rencofilstat (CRV431) / Hepion Pharma - LARVOL DELTA

Cyclophilin Inhibitor Rencofilstat Combined with Proteasome Inhibitor Ixazomib Increases Proteotoxic Cell Death in Advanced Prostate Cancer Cells with Minimal Effects on Non-Cancer Cells. (PubMed, Biomedicines) - "Rencofilstat increased extracellular secretion of cyclophilin B, but rencofilstat + ixazomib reduced glycosylation and, likely, the biological function of CD147 (CypB receptor) and decreased downstream ERK signaling. Rencofilstat + ixazomib may be a new strategy for increasing proteotoxic stress and apoptotic cell death in advanced prostate cancer cells with less toxic side effects."

Journal • Genito-urinary Cancer • Hematological Malignancies • Multiple Myeloma • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • BSG

A Novel Chemotherapy Combination to Enhance Proteotoxic Cell Death in Hepatocellular Carcinoma Experimental Models Without Killing Non-Cancer Cells. (PubMed, Int J Mol Sci) - "In the Hep3B xenograft model, rencofilstat + ixazomib significantly inhibited tumor volumes/weights without general toxicity. We conclude that rencofilstat + ixazomib amplified proteotoxic stress in hepatocellular carcinoma past a threshold pro-survival pathways could not tolerate, whereas non-cancer cells were less affected."

Journal • Hematological Malignancies • Hepatocellular Cancer • Multiple Myeloma • Oncology • Solid Tumor • Targeted Protein Degradation

Comprehensive analysis of extracellular matrix remodelling via cyclophilin inhibition in human models of alcohol-related liver fibrosis. (PubMed, Br J Pharmacol) - "This work provides evidence for a novel mechanism linking cyclophilins and ECM remodelling in advanced 3D models of liver disease, with potential applications in therapeutic development."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis

Efficacy of CRV431 and Semaglutide on liver fibrosis in a mouse model of MASH (EASL 2025) - "CRV431 showed the most substantial reduction in hepatic fibrosis among the treatments tested, aligning with historical observations of its antifibrotic efficacy in liver disease models. The absence of a synergistic effect and the higher fibrosis levels in the combination-treated group suggest possible antagonistic interactions between CRV431 and semaglutide, potentially diminishing the therapeutic benefits of CRV431 when used concurrently with semaglutide."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Dysfunction-Associated Steatohepatitis

Rencofilstat Treatment Improves Liver Function in MASH With Advanced Fibrosis as Quantified by HepQuant DuO. (PubMed, Liver Int) - P2 | "Although further studies are warranted, the decreases in DSI and SHUNT% suggest that rencofilstat 225 mg/d improves hepatic function and portal-systemic shunting. HepQuant DuO is simple to administer, well-tolerated and a useful tool for detecting the hepatic effects of treatment."

Clinical • Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

THE ORAL CHOLATE CHALLENGE TEST IDENTIFIES THE MASH PATIENTS WITH ≥F3 FIBROSIS WITH GREATEST HEPATIC IMPAIRMENT WHO SHOW THE MOST BENEFIT FROM SHORT-TERM RENCOFILSTAT THERAPY (AASLD 2024) - "RCF (225 mg) was associated with reduction in DSI and SHUNT% after 120 days, suggesting improvement in effective hepatic perfusion possibly due to fibrosis remodeling given RCF's anti-inflammatory and antifibrotic properties. These changes may be most effective in patients with more severe liver impairment. These results demonstrate the successful use of HepQuant DuO to assess hepatic function and the promise of RCF as a potential MASH treatment in patients with advanced fibrosis."

Clinical • Fibrosis • Hepatology • Immunology • Liver Failure • Metabolic Dysfunction-Associated Steatohepatitis

Single Dose ADME Study of [14C]-Rencofilstat in Healthy Male Subjects (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: Hepion Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

ALTITUDE: A Study to Evaluate the Safety and Efficacy of Rencofilstat in Adult Subjects With NASH F3 (clinicaltrials.gov) - P2 | N=60 | Completed | Sponsor: Hepion Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

The pan-cyclophilin inhibitor rencofilstat exhibits therapeutic anti-fibrotic effects in human relevant models of alcohol-related liver disease via extracellular matrix remodelling (EASL-ILC 2024) - "Despite promising results in animal models, a substantial "translational gap" persists and there are no approved therapies to target alcohol-related fibrosis. This study demonstrates the therapeutic effects of rencofilstat in relevant patient-derived 3D models of ALD and fibrosis and proves the significant impact of cyclophilin inhibition on ECM remodelling, with direct consequences on tissue stiffness."

Fibrosis • Hepatology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • TGFB1

ASCEND: A Study to Evaluate the Efficacy and Safety of Rencofilstat in Subjects With NASH and Advanced Liver Fibrosis (clinicaltrials.gov) - P2 | N=120 | Active, not recruiting | Sponsor: Hepion Pharmaceuticals, Inc. | Phase classification: P2b ➔ P2 | N=336 ➔ 120

Enrollment change • Metastases • Phase classification • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Cyclophilin D knockout significantly prevents HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH. (PubMed, PLoS One) - "We previously reported that non-immunosuppressive pan-cyclophilin inhibitor drugs like reconfilstat (CRV431) or NV556 decreased multiple aspects of non-alcoholic fatty liver disease (NAFLD) in mice under two different non-alcoholic steatohepatitis (NASH) mouse models...Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NAFLD/NASH. This study highlights the impact of CypD loss-of-function on the development of HCC, one of the most severe disease outcomes."

Journal • Preclinical • Diabetes • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • PPIF

Mice lacking cyclophilin B, but not cyclophilin A, are protected from the development of NASH in a diet and chemical-induced model. (PubMed, PLoS One) - "We previously reported that the pan-cyclophilin inhibitor drug reconfilstat (CRV431) decreased disease in mice under the western-diet and carbon tetrachloride (CCl4) non-alcoholic steatohepatitis (NASH) model...These data suggest that CypB is necessary for NASH disease progression. Further investigation is necessary to determine whether the specific role of CypB in the endoplasmic reticulum secretory pathway is of significance to its effect on NASH development."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • TNFA

Combined extracellular matrix remodelling by cyclophilin inhibitor rencofilstat and immune checkpoint blockade as a potential therapy for intrahepatic cholangiocarcinoma (LCS 2024) - " iCCA-PCTS from 4 patients were cultured for 7 days and exposed to rencofilstat (R) with/without nivolumab (N) and compared to untreated or standard of care (gem-cis + durvalumab). To conclude, we demonstrated the utility of iCCA PCTS for characterising patient-specific ECM and assessing combination therapies targeting the TME. In addition, PCTS represent a unique model to identify alternative surrogate measures of efficacy in vitro, that could be validated in patient cohorts. Finally, we show that R+N can favourably alter the TME in iCCA, suggesting that targeting both a dysfunctional ECM and exhausted tumour immune population to improve anti-cancer immune cell infiltration and function may be a promising avenue, deserving further investigation."

Checkpoint block • Checkpoint inhibition • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Hepion Pharmaceuticals Announces Major Reductions in Liver Stiffness with Rencofilstat Treatment in 17-week Phase 2 Study of Advanced (F3) MASH Liver Disease (Streetinsider.com) - P2 | N=60 | ALTITUDE-NASH (NCT05461105) | Sponsor: Hepion Pharmaceuticals, Inc. | "Additional rencofilstat efficacy data from Hepion’s ‘ALTITUDE-NASH’ clinical trial was presented earlier this afternoon by Dr. Mayo in a late-breaker poster presentation at the Liver Meeting 2023, hosted by the American Association for the Study of Liver Diseases ('AASLD'). Dr. Mayo’s presentation indicated that 17 weeks of rencofilstat treatment was associated with significant reduction in liver stiffness (FibroScan) in MASH subjects with advanced F3, an outcome suggesting reduction in hepatic fibro-inflammation."

P2 data • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

HEPATIC FUNCTIONAL IMPROVEMENT DETECTED BY HEPQUANT DUO WITHIN 120 DAYS OF TREATMENT WITH RENCOFILSTAT (RCF) IN MASH SUBJECTS WITH ≥ F3 FIBROSIS (AASLD 2023) - "RCF (225 mg) was associated with improvements in hepatic function and portal-systemic shunting. Subjects with the most impaired hepatic function at baseline showed the greatest improvements, suggesting a positive effect of RCF in MASH subjects with advanced fibrosis. These results demonstrate the successful use of HepQuant DuO to assess hepatic function and the promise of RCF as a potential MASH treatment in advanced fibrosis."

Clinical • Late-breaking abstract • Fibrosis • Hepatology • Immunology • Liver Failure

Using AI to Better Inform Clinical Study NASH Enrolment Success: Highlights from Recently Completed & Ongoing Phase 2 Trials with Rencofilstat (NASH Summit-US 2023) - "Synopsis Targeting advanced NASH subjects is critical for success Use of AI and biomarkers helps aide the selection of appropriate subjects for trials Simple enrichment strategies reduce placebo response and enhance success for active drug"

Clinical • P2 data • Hepatology • Non-alcoholic Steatohepatitis

USE OF AGILE 3+ AS A SCREENING TOOL SUCCESSFULLY TARGETS NON-ALCOHOLIC STEATOHEPATITIS (NASH) SUBJECTS WITH IMPAIRED HEPATIC FUNCTION AND PORTAL-SYSTEMIC SHUNTING EVALUATED BY HEPQUANT SHUNT TEST: LESSONS LEARNED FROM THE HEPION ALTITUDE-NASH (≥F3) TRIAL (AASLD 2023) - "Rencofilstat, a non-immunosuppressive pan-cyclophilin inhibitor, has demonstrated pleotropic effects well-suited for the treatment of NASH with advanced fibrosis... Use of AGILE 3+ as a screening tool for identifying subjects was successful in allowing a timely recruitment of F3 NASH subjects. In addition, the sequential use of AGILE 3+ coupled with the HepQuant SHUNT test may identify subjects at high risk for clinical complications from an otherwise well-compensated advanced NASH population."

Clinical • Cardiovascular • Diabetes • Fibrosis • Hepatology • Hypertension • Immunology • Metabolic Disorders • Non-alcoholic Steatohepatitis • Portal Hypertension

The Cyclophilin Inhibitor Rencofilstat Decreases HCV-Induced Hepatocellular Carcinoma Independently of Its Antiviral Activity. (PubMed, Viruses) - "We demonstrate that the nonimmunosuppressive cyclosporine A (CsA) analog (CsAa) rencofilstat possesses dual therapeutic activities for the treatment of HCV infection and HCV-induced HCC. Indeed, the CypI rencofilstat inhibits HCC, while other anti-HCV agents such as NS5A (NS5Ai) and NS5B (NS5Bi) fail to reduce HCC. In conclusion, this study shows for the first time that the CypI rencofilstat represents a potent therapeutic agent for the treatment of HCV-induced HCC."

Journal • Gastrointestinal Cancer • Hepatitis C • Hepatocellular Cancer • Infectious Disease • Oncology • Solid Tumor

Hepion Pharmaceuticals’ Rencofilstat Demonstrates Anti-Cancer Activity in Hepatitis C-Associated Cancer Model (GlobeNewswire) - "Hepion Pharmaceuticals, Inc...today announced the publication of a new research study in mice, where Hepion’s lead drug candidate, rencofilstat, prevented the growth of liver tumors that occurred as a result of chronic infection with the human hepatitis C virus ('HCV')....When initiated at week 0, rencofilstat treatment completely prevented HCC development measured at week 30 likely because the drug also blocked HCV infection and therefore eliminated a key driver of HCC development....When initiated at week 12, when tumors were in a small nodular stage, rencofilstat treatment similarly resulted in no visible nodules or tumors at week 30, suggesting that rencofilstat was able to completely regress small cancerous nodules..."

Preclinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Rencofilstat Produces Positive Outcomes in Translational Study on Idiopathic Pulmonary Fibrosis (GlobeNewswire) - "Hepion Pharmaceuticals, Inc...today announced positive results from a translational research study in which Hepion’s lead drug candidate, rencofilstat, was administered to diseased human lung tissue from patients with idiopathic pulmonary fibrosis ('IPF')...These analyses demonstrated: Rencofilstat monotherapy altered levels of between 8 and 28% of the 1,953 proteins identified in PCLuS depending on dose and donor. This represented changes 2 - 4-times greater than nintedanib or pirfenidone in PCLuS from the first donor, and 2-fold greater than nintedanib in the second donor; Rencofilstat, in combination with nintedanib, altered levels of 16 - 42% of the 1,953 proteins depending on donor, which represented 2.7 - 7.8-fold more than nintedanib alone."

Clinical data • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases

Hepion Pharmaceuticals Discovers Novel Rencofilstat Action in Liver Cancer (GlobeNewswire) - "Hepion Pharmaceuticals...announced new research findings uncovering a previously unknown mechanism by which Hepion’s lead drug candidate, rencofilstat, may exert anti-cancer activity....Rencofilstat predominantly closed DNA in the cell line in which it also suppressed cell growth, suggesting that the drug candidate’s anti-cancer effect on the cells resulted in part from DNA closure and gene silencing."

Preclinical • Gastrointestinal Cancer • Liver Cancer • Oncology • Solid Tumor

New Anti-Cancer Opportunities Revealed for Hepion Pharmaceuticals’ Rencofilstat in Cancer Screening Program (GlobeNewswire) - "Hepion Pharmaceuticals, Inc...today announced results from a study with in which the anti-cancer activity of Hepion’s lead drug candidate, rencofilstat, was tested in a high through-put screen on 850 cancer cell lines spanning 28 types of cancer at the PRISM lab at the Broad Institute of MIT and Harvard....Rencofilstat was administered at eight concentrations to each cancer cell line in culture for 5 days, followed by measurement of surviving cells to determine how effectively the drug candidate killed or suppressed proliferation of the cancer cells. Defining 'anti-cancer responsiveness' as 50% or greater reduction in viability following treatment, 26% of all tested cancer cell lines (220/850) spanning 86% of cancer cell types (24/28) were responsive to rencofilstat. Some of the rencofilstat-sensitive cell lines were HCC cells, which further supports Hepion’s plans for a clinical trial in this indication."

Preclinical • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Cyclophilin inhibition with rencofilstat shifts the liver transcriptome and lipidome in preclinical models toward resolution of nonalcoholic steatohepatitis (EASL-ILC 2023) - "Elafibranor (ELF) and obeticholic acid (OCA) were additionally administered in the DIAMOND mouse study. Despite no known mechanisms of transcriptional regulation, rencofilstat positively changed gene expression networks similarly to FXR and PPAR agonists. Rencofilstat also altered liver lipid signatures consistent with attenuation of lipotoxic processes. These findings suggest that cyclophilins contribute to many pathophysiologic processes and blocking their modulatory actions with rencofilstat shifts the liver transcriptome and lipidome towards NASH resolution."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Non-alcoholic Steatohepatitis

Mice lacking Cyclophilin B, but not Cyclophilin A, are significantly protected from the development of major features of NAFLD/NASH in a diet and chemical-induced model (EASL-ILC 2023) - "We previously reported that the pan-cyclophilin inhibitor drug CRV431 (reconfilstat) decreased NASH in mice under the western-diet/CCl4 model... Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NAFLD/NASH. In this study, mice without CypB, but not mice without CypA, were significantly protected from the development of the characteristic features of NASH. Further investigation is necessary to determine whether the specific role of CypB in the ER secretory pathway is of significance to its effect on NASH development."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Cyclophilin inhibition exhibits preventive and curative antifibrotic effects via extracellular matrix remodelling (EASL-ILC 2023) - "This study confirms the key role of cyclophilins in liver fibrosis and inflammation in patient-derived 3D and multicellular models revealing the remarkable potential of cyclophilin inhibition as anti-fibrotic therapy in relevant models of human disease. We also provide novel insights regarding rencofilstat’s mechanism of action in the remodelling of the ECM in liver fibrosis, demonstrating a direct consequence on tissue stiffness."

Fibrosis • Hepatology • Inflammation • Liver Cirrhosis • Non-alcoholic Steatohepatitis