clesacostat (PF-05221304) / Pfizer - LARVOL DELTA

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

SomaLogic proteomics reveals new biomarkers and provides mechanistic, clinical insights into Acetyl coA Carboxylase (ACC) inhibition in Non-alcoholic Steatohepatitis (NASH). (PubMed, Sci Rep) - P2a | "We performed SomaLogic serum proteome profiling with baseline (n = 231) and on-treatment (n = 72, Weeks 12 and 16, Placebo and 25 mg PF-05221304) samples from a Phase 2a trial (NCT03248882) with Clesacostat (PF-05221304), an acetyl coA carboxylase inhibitor (ACCi) in patients with NAFLD/NASH...Our data demonstrate the utility of SomaLogic- analyte panel for diagnosis and treatment response in NAFLD/NASH and provide potential new mechanistic insights into liver steatosis reduction, inflammation and serum triglyceride elevation with ACC inhibition. (Clinical Trial Identifier: NCT03248882)."

Biomarker • Clinical • Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

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

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7. (PubMed, Cardiovasc Diabetol) - "Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials...Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials...Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ABCA1 • ACACA • ACSL3 • BMP2 • CD36 • COL1A1 • CPT1A • CTGF • EHHADH • HMGB1 • IFNA1 • IL1B • IL6 • MALT1 • RUNX2 • SCARB1 • SMAD7 • TCF7L2 • TNFA

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

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

Pharmacokinetics, Mass Balance, Metabolism, and Excretion of the Liver-Targeted Acetyl-CoA Carboxylase Inhibitor PF-05221304 (Clesacostat) in Humans. (PubMed, Xenobiotica) - "In plasma, unchanged PF-05221304 represented 96.1% circulating radioactivity. Metabolites M1, M2b, and M2a represented 1.94, 1.76, and 0.18% of circulating radioactivity, respectively.Overall, these data suggest that PF-05221304 is well absorbed in humans and eliminated largely via phase I metabolism."

Journal • PK/PD data

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

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

Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism (clinicaltrials.gov) - P1b; N=0; Withdrawn; Sponsor: Columbia University; Trial completion date: Sep 2022 ➔ Aug 2021; Not yet recruiting ➔ Withdrawn; Trial primary completion date: Mar 2022 ➔ Aug 2021

Clinical • Trial completion date • Trial primary completion date • Trial withdrawal • Dyslipidemia • Hepatology • 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; 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

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

[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

Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase (ACC) Inhibitors Through Liver Targeting. (PubMed, J Med Chem) - "Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a non-human primate model."

Benefit-risk assessment • Journal • Hepatology • Metabolic Disorders • 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

Metabolic Interventions to Resolve Non-alcoholic Steatohepatitis (NASH) With Fibrosis (MIRNA) (clinicaltrials.gov) - P2; N=450; Recruiting; Sponsor: Pfizer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Acetyl-CoA Carboxylase inhibition improves multiple dimensions of NASH pathogenesis in model systems. (PubMed, Cell Mol Gastroenterol Hepatol) - "The liver directed dual ACC1/ACC2 inhibitor directly improved multiple NAFLD/NASH pathogenic factors including steatosis, inflammation and fibrosis in both human derived in vitro systems and rat models."

Journal • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • 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=90; Not yet recruiting; Sponsor: Pfizer

Clinical • New P2a trial • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • MRI

Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism (clinicaltrials.gov) - P1b; N=8; Not yet recruiting; Sponsor: Henry N. Ginsberg

Clinical • New P1 trial • Dyslipidemia • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Metabolic Interventions to Resolve Non-alcoholic Steatohepatitis (NASH) With Fibrosis (MIRNA) (clinicaltrials.gov) - P2; N=450; Not yet recruiting; Sponsor: Pfizer

Clinical • New P2 trial

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304): A Three-Part Randomized Phase 1 Study. (PubMed, Clin Pharmacol Drug Dev) - "Steady-state pharmacokinetics generally increased dose-proportionally, with a half-life of 14-18 hours and a minimal food effect on plasma exposure. The observed safety and tolerability, pharmacokinetics, and pharmacodynamics support the continued evaluation of PF-05221304 for the treatment of nonalcoholic steatohepatitis."

Clinical • Journal • P1 data • PK/PD data

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 2020) - No abstract available

Clinical

A Study To Assess Pharmacodynamics, Safety And Tolerability Of PF-05221304 And PF-06865571 Co-Administered For 6 Weeks In Adults With Non-Alcoholic Fatty Liver Disease. (clinicaltrials.gov) - P2a; N=99; Completed; Sponsor: Pfizer; Recruiting ➔ Completed

Clinical • Trial completion