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Rencofilstat, a cyclophilin inhibitor: A phase 2a, multicenter, single-blind, placebo-controlled study in F2/F3 NASH
Stephen A Harrison1, Patrick R Mayo2, Todd M Hobbs3
1Radcliffe Department of Medicine, University of Oxford, Pinnacle Clinical Research, Live Oak, Texas, USA.
Abstract:
Rencofilstat (RCF) demonstrated antifibrotic effects in preclinical models and was safe and well tolerated in Phase 1 studies. The aim of this Phase 2a study was safety, tolerability, pharmacokinetics, and exploration of efficacy biomarkers in subjects with nonalcoholic steatohepatitis (NASH). This Phase 2a, multicenter, single-blind, placebo-controlled study randomized 49 presumed F2/F3 subjects to RCF 75 mg once daily (QD), RCF 225 mg QD, or placebo for 28 days. Primary safety and tolerability endpoints were explored using descriptive statistics with post hoc analyses comparing active to placebo groups. Pharmacokinetics were evaluated using population pharmacokinetics methods. Efficacy was explored using biomarkers, transcriptomics, and lipidomics. RCF was safe and well tolerated, with no safety signals identified. The most frequently reported treatment-emergent adverse events were constipation, diarrhea, back pain, dizziness, and headache. No clinically significant changes in laboratory parameters were observed, and RCF pharmacokinetics were unchanged in subjects with NASH. Alanine transaminase (ALT) reduction was greater in active subjects than in placebo groups. Nonparametric analysis suggested that ALT reductions were statistically different in the 225-mg cohort compared with matching placebo: -16.3 ± 25.5% versus -0.7 ± 13.4%, respectively. ProC3 and C6M reduction was statistically significant in groups having baseline ProC3 > 15.0 ng/ml. RCF was safe and well tolerated after 28 days in subjects with presumed F2/F3 NASH. Presence of NASH did not alter its pharmacokinetics. Reductions in ALT, ProC3, and C6M suggest direct antifibrotic effects with longer treatment duration. Reductions in key collagen genes support a mechanism of action via suppression and/or regression of collagen deposition. Conclusion: These results support advancement of rencofilstat into a larger and longer Phase 2b study.
Insights
Rencofilstat (RCF) is safe and well-tolerated in nonalcoholic steatohepatitis (NASH) patients. The drug showed potential antifibrotic effects by reducing liver enzymes and collagen biomarkers, supporting further clinical trials.
Area of Science:
- Hepatology
- Pharmacology
- Clinical Trials
Background:
- Nonalcoholic steatohepatitis (NASH) is a progressive liver disease characterized by fat accumulation, inflammation, and fibrosis.
- Rencofilstat (RCF) has shown promise as an antifibrotic agent in preclinical studies and demonstrated safety in Phase 1 trials.
- Identifying safe and effective treatments for NASH, particularly for patients with advanced fibrosis (F2/F3 stages), is a critical unmet medical need.
Purpose of the Study:
- To evaluate the safety, tolerability, and pharmacokinetics of Rencofilstat (RCF) in patients with nonalcoholic steatohepatitis (NASH).
- To explore potential efficacy biomarkers, including liver enzymes and fibrotic markers, associated with RCF treatment.
- To assess the impact of NASH on RCF pharmacokinetics.
Main Methods:
- A Phase 2a, multicenter, single-blind, placebo-controlled study involving 49 subjects with presumed F2/F3 NASH.
- Randomization to Rencofilstat (RCF) 75 mg QD, RCF 225 mg QD, or placebo for 28 days.
- Safety and tolerability assessed via descriptive statistics; pharmacokinetics evaluated using population methods; efficacy explored through biomarkers, transcriptomics, and lipidomics.
Main Results:
- Rencofilstat (RCF) was found to be safe and well-tolerated, with no significant safety signals identified.
- Treatment-emergent adverse events were primarily mild, including constipation and headache; no clinically significant laboratory changes were observed.
- Statistically significant reductions in alanine transaminase (ALT) were observed in the 225 mg RCF group compared to placebo. Significant reductions in ProC3 and C6M were noted in patients with elevated baseline ProC3 levels.
Conclusions:
- Rencofilstat (RCF) is safe and well-tolerated in patients with presumed F2/F3 NASH over a 28-day treatment period.
- The pharmacokinetics of RCF were not significantly altered by the presence of NASH.
- Observed reductions in ALT, ProC3, and C6M suggest RCF possesses direct antifibrotic effects, supporting its advancement to Phase 2b studies for NASH treatment.
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