Jump to content

Clesacostat

Add links
From Wikipedia, the free encyclopedia

Clesacostat
Clinical data
Other namesPF-05221304
Drug classAcetyl-CoA carboxylase inhibitor
Identifiers
  • 4-[6-methoxy-4-(7-oxo-1-propan-2-ylspiro[4,6-dihydroindazole-5,4'-piperidine]-1'-carbonyl)pyridin-2-yl]benzoic acid
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC28H30N4O5
Molar mass502.571 g·mol−1
3D model (JSmol)
  • CC(C)N1C2=C(CC3(CCN(CC3)C(=O)C4=CC(=NC(=C4)OC)C5=CC=C(C=C5)C(=O)O)CC2=O)C=N1
  • InChI=InChI=1S/C28H30N4O5/c1-17(2)32-25-21(16-29-32)14-28(15-23(25)33)8-10-31(11-9-28)26(34)20-12-22(30-24(13-20)37-3)18-4-6-19(7-5-18)27(35)36/h4-7,12-13,16-17H,8-11,14-15H2,1-3H3,(H,35,36)
  • Key:LXZMHBHEXAELHH-UHFFFAOYSA-N

Clesacostat (developmental code PF-05221304) is an investigational pharmaceutical compound developed by Pfizer for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), with liver fibrosis.[1] It is a liver-targeted inhibitor of acetyl-CoA carboxylase (ACC), an enzyme that plays a central role in fatty acid metabolism.[2]

Medical uses

[edit]

Clesacostat is currently being investigated as a treatment for NASH with liver fibrosis, both as a monotherapy and in combination with ervogastat (PF-06865571), a diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor.[3] The combination therapy has received FDA Fast Track designation from the U.S. Food and Drug Administration (FDA), which is designed to expedite the development and review of treatments for serious conditions with unmet medical needs.[4]

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

[edit]

Clesacostat functions as a dual inhibitor of acetyl-CoA carboxylase 1 and 2 (ACC1/2).[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 (DNL) - 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

The drug is designed to be liver-targeted, which helps optimize its therapeutic benefits while potentially minimizing systemic side effects.[2]

Pharmacology

[edit]

Pharmacokinetics

[edit]

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.[2] 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.[2]

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

[edit]

Clinical studies have investigated potential pharmacokinetic drug interactions between clesacostat and ervogastat when used in combination therapy.[1] These studies aim to inform optimal dosing strategies for the combination treatment approach.

Clinical development

[edit]

Preclinical development

[edit]

Preclinical studies demonstrated that clesacostat selectively inhibits de novo lipogenesis (DNL) in the liver while maintaining considerable safety margins against platelet reduction in non-human primate models.[5] Laboratory studies showed that co-administration of clesacostat with ervogastat improved non-alcoholic fatty liver disease (NAFLD) and NASH endpoints while mitigating clesacostat-induced elevations in circulating triglycerides.

Phase I studies

[edit]

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 (IC50 = 13 nM) and ACC2 (IC50 = 9 nM).[5][6][7]

A dedicated Phase I drug interaction study (NCT03534648) 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 (CYP3A), and has been identified as a potential CYP3A time-dependent inactivator.[8][9]

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.[10][11][12][8]

Phase II studies

[edit]

MIRNA trial

[edit]

The primary Phase II investigation is the MIRNA (Metabolic Interventions to Resolve NASH with fibrosis) trial (NCT04321031), 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.[13]

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.[14]

Regulatory status

[edit]

The combination of clesacostat and ervogastat has received Fast Track designation from the FDA for the treatment of NASH with liver fibrosis.[4] This designation facilitates development and expedites regulatory review for treatments addressing serious conditions with unmet medical needs.[15]

As of September 2025, clesacostat remains in clinical development and has not received marketing approval from any regulatory agency.[16]

See also

[edit]

References

[edit]
  1. ^ a b Amin N, Carvajal-Gonzalez S, Purohit V (2022). "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". BMJ Open. 12 (3) e056159. doi:10.1136/bmjopen-2021-056159. PMC 8968568. PMID 35354614.
  2. ^ a b c d e Ryder TF, Bergman A, King-Ahmad A, Amin NB, Lall MS, Ballard TE, et al. (March 2022). "Pharmacokinetics, mass balance, metabolism, and excretion of the liver-targeted acetyl-CoA carboxylase inhibitor PF-05221304 (clesacostat) in humans". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 52 (3): 240–253. doi:10.1080/00498254.2022.2062487. PMID 35382680.
  3. ^ Amin N, Darekar A, Anstee Q (2025). "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". The Lancet. 10 (10): 924–940. doi:10.1016/S2468-1253(25)00128-1. PMID 40753985.
  4. ^ a b "Pfizer Granted FDA Fast Track Designation for Ervogastat/Clesacostat Combination for the Treatment of Non-Alcoholic Steatohepatitis (NASH)" (Press release). Pfizer Inc. 2022.
  5. ^ a b "Clesacostat (PF-05221304)". InvivoChem. Retrieved 8 September 2025.
  6. ^ Pfizer (18 May 2020). A Phase 1, Open Label, Two-Period, Randomized Crossover Study to Compare the Pharmacokinetics of Two Different Formulations of PF-05221304 Administered Orally to Healthy Adult Subjects (Report). clinicaltrials.gov. NCT03871439.
  7. ^ Pfizer (26 November 2018). A Phase 1, 2-part Study Of Pf-05221304 In Healthy Japanese Adults: Part 1 - Randomized, Double-blind, Crossover, Single Dose Assessment Of Pharmacokinetics And Safety; Part 2- Randomized, Double-blind, Placebo-controlled, Multiple Dose Assessment Of Safety, Tolerability And Pharmacokinetics Of PF-05221304 (Report). clinicaltrials.gov. NCT03597217.
  8. ^ a b Pfizer (16 September 2018). A Phase 1, Open Label, Two-cohort, Non-randomized Fixed Sequence Study To Evaluate The Pharmacokinetic Drug Drug Interaction Between PF-05221304 and PF-06865571 In Healthy Adult Subjects (Report). clinicaltrials.gov. NCT03534648.
  9. ^ Pfizer (19 June 2019). A Phase 1, Non-Randomized, Open-Label, Single-Dose, Parallel Cohort Study to Compare the Pharmacokinetics of PF-05221304 in Adult Subjects With Varying Degrees of Hepatic Impairment Relative to Subjects Without Hepatic Impairment (Report). clinicaltrials.gov. NCT03309202.
  10. ^ Pfizer (3 December 2018). A Phase 1, Open Label, Single-period, Non-randomized Study To Evaluate The Pharmacokinetics, Excretion, Mass Balance, And Metabolism Of [14c]Pf-05221304 Administered Orally To Healthy Adult Male Subjects (Report). clinicaltrials.gov. NCT03448172.
  11. ^ Columbia University (19 August 2021). A Phase 1B, Single-Blinded, Linear Two Period, Placebo-controlled Study to Evaluate the Effects of 10 mg/Day of PF-05221304, Liver Targeted Acetyl-CoA Carboxylase Inhibitor (ACCi) on Very Low Density Lipoprotein ApoB100 and TG Secretion (Report). clinicaltrials.gov.
  12. ^ Pfizer (22 May 2018). A Phase 1, 3-part Study Of Pf-05221304 In Healthy Adults: Part 1 - Randomized, Double-blind, Placebo-controlled Assessment Of Safety And Pharmacokinetics Of Single, Escalating, Oral Doses; Part 2 - Randomized, Double-blind, Placebo-controlled Assessment Of Safety And Pharmacokinetics Of Repeated, Escalating, Oral Doses; Conditional Part 3 - Effect Of Food On The Pharmacokinetics Of Pf-05221304 (Report). clinicaltrials.gov. NCT02871037.
  13. ^ Pfizer (4 March 2025). A Phase 2, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Dose-Ranging, Dose-Finding, Parallel Group Study to Assess Efficacy and Safety of Pf-06865571 (dgat2i) Alone and When Coadministered With Pf-05221304 (ACCI) in Adult Participants With Biopsy-Confirmed Nonalcoholic Steatohepatitis and Fibrosis Stage 2 or 3 (Report). clinicaltrials.gov. NCT04321031.
  14. ^ Wong VW, Amin NB, Takahashi H, Darekar A, Tacke F, Kiszko J, et al. (October 2025). "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". The Lancet. Gastroenterology & Hepatology. 10 (10): 924–940. doi:10.1016/S2468-1253(25)00128-1. PMID 40753985.
  15. ^ "With the right partner, Pfizer gains fast-track tag for previously shelved NASH drug". FierceBiotech. 26 May 2022. Retrieved 8 September 2025.
  16. ^ "Clesacostat". DrugBank. University of Alberta. Retrieved 8 September 2025.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Clesacostat&oldid=1319760915"