Rencofilstat

Summary

Rencofilstat (formerly CRV431) is a non-immunosuppressive cyclophilin inhibitor derived from cyclosporine. It is being investigated primarily for the treatment of non-alcoholic steatohepatitis (NASH) and liver fibrosis, as well as for antiviral activity against hepatitis B (HBV) and hepatitis D (HDV). By inhibiting cyclophilins without calcineurin inhibition, it avoids the immunosuppressive side effects of cyclosporine while retaining antifibrotic and antiviral properties.

Mechanism of Action

Selectively inhibits cyclophilin A (CypA) and other cyclophilins by binding to their peptidylprolyl isomerase (PPIase) active site, blocking cyclophilin-mediated protein folding and signaling without inhibiting calcineurin, thereby avoiding immunosuppression. This disrupts viral replication cycles dependent on cyclophilins and reduces fibrogenic and inflammatory signaling in hepatic stellate cells.

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

No sources recorded yet.

Frequently Asked Questions