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. Issue 4 (17th January 2023) - Saxena, Aditi R.
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 −5.26% (−12.86%, 2.99%), −17.05% (−24.01%, −9.46%) and −19.13% (−25.51%, −12.20%) 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.