Rencofilstat

Summary

Rencofilstat (CRV431) is an oral, investigational cyclophilin inhibitor being explored for liver diseases. It is a non‑immunosuppressive analogue of cyclosporine A and has been studied in patients with metabolic‑associated steatohepatitis (MASH/NASH) and in animal models of hepatitis C virus‑driven hepatocellular carcinoma. Early clinical trials suggest it may improve liver function, reduce fibrosis biomarkers, and limit tumour progression, while pre‑clinical work points to remodeling of the extracellular matrix in fibrotic liver tissue.

Mechanism of Action

Rencofilstat binds to the active site of multiple cyclophilin isoforms, blocking their peptidyl‑prolyl isomerase activity. Cyclophilins modulate inflammatory signalling, collagen synthesis, and viral replication. Inhibiting these proteins reduces hepatic inflammation and fibrogenesis, alters extracellular‑matrix composition and stiffness, and interferes with hepatitis C virus‑related oncogenic pathways, leading to antifibrotic and anti‑tumour effects independent of direct antiviral activity.

What the Research Shows

A phase 2a, single‑blind, placebo‑controlled study in 49 subjects with presumed F2/F3 NASH reported that 28‑day treatment with rencofilstat (75 mg or 225 mg daily) was safe, well tolerated, and produced greater ALT reductions (−16.3% vs −0.7% for placebo) and significant declines in fibrosis biomarkers ProC3 and C6M in subjects with elevated baseline levels. In a separate randomised trial of 70 patients with advanced MASH, 225 mg daily for 120 days decreased portal‑systemic shunting (−1.55%) and improved the HepQuant disease‑severity index (−1.61). Human precision‑cut liver slices and primary hepatic stellate cells treated with rencofilstat showed extensive extracellular‑matrix remodeling, reduced core ECM protein abundance, and lower tissue stiffness without altering stellate cell activation. In humanised mouse models of HCV infection, rencofilstat halted progression of HCV‑induced hepatocellular carcinoma even when administered after tumours were established, an effect not reproduced by standard antiviral agents. A phase 1 bioavailability study indicated that a high‑fat meal modestly increased systemic exposure but did not produce clinically relevant safety concerns.

Reported Benefits

Current evidence suggests rencofilstat may improve liver functional metrics (lower SHUNT% and DSI), reduce serum ALT and fibrosis‑related biomarkers (ProC3, C6M), and remodel the extracellular matrix to lessen tissue stiffness. In pre‑clinical HCV‑driven cancer models, it markedly slowed tumour development independent of antiviral action. Across studies, the drug was generally well tolerated, supporting its potential as a disease‑modifying therapy for fibrotic liver disease and HCV‑related hepatocellular carcinoma.

Limitations of the Evidence

Findings are limited to early‑phase trials with small cohorts and short treatment durations (28–120 days). The phase 2a NASH study lacked a double‑blind design and used surrogate biomarkers rather than histologic endpoints. Long‑term safety, efficacy on hard clinical outcomes (cirrhosis, liver‑related mortality), and effectiveness across diverse patient populations remain unproven. Pre‑clinical cancer data are confined to mouse models, and no human oncology trials have been reported.

Safety Considerations

Rencofilstat was well tolerated in all reported studies. No serious adverse events occurred. The most frequently reported treatment‑emergent events were mild gastrointestinal symptoms (constipation, diarrhea), back pain, dizziness, and headache. In the high‑fat meal pharmacokinetic study, one adverse event was recorded, but overall exposure changes were deemed unlikely to affect safety. Laboratory parameters remained stable, and no immunosuppressive effects were observed.

How It Is Administered

Rencofilstat is administered orally as a soft‑gelatin capsule, typically once daily at doses of 75 mg or 225 mg. Clinical trials have evaluated both fasted and high‑fat fed conditions, with the latter modestly increasing systemic exposure. The formulation is designed for oral absorption; no parenteral routes have been described.

Routes of Administration

Goals & Uses

• Antiviral activity against HBVInfectious DiseaseLow
• Antiviral activity against HDVInfectious DiseaseLow
• Treatment of NASH (Non-Alcoholic Steatohepatitis)Metabolic/Hepatic DiseaseModerate
• Liver fibrosis reductionHepatic DiseaseModerate
• Reduction of liver inflammationHepatic DiseaseModerate

Contraindications

• Severe renal impairmentOrganModerateKidney function concerns
• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• Known hypersensitivity to cyclosporine analoguesAllergyHigh

Adverse Effects

• HeadacheNeurologicUncommonPain in the head or upper neck
• Gastrointestinal disturbances (nausea, diarrhea)GastrointestinalCommon
• FatigueGeneralUncommonLow energy or tiredness
• Elevated liver enzymes (transaminases)HepaticUncommon

Drug Interactions

• CYP3A4 inducers (e.g., rifampin, carbamazepine)Moderate
• P-glycoprotein substrates/inhibitorsLow
• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir)Moderate

Population Constraints

• Immunocompromised patients on immunosuppressive therapyImmunologicalRelative
• Pediatric patientsAgeRelative
• Patients with severe hepatic impairment (Child-Pugh C)Hepatic DiseaseRelative
• Pregnant womenReproductiveRelative

Regulatory Status

• European UnionInvestigationalNo EMA approval; clinical development ongoing.
• United StatesInvestigationalIND held by Hepion Pharmaceuticals; Phase 2 clinical trials ongoing for NASH and liver fibrosis as of 2024. Not FDA-approved.
• United KingdomInvestigationalNo MHRA approval; status mirrors EU investigational stage.

Under clinical investigation in the United States (IND held by Hepion Pharmaceuticals). No FDA, EMA, or MHRA approval as of 2024. Orphan Drug Designation may be under consideration for HDV. Phase 2 trials ongoing for NASH/liver fibrosis.

Evidence & Sources

• Rencofilstat Treatment Improves Liver Function in MASH With Advanced Fibrosis as Quantified by HepQuant DuO
  Journal ArticleModerateHarrison SA, et al.2025-01-01T00:00:00.000000Z
• The Cyclophilin Inhibitor Rencofilstat Decreases HCV-induced Hepatocellular Carcinoma Independently of Its Antiviral Activity
  Journal ArticleLowStauffer W, et al.2023-01-01T00:00:00.000000Z
• Comprehensive analysis of extracellular matrix remodelling via cyclophilin inhibition in human models of alcohol-related liver fibrosis
  Journal ArticleLowRastovic U, et al.2025-01-01T00:00:00.000000Z
• The Cyclophilin Inhibitor Rencofilstat Decreases HCV-Induced Hepatocellular Carcinoma Independently of Its Antiviral Activity
  Journal ArticleLowStauffer W, et al.2023-01-01T00:00:00.000000Z
• Effect of a High-Fat Meal on Single-Dose Rencofilstat (CRV431) Oral Bioavailability in Healthy Human Subjects
  Journal ArticleModerateRemenchik E, et al.2023-01-01T00:00:00.000000Z
• Rencofilstat, a cyclophilin inhibitor: A phase 2a, multicenter, single-blind, placebo-controlled study in F2/F3 NASH
  Journal ArticleModerateHarrison SA, et al.2022-01-01T00:00:00.000000Z

Frequently Asked Questions