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科学家完成在非酒精性脂肪肝患者中单独使用ACC抑制剂或与DGAT2抑制剂共同使用的临床试验
作者:小柯机器人 发布时间:2021/10/17 16:28:45

美国辉瑞公司William P. Esler团队完成在非酒精性脂肪肝患者中单独使用ACC抑制剂或与DGAT2抑制剂共同使用的临床试验。这一研究成果于2021年10月11日在线发表在国际学术期刊《自然—医学》上。

两项平行的2a期研究调查了肝脏导向的ACC1/2抑制对非酒精性脂肪肝成人患者的影响。第一项研究(NCT03248882)考察了新型ACC1/2抑制剂PF-05221304(2、10、25和50毫克,每日一次(QD))在治疗16周后与安慰剂相比的效果;第二项研究(NCT03776175)考察了PF-05221304(15毫克,每日两次(BID))与DGAT2抑制剂PF-06865571(300毫克,BID)共同使用,在治疗6周后与安慰剂的效果。两项研究的主要终点是通过磁共振成像-质子密度脂肪分数评估肝脏脂肪从基线的变化百分比。PF-05221304单药剂量≥10mg QD时,肝脏脂肪的剂量依赖性减少达到50-65%;最小二乘法平均值(LSM)80%置信区间(CI)为-7.2(-13.9,0.0),-17。 1(-22.7,-11.1),-49.9(-53.3,-46.2),-55.9(-59.0,-52.4)和-64.8(-67.5,-62.0),分别与16周安慰剂和PF-05221304 2、10、25和50mg QD。

不良事件(AE)的总体发生率没有随着PF-05221304剂量的增加而增加,除了23/305(8%)患者的血清甘油三酯(肝脏乙酰辅酶A羧化酶(ACC)抑制的已知后果)剂量依赖性升高,导致13/305(4%)患者停药,以及其他血清脂类的剂量依赖性升高。与安慰剂相比,联合使用PF-05221304和PF-06865571降低了肝脂肪(安慰剂调整的LSM(90%CI)-44.6%(-54.8,-32.2))。单独使用PF-05221304或PF-06865571 6周后,经安慰剂调整的LSM(90%CI)降低肝脏脂肪为-44.5%(-55.0,-31.7)和-35.4%(-47.4,-20.7)。10/28(36%)的患者在联合使用PF-05221304和PF-06865571后报告了AE,没有因AE而停药,ACC抑制剂介导的对血清甘油三酯的影响得到了缓解,这表明PF-05221304和PF-06865571联合使用有可能解决单独抑制ACC的一些局限性。

据介绍,脂质代谢的改变可能有助于非酒精性脂肪肝(NAFLD)的发病机制。然而,目前在美国或欧盟没有任何药理制剂被批准用于治疗非酒精性脂肪肝。

附:英文原文

Title: ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials

Author: Calle, Roberto A., Amin, Neeta B., Carvajal-Gonzalez, Santos, Ross, Trenton T., Bergman, Arthur, Aggarwal, Sudeepta, Crowley, Collin, Rinaldi, Anthony, Mancuso, Jessica, Aggarwal, Naresh, Somayaji, Veena, Inglot, Malgorzata, Tuthill, Theresa A., Kou, Kou, Boucher, Magalie, Tesz, Greg, Dullea, Robert, Bence, Kendra K., Kim, Albert M., Pfefferkorn, Jeffrey A., Esler, William P.

Issue&Volume: 2021-10-11

Abstract: Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study (NCT03248882) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study (NCT03776175) investigated the effects of PF-05221304 (15mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging–proton density fat fraction. Dose-dependent reductions in liver fat reached 50–65% with PF-05221304 monotherapy doses ≥10mg QD; least squares mean (LSM) 80% confidence interval (CI) was 7.2 (13.9, 0.0), 17.1 (22.7, 11.1), 49.9 (53.3, 46.2), 55.9 (59.0, 52.4) and 64.8 (67.5, 62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) 44.6% (54.8, 32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was 44.5% (55.0, 31.7) and 35.4% (47.4, 20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone.

DOI: 10.1038/s41591-021-01489-1

Source: https://www.nature.com/articles/s41591-021-01489-1

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex