Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.
Nat Med. 2021 Oct;27(10):1836-1848. doi: 10.1038/s41591-021-01489-1. Epub 2021 Oct 11.
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 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study ( NCT03776175 ) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg 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 ≥10 mg 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 50 mg 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.
脂质代谢的改变可能有助于非酒精性脂肪性肝病 (NAFLD) 的发病机制。然而，目前在美国或欧盟没有批准任何用于治疗 NAFLD 的药物。两项平行的 2a 期研究调查了肝脏靶向 ACC1/2 抑制在患有 NAFLD 的成年人中的作用。第一项研究（NCT03248882）研究了新型 ACC1/2 抑制剂 PF-05221304（2、10、25 和 50mg 每日一次（QD））单药治疗与安慰剂在 16 周治疗中的疗效；第二项研究（NCT03776175）研究了 PF-05221304（15mg 每日两次（BID））与 DGAT2 抑制剂 PF-06865571（300mg BID）联合用药的效果在 6 周治疗后与安慰剂相比。这两项研究的主要终点均为磁共振成像质子密度脂肪分数评估的肝脂肪从基线的百分比变化。PF-05221304 单药治疗剂量≥10mg QD 可使肝脂肪减少 50-65%；最小二乘均值（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），安慰剂和 PF-05221304 2、10、25 和 50mg QD 的 16 周 LSM 分别为 16 周。随着 PF-05221304 剂量的增加，不良事件（AE）的总发生率并没有增加，除了血清甘油三酯的剂量依赖性升高（已知是由于肝乙酰辅酶 A 羧化酶（ACC）抑制）在 23/305（8%）患者中，导致 13/305（4%）患者停药，以及其他血清脂质的剂量依赖性升高。PF-05221304 和 PF-06865571 联合用药与安慰剂相比降低了肝脂肪（安慰剂调整后的 LSM（90%CI）-44.6%（-54.8，-32.2））。PF-05221304 或 PF-06865571 单独治疗 6 周后，安慰剂调整后的 LSM（90%CI）降低了肝脂肪-44.5%（-55.0，-31.7）和-35.4%（-47.4，-20.7）。联合使用 PF-05221304 和 PF-06865571 后，10/28（36%）患者报告了 AE，无因 AE 而停药，并且 ACC 抑制剂对血清甘油三酯的影响得到缓解，这表明 PF-05221304 和 PF-06865571 联合使用有可能解决单独使用 ACC 抑制剂的一些局限性。
