Clesacostat
Clesacostat is an investigational pharmaceutical compound developed by Pfizer for the treatment of metabolic dysfunction-associated steatohepatitis, formerly known as non-alcoholic steatohepatitis, with liver fibrosis. It is a liver-targeted inhibitor of acetyl-CoA carboxylase, an enzyme that plays a central role in fatty acid metabolism.
Medical uses
Clesacostat is currently being investigated as a treatment for NASH with liver fibrosis, both as a monotherapy and in combination with ervogastat, a diacylglycerol O-acyltransferase 2 inhibitor. The combination therapy has received FDA Fast Track designation from the U.S. Food and Drug Administration, which is designed to expedite the development and review of treatments for serious conditions with unmet medical needs.The drug is specifically being studied for its potential to address the metabolic perturbations associated with fatty liver disease by targeting key pathways in lipid metabolism.
Mechanism of action
Clesacostat functions as a dual inhibitor of acetyl-CoA carboxylase 1 and 2. ACC is a rate-limiting enzyme that catalyzes the ATP-dependent condensation of acetyl-CoA with bicarbonate to produce malonyl-CoA, which serves as a key substrate for de novo lipogenesis - the process by which the liver synthesizes new fatty acids from non-lipid precursors.By inhibiting ACC, clesacostat achieves multiple therapeutic effects:
- Reduction of de novo lipogenesis: Decreased malonyl-CoA production reduces the synthesis of new fatty acids in the liver
- Enhancement of fatty acid oxidation: Lower malonyl-CoA levels relieve the inhibition of carnitine palmitoyltransferase I, allowing increased mitochondrial fatty acid oxidation
- Improvement of hepatic steatosis: The combined effect of reduced fatty acid synthesis and increased fatty acid breakdown helps reduce liver fat accumulation
Pharmacology
Pharmacokinetics
Clesacostat is administered orally and is bioavailable as an oral formulation. Following administration, the drug undergoes hepatic metabolism and is eliminated through both renal and fecal routes. In mass balance studies conducted with radiolabeled clesacostat in healthy human subjects, approximately 89.9% of the administered dose was recovered in urine and feces over an 11-day study period.The compound's liver-targeting properties are designed to concentrate its therapeutic activity in hepatic tissue while limiting exposure to other organs, thereby improving its therapeutic index.
Drug interactions
Clinical studies have investigated potential pharmacokinetic drug interactions between clesacostat and ervogastat when used in combination therapy. These studies aim to inform optimal dosing strategies for the combination treatment approach.Clinical development
Preclinical development
Preclinical studies demonstrated that clesacostat selectively inhibits de novo lipogenesis in the liver while maintaining considerable safety margins against platelet reduction in non-human primate models. Laboratory studies showed that co-administration of clesacostat with ervogastat improved non-alcoholic fatty liver disease and NASH endpoints while mitigating clesacostat-induced elevations in circulating triglycerides.Phase I studies
Initial Phase I studies evaluated the safety, tolerability, and pharmacokinetics of clesacostat in healthy volunteers. These studies established that clesacostat demonstrates potent and selective inhibition of human ACC1 and ACC2.A dedicated Phase I drug interaction study investigated the pharmacokinetic interaction between clesacostat and ervogastat in healthy adult participants. This study was critical for determining optimal dosing strategies for the combination therapy, as clesacostat is metabolized via organic anion-transporting polypeptide-mediated hepatic uptake and cytochrome P450 family 3A, and has been identified as a potential CYP3A time-dependent inactivator.
Separate Phase I studies examined the pharmacokinetics, mass balance, metabolism, and excretion of radiolabeled clesacostat in healthy human subjects, providing comprehensive understanding of the drug's ADMET properties.
Phase II studies
MIRNA trial
The primary Phase II investigation is the MIRNA trial, a phase II, dose-ranging, dose-finding, randomised, placebo-controlled study. This study evaluated the efficacy and safety of ervogastat administered alone or in combination with clesacostat in adults with biopsy-confirmed NASH and F2-F3 liver fibrosis.The MIRNA trial was designed as a randomised, double-blind, double-dummy study that enrolled patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and F2-F3 fibrosis. Results published in The Lancet in January 2025 demonstrated the efficacy and safety profile of both ervogastat monotherapy and the combination of ervogastat with clesacostat.
Regulatory status
The combination of clesacostat and ervogastat has received Fast Track designation from the FDA for the treatment of NASH with liver fibrosis. This designation facilitates development and expedites regulatory review for treatments addressing serious conditions with unmet medical needs.As of September 2025, clesacostat remains in clinical development and has not received marketing approval from any regulatory agency.