Pfizer Inc., Worldwide Research, Development, and Medicine, Cambridge, MA 02139, USA.
Pfizer Inc., Worldwide Research, Development, and Medicine, Cambridge, MA 02139, USA.
Med. 2021 Jul 9;2(7):800-813.e3. doi: 10.1016/j.medj.2021.04.007. Epub 2021 Apr 27.
Increased consumption of the lipogenic sugar fructose promotes the current epidemic of metabolic disease. Ketohexokinase (KHK) catalyzes the first committed step in fructose metabolism. In animal models, KHK inhibition decreases hepatic de novo lipogenesis and steatosis and corrects many metabolic abnormalities associated with insulin resistance. The consequences of inhibiting fructose metabolism in humans have not been tested. This randomized, double-blind, placebo-controlled, phase 2a study (NCT03256526) assessed the effect of the reversible KHK inhibitor PF-06835919 on metabolic parameters in participants with non-alcoholic fatty liver disease (NAFLD).
Adults with NAFLD (>6% whole liver fat [WLF] by magnetic resonance imaging-proton density fat fraction) received once-daily oral placebo or PF-06835919 75 mg or 300 mg for 6 weeks. Randomization (1:1:1) was via computer-generated randomization code with random permuted blocks. Endpoints included WLF (primary endpoint), safety/tolerability, and metabolic parameters.
Overall, 158 participants were screened and 53 randomized; 48 completed the trial (placebo, n = 17; PF-06835919 75 mg, n = 17; PF-06835919 300 mg, n = 14). Compared with placebo, significant reductions in WLF were observed in participants receiving PF-06835919 300 mg (difference of -18.73%; p = 0.04), but not with 75 mg. In addition, inhibition of KHK resulted in improvement in inflammatory markers. The incidence of treatment-emergent adverse events (AEs) was low and similar across treatment groups (26.3%, 23.5%, and 29.4% of participants in the placebo and PF-06835919 75 mg and 300 mg groups, respectively). No serious AEs were reported.
Data suggest that KHK inhibition may be clinically beneficial in the treatment of adults with NAFLD and insulin resistance.
This study was sponsored by Pfizer Inc.
摄入更多的生糖果糖会促进目前代谢疾病的流行。己酮糖激酶（KHK）催化果糖代谢的第一步。在动物模型中，KHK 抑制可减少肝从头合成脂肪和脂肪变性，并纠正与胰岛素抵抗相关的许多代谢异常。尚未在人体中测试抑制果糖代谢的后果。这项随机、双盲、安慰剂对照、2a 期研究（NCT03256526）评估了可逆 KHK 抑制剂 PF-06835919 对非酒精性脂肪性肝病（NAFLD）患者代谢参数的影响。
患有 NAFLD（磁共振成像质子密度脂肪分数>6%的全肝脂肪[WLF]）的成年人每天口服接受安慰剂或 PF-06835919 75mg 或 300mg，持续 6 周。随机化（1:1:1）通过计算机生成的随机化代码和随机排列的块进行。终点包括 WLF（主要终点）、安全性/耐受性和代谢参数。
共有 158 名患者接受了筛选，53 名患者被随机分组；48 名患者完成了试验（安慰剂组，n=17；PF-06835919 75mg 组，n=17；PF-06835919 300mg 组，n=14）。与安慰剂相比，接受 PF-06835919 300mg 的患者 WLF 显著降低（差异-18.73%；p=0.04），但 75mg 组无显著降低。此外，KHK 抑制可改善炎症标志物。治疗中出现的不良事件（AE）的发生率低，且在各治疗组中相似（安慰剂和 PF-06835919 75mg 和 300mg 组的参与者分别为 26.3%、23.5%和 29.4%）。未报告严重 AE。
数据表明，KHK 抑制在治疗 NAFLD 和胰岛素抵抗的成年人中可能具有临床益处。
这项研究由辉瑞公司赞助。
