PF-06835919 / Pfizer - LARVOL DELTA

Unique Nonclinical Safety Profile of PF-06835919, A Ketohexokinase Inhibitor, Highlights A Species-Dependent Mechanism. (PubMed, Regul Toxicol Pharmacol) - "In vitro, PF-06835919 showed little effect on PPAR α, β/δ or γ activities at therapeutic concentrations. It is concluded that PF-06835919 does not directly activate PPARs at exposures achieved at planned clinical doses and most of these rat findings reflect species-specific adaptive changes to liver enzyme induction in addition to the pharmacology of the compound."

Journal • Diabetes • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus

Ketohexokinase: A Central Mediator of Fructose-Associated Pathogenesis and Promising Therapeutic Target. (PubMed, Pharmacol Res) - "Translational development of KHK inhibitors has achieved notable progress, with the first-generation PF-06835919 completing Phase 2 trials for metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, and hereditary fructose intolerance, and the second-generation LY3522348 finishing Phase 1 evaluation in healthy participants, though key gaps including isoform selectivity and tissue-specific delivery remain unaddressed. Despite growing recognition of KHK's multifaceted roles in health and disease, existing literature lacks a consolidated synthesis of its regulation, tissue-specific functions, and translational progress. This review aims to provide a systematic overview of KHK's molecular characteristics, regulatory networks, pathophysiological roles, and therapeutic potential, establishing KHK as a promising actionable target for fructose-related disorders and offering a foundational framework to guide future research and drug development."

Journal • Review • Diabetes • Diabetic Nephropathy • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Nephrology • Obesity • Oncology • Renal Disease • Type 2 Diabetes Mellitus

Enhancing Fat Loss in Obese Mice through GLP1 Agonism and KHK Inhibition (ENDO 2026) - "Even after semaglutide withdrawal, an underlying metabolic benefit from KHKi administration persists, making the mice resilient to weight rebound. Thus, while HFHS-rich consumption may promote obesity and related metabolic disorders, our findings confirm that there is compelling evidence to support the use of both PF-06835919 and semaglutide in more effective weight-loss clinical trials."

Preclinical • Genetic Disorders • Obesity

Thyroid dysregulation underlies altered ovarian cyclicity in rats exposed to PF-06835919, a ketohexokinase inhibitor. (PubMed, Reprod Toxicol) - "Liver UGT enzyme induction, including UGT1A1, was confirmed to be induced in a separate 2-week rat study. All available data support the hypothesis that PF-06835919-related induction of one or more UGT enzymes and consequent thyroid dysregulation were the cause of ovarian changes in the rat."

Journal • Preclinical • Endocrine Disorders • Hepatology • Metabolic Dysfunction-Associated Steatotic Liver Disease • UGT1A1

Combination of Semaglutide and KHK Inhibitor Improves Fat Loss in Mice Fed on a Western Diet (OBESITY WEEK 2025) - "KHK inhibition with PF-06835919 effectively reverses HFHS-induced weight gain, underscoring the role of fructose metabolism in obesity development. Moreover, the combination of semaglutide and PF-06835919 yields an additional 10% weight loss compared to semaglutide alone, providing compelling preclinical evidence to support human trials exploring PF-06835919 as a potential obesity treatment."

Preclinical • Genetic Disorders • Metabolic Disorders • Obesity

Ketohexokinase Inhibition Attenuates Intestinal Lipid Metabolism Under High-Fat, High-Sucrose Diet (OBESITY WEEK 2025) - "Cells were then treated apically with 1.5 mL of media containing fructose, glucose, fatty acids, and/or KHKi (PF-06835919) for 4 hours... Intestinal fructose metabolism influences lipid handling under HFHS conditions. HFHS diets increase MTP expression across the small intestine, potentially enhancing chylomicron formation and lipid absorption. KHKi reverses these effects, implicating KHK-mediated fructose phosphorylation in intestinal lipid dysregulation."

Metabolic Disorders • ALDOB • APOB • VCL

Pharmacophore-based virtual screening and in silico investigations of small molecule library for discovery of human hepatic ketohexokinase inhibitors for the treatment of fructose metabolic disorders. (PubMed, Front Pharmacol) - "Pfizer's PF-06835919 has progressed to phase II trials, demonstrating a reduction in liver fat and improved insulin sensitivity, while Eli Lilly's LY-3522348 also shows significant potential. ADMET profiling refined the selection to five compounds (1, 2, and 4-6), and molecular dynamics simulations identified compound 2 as the most stable and promising candidate compared to the clinical candidate PF-06835919. These findings highlight compound 2 as a potent KHK-C inhibitor with predicted pharmacokinetics and toxicity profiles supporting its potential for treating fructose-driven metabolic disorders, warranting further validation."

Journal • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Oncology

Exploring Marine-Derived Compounds: In Silico Discovery of Selective Ketohexokinase (KHK) Inhibitors for Metabolic Disease Therapy. (PubMed, Mar Drugs) - "Additionally, shape-based screening was conducted to assess structural similarities. The findings highlight several potential inhibitors with favorable ADMET profiles, offering promising candidates for further development in the treatment of fructose-related metabolic disorders."

Journal • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Pharmacological inhibition of fructose metabolism reduces liver fat and improves insulin sensitivity in participants with MASLD (EASD 2024) - P2 | "Six weeks of KHK inhibition suppresses intrahepatic fructose metabolism, reduces IHL content, and improves insulin sensitivity in MASLD participants."

Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Study of the ketohexokinase inhibitor PF-06835919 as a clinical cytochrome P450 3A inducer: Integrated use of oral midazolam and liquid biopsy. (PubMed, Clin Transl Sci) - "Likewise, minimal induction of CYP3A4 activity (geometric mean, 90% CI) in both liver (1.1, 90% CI: 0.9-1.3) and non-liver (0.9, 90% CI: 0.5-1.5) sEVs was evident (predicted AUCR = 0.9, 90% CI: 0.6-1.4). The results showcase the integrated use of an oral CYP3A probe (midazolam) and plasma-derived sEVs to assess a drug candidate as inducer."

Biopsy • Journal • Liquid biopsy • CYP3A4

Discovery of a Novel Ketohexokinase Inhibitor with Improved Drug Distribution in Target Tissue for the Treatment of Fructose Metabolic Disease. (PubMed, J Med Chem) - "Among them, compound 14 exhibited more potent activity than PF-06835919 based on the rat KHK inhibition assay in vivo, and higher drug distribution concentration in the liver. Its good absorption, distribution, metabolism, and excretion and pharmacokinetic properties make it a promising clinical candidate."

Journal • Genetic Disorders • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Obesity

Short-term safety and efficacy of inhibition of fructose metabolism in people with hereditary fructose intolerance. Korte termijn veiligheid en werking van het blokkeren van fructose metabolisme in mensen met hereditaire fructose intolerantie. (clinicaltrialsregister.eu) - P2 | N=8 | Ongoing | Sponsor: Maastricht University

New P2 trial • Metabolic Disorders

A phase 2a, randomized, double-blind, placebo-controlled, 3-arm, parallel-group study to assess the efficacy, safety, tolerability, and pharmacodynamics of PF-06835919 in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. (PubMed, Diabetes Obes Metab) - "PF-06835919 administration over 16 weeks was generally safe and well-tolerated and resulted in reductions in WLF in participants with NAFLD and T2DM."

Clinical • Journal • P2a data • PK/PD data • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Type 2 Diabetes Mellitus

Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, A First-in-class Ketohexokinase Inhibitor for Metabolic Disorders and Non-alcoholic Fatty Liver Disease. (PubMed, Drug Metab Dispos) - "Phenotyping studies using transfected systems, human hepatocytes and liver microsomes signifies the role of OAT2 and OATP1B1 in the hepatic uptake and multiple enzymes in the metabolism of PF-06835919. Data presented suggest hepatic transporter-enzyme interplay in determining its systemic concentrations and potential enrichment in liver, a target site for KHK inhibition."

Journal • PK/PD data • Addiction (Opioid and Alcohol) • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • CYP2C8 • CYP2C9

Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: A randomized phase 2 trial. (PubMed, Med (N Y)) - P2a | "Data suggest that KHK inhibition may be clinically beneficial in the treatment of adults with NAFLD and insulin resistance."

Clinical • Journal • P2 data • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease

Effect of a ketohexokinase inhibitor (PF-06835919) on in vivo OATP1B activity: Integrative risk assessment using endogenous biomarker and a probe drug. (PubMed, Clin Pharmacol Ther) - "PF-06835919 is a first-in-class ketohexokinase inhibitor (KHKi), recently under development for the treatment of metabolic and fatty liver diseases, which inhibited organic anion transporting polypeptide (OATP)1B1 in vitro and presented drug-drug interaction (DDI) risk. Model-based analysis correctly predicted "no-effect" (AUC ratio < 1.25) at low dose range and "weak" effect (AUC ratio < 2) on atorvastatin pharmacokinetics at high dose range of KHKi. This study exemplified the utility of biomarker-informed model-based approach in discerning even small effects on OATP1B activity in vivo, and to project DDI risk at the clinically relevant doses."

Journal • Preclinical • Hepatology

[VIRTUAL] Results of a Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability & Pharmacodynamics of the Fructokinase Inhibitor PF-06835919 Administered Daily for 16 Weeks in Adults with NAFLD & T2DM (NASH Summit-US 2021) - "Understanding the steps taken to further assess the potential utility of PF-06835919 for the treatment of NASH and/or insulin resistance, a 16-week randomized, double blind, placebo- controlled study assessing two active doses of PF-06835919 in patients with NAFLD and T2DM was designed and conducted. Analyzing our study results in depth"

Clinical • P2a data • PK/PD data • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus

A STUDY TO COMPARE THE PHARMACOKINETICS OF PF-06835919 IN PARTICIPANTS WITH AND WITHOUT HEPATIC IMPAIRMENT (clinicaltrials.gov) - P1; N=23; Completed; Sponsor: Pfizer; Recruiting ➔ Completed

Trial completion • Hepatology

Study of Multiple Oral Doses of PF-06835919 in Healthy Adult Japanese Participants (clinicaltrials.gov) - P1; N=8; Completed; Sponsor: Pfizer; Recruiting ➔ Completed

Clinical • Trial completion

A Double-blind Study to Assess 2 Doses of an Investigational Product for 16 Weeks in Participants With Non-alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2a; N=164; Completed; Sponsor: Pfizer; Active, not recruiting ➔ Completed

Clinical • Trial completion • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • CRP

A Double-blind Study to Assess 2 Doses of an Investigational Product for 16 Weeks in Participants With Non-alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2a; N=150; Not yet recruiting; Sponsor: Pfizer

Clinical • New P2a trial • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • CRP

A Double-blind Study to Assess 2 Doses of an Investigational Product for 16 Weeks in Participants With Non-alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2a; N=150; Recruiting; Sponsor: Pfizer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • CRP

A Double-blind Study to Assess 2 Doses of an Investigational Product for 16 Weeks in Participants With Non-alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2a; N=150; Active, not recruiting; Sponsor: Pfizer; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • CRP

Pharmacologic inhibition of Ketohexokinase prevents fructose-induced metabolic dysfunction. (PubMed, Mol Metab) - "Fructose consumption in rats promoted features of metabolic dysfunction seen in metabolic diseases such as T2D and NASH, including insulin resistance, hypertriglyceridemia and hepatic steatosis, all of which were reversed by KHK inhibition."

Journal • Addiction (Opioid and Alcohol) • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Hypertriglyceridemia • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

Study of Multiple Oral Doses of PF-06835919 in Healthy Adult Japanese Participants (clinicaltrials.gov) - P1; N=8; Recruiting; Sponsor: Pfizer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open