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

Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease

“…PF-06835919 administration to NAFLD subjects showed a reduction in hepatic fat content and insulin resistance, ALT, AST, and gamma-glutamyl transferase (GGT) [51]. In a recent phase II study in participants with NAFLD, a significant reduction in the whole liver fat and improvement in inflammatory markers were observed in participants receiving PF-06835919300, while no serious adverse effects were reported [52].…”

Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, a First-In-Class Ketohexokinase Inhibitor for Metabolic Disorders and Nonalcoholic Fatty Liver Disease

“…PF-06835919 represents a first-in-class selective KHK inhibitor to have entered clinical trials for the treatment of metabolic disorders and NAFLD/NASH (Futatsugi et al, 2020). In early clinical studies, PF-06835919 was found to be safe and well-tolerated in healthy study participants, and dose-dependently increased plasma fructose indicative of KHK inhibition (Gutierrez et al, 2021;Kazierad et al, 2021). The present study characterizes the transport and metabolic pathways involved in the hepatic clearance of PF-06835919, and thus understand the primary drivers to its clinical PK and target tissue exposure.…”

“…PF-06835919 is a highly selective inhibitor of KHK (two isoforms-A/C) in in vitro selectivity assays and showed no development-limiting findings in rat and dog toxicology studies (Futatsugi et al, 2020). In a phase 2 study, KHK inhibition by PF-06835919 lead to reduction in whole liver fat and inflammatory markers and was tolerated in adults with NAFLD (Kazierad et al, 2021).…”

A review on benefits of quercetin in hyperuricemia and gouty arthritis

“…This result indicated that lack of fructokinase could prevent the increase in serum and hepatic urate ( Ishimoto et al, 2013 ). In a clinical study of adults with non-alcoholic fatty liver disease, serum urate levels of participants receiving a KHK inhibitor PF-06835919 at a dose of 300 mg for 6 weeks were reduced by 11.5% compared to baseline ( Kazierad et al, 2021 ). Interestingly, quercetin has reported to suppress the mRNA expression level of KHK and several genes of carbohydrate and lipid metabolism enzymes in the liver of rats receiving high-fructose diet ( Mzhel’skaya et al, 2019 ).…”