ervogastat (PF-06865571) / Pfizer - LARVOL DELTA

THE LIPID SYNTHESIS INHIBITORS ACC (FIRSOCOSAT) AND DGAT2 (ERVOGASTAT) REDUCE TRIGLYCERIDE CONTENT INDEPENDENTLY, BUT ONLY ERVOGASTAT ALSO REDUCES FIBROSIS BIOMARKERS IN HUMAN LIVER SPHEROIDS (AASLD 2025) - "The DGAT2 inhibitor Ervogastat and ACC inhibitor Firsocostat did not show any significant elevation of LDH secretion. We show a robust platform for MASH drug candidates and identify the DGAT2 inhibitor as a clinical candidate improving steatosis and fibrosis in human liver spheroid model. This data show that supressing steatosis would result in fibrosis prevention."

Biomarker • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Acetyl-CoA Carboxylase Inhibitors for Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PubMed, Pharmaceuticals (Basel)) - "Interventions included firsocostat, clesacostat, and combined regimens with semaglutide, selonsertib, and cilofexor or ervogastat. Dual ACC 1/2 inhibitors reduce hepatic steatosis and ALT levels but do not improve fibrosis. Their consistent association with hypertriglyceridemia raises concerns regarding potential long-term cardiometabolic risks, particularly in NAFLD patients with metabolic dysfunction."

Journal • Retrospective data • Review • Dyslipidemia • Fibrosis • Hepatology • Hypertriglyceridemia • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

Effect of Varying Degrees of Hepatic Impairment on the Pharmacokinetics of Ervogastat, a Diacylglycerol Acyltransferase 2 (DGAT2) Inhibitor, and Clesacostat, an Acetyl-CoA Carboxylase (ACC) Inhibitor. (PubMed, J Clin Pharmacol) - P1 | "Taking into consideration the safety margins at the highest doses evaluated in Phase 2, no dose adjustment of ervogastat or clesacostat is currently warranted for patients with hepatic impairment. NCT: NCT04091061, NCT03309202."

Journal • PK/PD data • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Efficacy and safety of ervogastat alone and in combination with clesacostat in patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and F2-F3 fibrosis (MIRNA): results from a phase 2, randomised, double-blind, double-dummy study. (PubMed, Lancet Gastroenterol Hepatol) - P2 | "The combined efficacy, safety, and tolerability data with ervogastat supports continued investigation for its use in MASH. Larger and longer trials are needed to further assess ervogastat and ervogastat plus clesacostat for MASH treatment."

Journal • P2 data • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • STAT3

Exposure-response modeling of liver fat imaging endpoints in non-alcoholic fatty liver disease populations administered ervogastat alone and co-administered with clesacostat. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Simultaneous modeling of both MRI-PDFF and CAP™ was successful with both measurements being adequately described. By describing the underlying changes of steatosis with a latent variable, this model may be extended to describe biopsy results from future studies."

Journal • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • STAT3

Metabolic Interventions to Resolve Non-alcoholic Steatohepatitis (NASH) With Fibrosis (MIRNA) (clinicaltrials.gov) - P2 | N=258 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Investigation of pharmacokinetic drug interaction between clesacostat and DGAT2 inhibitor ervogastat in healthy adult participants. (PubMed, Clin Transl Sci) - "co-administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co-administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD."

Journal • PK/PD data • Addiction (Opioid and Alcohol) • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • STAT3

Mitigating a Bioactivation Liability with an Azetidine-Based Inhibitor of Diacylglycerol Acyltransferase 2 (DGAT2) En Route to the Discovery of the Clinical Candidate Ervogastat. (PubMed, Chem Res Toxicol) - "We recently disclosed SAR studies on systemically acting, amide-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) that addressed metabolic liabilities with the liver-targeted DGAT2 inhibitor PF-06427878. Replacement of the azetidine substituent with a pyridine ring furnished 8, which mitigated the formation of the electrophilic aldehyde metabolite, and was a more potent DGAT2 inhibitor than 2. Further structural refinements in 8, specifically introducing amide bond substituents with greater metabolic stability, led to the discovery of PF-06865571 (ervogastat) that is currently in phase 2 clinical trials for the treatment of nonalcoholic steatohepatitis."

Journal • Hepatology • Non-alcoholic Steatohepatitis

Inhibition of Diacylglycerol Acyltransferase 2 Versus Diacylglycerol Acyltransferase 1: Potential Therapeutic Implications of Pharmacology. (PubMed, Clin Ther) - P1, P1b | "Although pharmacologic DGAT1is are limited by an adverse safety profile, data support use of DGAT2i as an effective and well-tolerated therapeutic strategy for patients with NAFLD, NASH, and NASH with liver fibrosis."

Clinical • Journal • Review • Fibrosis • Gastrointestinal Disorder • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity

Metabolic Interventions to Resolve Non-alcoholic Steatohepatitis (NASH) With Fibrosis (MIRNA) (clinicaltrials.gov) - P2 | N=231 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=350 ➔ 231

Enrollment change • Enrollment closed • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis. (PubMed, J Med Chem) - "Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis

Study of Pharmacodynamics and Safety of DGAT2i and ACCi Coadministered in Participants With Sponsor-defined Presumed Non Alcoholic Steatohepatitis (clinicaltrials.gov) - P2a | N=76 | Completed | Sponsor: Pfizer | Recruiting ➔ Completed | N=180 ➔ 76 | Trial completion date: Sep 2022 ➔ Apr 2022 | Trial primary completion date: Aug 2022 ➔ Mar 2022

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

The postnatal resolution of developmental toxicity induced by pharmacological diacylglycerol acyltransferase 2 (DGAT2) inhibition during gestation in rats. (PubMed, Toxicol Sci) - "Extended dosing in rats through the end of gestation and lactation (pre- and post-natal development study) caused impaired skin development, reduced offspring viability and growth retardation. The spectrum of developmental effects in rats is consistent with the intended pharmacology (altered triglyceride metabolism) and the transient nature of the skeletal findings, along with the late gestational window of sensitivity for the effects on skin barrier development, reduce the concern for potential adverse developmental effects following unintended early gestational exposure to ervogastat in humans where treatment can be discontinued once pregnancy is determined."

Journal • Preclinical • Developmental Disorders • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis

Efficacy and safety of an orally administered DGAT2 inhibitor alone or coadministered with a liver-targeted ACC inhibitor in adults with non-alcoholic steatohepatitis (NASH): rationale and design of the phase II, dose-ranging, dose-finding, randomised, placebo-controlled MIRNA (Metabolic Interventions to Resolve NASH with fibrosis) study. (PubMed, BMJ Open) - P2 | "Small molecule inhibitors of the terminal step in intrahepatic triglyceride synthesis (diacylglycerol acyltransferase 2 inhibitor (DGAT2i, PF-06865571, ervogastat)) and upstream blockade of de novo lipogenesis via acetyl-coenzyme A carboxylase inhibitor (ACCi, PF-05221304, clesacostat) showed promise in reducing hepatic steatosis in early clinical trials. Details of all IRB/ECs, as well as results, will be published in a peer-reviewed journal and publicly disclosed through ClinicalTrials.gov, EudraCT, and/or www.pfizer.com and other public registries as per applicable local laws/regulations. NCT04321031."

Journal • P2 data • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis

Metabolic Interventions to Resolve Non-alcoholic Steatohepatitis (NASH) With Fibrosis (MIRNA) (clinicaltrials.gov) - P2; N=450; Recruiting; Sponsor: Pfizer; Trial completion date: Dec 2022 ➔ Dec 2023; Trial primary completion date: Nov 2022 ➔ Nov 2023

Clinical • Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • MRI

A Drug-Drug Interaction Study Between PF-06882961 and PF-06865571 in Healthy Adult Participants and Overweight Adults or Adults With Obesity Who Are Otherwise Healthy (clinicaltrials.gov) - P1; N=27; Completed; Sponsor: Pfizer; Recruiting ➔ Completed

Clinical • Trial completion • Genetic Disorders • Obesity

ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials. (PubMed, Nat Med) - P2a | "Placebo-adjusted LSM (90% CI) reduction in liver fat was -44.5% (-55.0, -31.7) and -35.4% (-47.4, -20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone."

Clinical • Journal • P2a data • Addiction (Opioid and Alcohol) • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • MRI

A Study in Healthy Adult Male Participants to Assess Absorption, Distribution, Metabolism and Excretion (ADME) of Radiolabeled PF-06865571. (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Pfizer; Recruiting ➔ Completed

Clinical • Trial completion

Study of Pharmacodynamics and Safety of DGAT2i and ACCi Coadministered in Participants With Sponsor-defined Presumed Non Alcoholic Steatohepatitis (clinicaltrials.gov) - P2a; N=180; Recruiting; Sponsor: Pfizer; Trial completion date: Jul 2023 ➔ Sep 2022; Trial primary completion date: Jun 2023 ➔ Aug 2022

Clinical • Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • MRI

A Study in Healthy Adult Male Participants to Assess Absorption, Distribution, Metabolism and Excretion (ADME) of Radiolabeled PF-06865571. (clinicaltrials.gov) - P1; N=6; Recruiting; Sponsor: Pfizer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Study in Healthy Adult Male Participants to Assess Absorption, Distribution, Metabolism and Excretion (ADME) of Radiolabeled PF-06865571. (clinicaltrials.gov) - P1; N=6; Not yet recruiting; Sponsor: Pfizer

Clinical • New P1 trial

Study of Pharmacodynamics and Safety of DGAT2i and ACCi Coadministered in Participants With Sponsor-defined Presumed Non Alcoholic Steatohepatitis (clinicaltrials.gov) - P2a; N=180; Recruiting; Sponsor: Pfizer; Trial completion date: Sep 2022 ➔ Jul 2023; Trial primary completion date: Sep 2022 ➔ Jul 2023

Clinical • Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • MRI

A Drug-Drug Interaction Study Between PF-06882961 and PF-06865571 in Healthy Adult Participants and Overweight Adults or Adults With Obesity Who Are Otherwise Healthy (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Pfizer

New P1 trial • Genetic Disorders • Obesity

[VIRTUAL] Co-administration of PF-05221304 and PF-06865571 delivers robust whole liver fat reduction and mitigation of acetyl-coa carboxilase inhibitor induced hypertriglyceridemia in patients with NAFLD (EASL-ILC-I 2020) - "Co-administration of ACCi+DGAT2i for 6 weeks resulted in greater reductions in WLF than DGAT2i monotherapy and was safe and well-tolerated in adults with NAFLD. ACCi-induced TG elevation was observed and was mitigated by co-administration with DGAT2i after 6 weeks. Decreases from baseline were observed in alanine aminotransferase (ALT), HDL-Cholesterol and LDL- Cholesterol in the ACCi+DGAT2i group, relative to placebo."

Clinical • Diabetes • Dyslipidemia • Hepatology • Hypertriglyceridemia • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Study of Pharmacodynamics and Safety of DGAT2i and ACCi Coadministered in Participants With Sponsor-defined Presumed Non Alcoholic Steatohepatitis (clinicaltrials.gov) - P2a; N=180; Recruiting; Sponsor: Pfizer; Not yet recruiting ➔ Recruiting; N=90 ➔ 180

Clinical • Enrollment change • Enrollment open • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis