取得良好的安全性和藥效學生物標誌物頂線數據。
ASC42在美國的I期試驗是一項首次在人體中開展的隨機、安慰劑對照、雙盲、單劑量和多劑量遞增以及食物影響的臨牀試驗。參加研究的64例健康受試者分別接受ASC42或匹配安慰劑的給藥。在單劑量遞增研究中，給藥劑量為5mg至200mg，單次給藥；在多劑量遞增研究中，給藥劑量為5mg至50mg，每日一次，連續14天給藥。另外，在15mg隊列中，還研究了食物對ASC42藥代動力學的影響。該試驗的主要目的是評估ASC42對比安慰劑的安全性、藥代動力學和藥效學。試驗通過測量7α-羥基-4-膽甾烯-3-酮(C4)和成纖維細胞生長因子19(FGF19)，評估了FXR靶向激活的生物標誌物水平。其中C4是膽汁酸合成的血液生物標誌物，會隨着FXR的激活而減少；FGF19是FXR激活後在腸道產生的激素，用於調節膽汁酸的合成以及葡萄糖和脂肪的代謝。
基於小鼠和大鼠非酒精性脂肪性肝炎動物模型，預測得出人體的治療劑量為每日一次、每次15mg。ASC42I期頂線數據顯示，在為期14天、每日一次、每次15mg的治療過程中，FXR靶向激活的生物標誌物FGF19相較於給藥前分別在第1天和第14天顯示出1,195%和1,632%的增幅；FXR靶向激活的生物標誌物C4相較於基線分別在第1天和第14天顯示出88%和93%的降幅。基於上述數據，每日一次、每次15mg的劑量已被確定作為非酒精性脂肪性肝炎患者II期試驗的三個劑量一，該試驗將於2021年年底前啟動。FGF19增加和╱或C4減少的幅度可以預測非酒精性脂肪性肝炎患者肝臟脂肪減少的水平，同時，通過MRI-PDFF檢測，≥30%的相對肝臟脂肪減少可以預測肝臟組織學獲益。
總體而言，ASC42表現出良好的安全性和耐受性。在試驗過程中，沒有和試驗藥物相關的嚴重不良事件或提前停藥事件發生。值得注意的是，在為期14天、每日一次、每次15mg的治療過程中，未觀察到瘙癢症狀或治療引起的丙氨酸氨基轉移酶(ALT)和天門冬氨酸氨基轉移酶(AST)升高，且低密度脂蛋白膽固醇(LDL-C)的平均值維持在正常值範圍內。
此外，試驗結果表明，高脂餐對ASC42的藥代動力學參數沒有顯著影響。
ASC42是一款由甘萊完全自主研發、有望成為同類最佳(best-in-class)的新型高效選擇性非甾類FXR激動劑。ASC42口服片劑由甘萊專有製劑技術開發，具有室温下穩定的特點。ASC42既可作為單藥使用，也可與甲狀腺激素β受體(THR-β)激動劑ASC41或脂肪酸合成酶(FASN)抑制劑ASC40聯合使用。
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