A phase 2a, randomized, double‐blind, placebo‐controlled, three‐arm, parallel‐group study to assess the efficacy, safety, tolerability and pharmacodynamics of PF‐06835919 in patients with non‐alcoholic fatty liver disease and type 2 diabetes

Abstract

Aim: To assess the safety, tolerability and pharmacodynamics (PD) of the ketohexokinase inhibitor PF-06835919 in participants with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Materials and methods:This double-blind, placebo-controlled, parallel-group study enrolled adults with NAFLD (≥ 8% whole liver fat [WLF] using MRI proton density fat fraction [MRI-PDFF]) and T2D on stable doses of metformin (≥ 500 mg/day). Participants received once-daily placebo, PF-06835919 150 or 300 mg for 16 weeks. Randomization (1:1:1) was via an interactive response technology system. Endpoints included percentage change from baseline (CFB) in WLF using MRI-PDFF (primary endpoint) and CFB in HbA1c (co-primary endpoint) at 16 weeks, PD, safety and tolerability.Results: Among 164 participants randomized and treated, 145 completed the treatment (placebo, n = 50; PF-06835919 150 mg, n = 46; PF-06835919 300 mg, n = 49). At week 16, least squares mean (90% confidence interval) percentage CFB in WLF was À5.26% (À12.86%, 2.99%), À17.05% (À24.01%, À9.46%) and À19.13% (À25.51%, À12.20%) in the placebo, PF-06835919 150-mg and 300-mg groups, respectively (PF-06835919 300-mg group vs. placebo, P = .0288). Modest numerical reductions in HbA1c were observed in all groups that did not reach statistical significance. Treatment-emergent adverse event incidence was similar across groups (40.7%, 45.5% and 32.7% in the placebo, PF-06835919 150-mg and 300-mg groups, respectively), with no apparent dose-related trend.Conclusions: PF-06835919 administration over 16 weeks was generally safe and well tolerated and resulted in reductions in WLF in participants with NAFLD and T2D. † Affiliation at the time this study was conducted.

Overview and prospect of NAFLD: Significant roles of nutrients and dietary patterns in its progression or prevention

“…Yet, the clinical improvements were not significant enough to support further development. 297 The phase 1 clinical trial of another KHK inhibitor, XZP-6019, is currently ongoing.…”

Potential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease

“…There were data indicating that participants receiving PF-06835919 at the 300 mg dose demonstrated significant reductions in LFC compared to the placebo group, with a difference of −18.73% (p = 0.04) [81] Another phase 2 study conducted on a group of patients with NAFLD and DMT2 demonstrated that at week 16, the least-squares mean (90% CI) percentage changes from baseline in LFC using MRI-PDFF were as follows: (−5.26%) [(−12.86%)-2.99%] in the placebo group, (−17.05%) [(−24.01%)-(−9.46%)] in the 150 mg dose PF-06835919 group, and (−19.13%) [(−25.51%)-(−12.20%)] in the 300 mg dose PF-06835919 group. Notably, the 300 mg dose PF-06835919 group exhibited a statistically significant reduction in LFC compared to the placebo group (p = 0.0288) [82]. The currently ongoing study [83] aims to explore additional health effects resulting from KHK inhibition with PF-0683591 in NAFLD patients without DMT2.…”

Crystal structures of human and mouse ketohexokinase provide a structural basis for species- and isoform-selective inhibitor design

“…This offers a novel therapeutic concept for the treatment of type 2 diabetes and obesity. Accordingly, KHK inhibitors that target both isoforms have been investigated in clinical trials (Futatsugi et al, 2020;Kazierad et al, 2021;Saxena et al, 2022;Koene & Schrauwen, 2022) and have been released as chemical probes to the scientific community (Heine et al, 2023); however, no KHK inhibitor has yet made it to the market.…”