Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: A randomized phase 2 trial

Abstract

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 75mg or 300mg for 6weeks. 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 75mg, n= 17; PF-06835919 300mg, n= 14). Compared with placebo, significant reductions in WLF were observed in participants receiving PF-06835919 300mg (difference of -18.73%; p= 0.04), but not with 75mg. 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 75mg and 300mg 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.