alisporivir (DEB-025) / Debiopharm, Solid BioSci - LARVOL DELTA

Cyclophilin D knockout promotes cell death pathways in preventing HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH (EASL-ILC 2022) - "Background and aims: Cyclophilins are a diverse family of peptidyl prolyl isomerases which promote protein folding and perform a variety of functions in the liver and other tissues.We have previously reported that the pan-cyclophilin inhibitor (CypI) compounds, CRV431, NV556 and Debio-025/Alisporivir, decreased the severity of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) in a streptozotocin (STZ)-induced HCC murine model. Cyclophilin inhibition represents a promising avenue for the treatment of HCC development in mouse models. These data show for the first time that mice without CypD are significantly protected from HCC development, suggesting CypD inhibition is at least partly responsible for the previously established anti-tumor effects of CypI antagonist compounds. Molecular analyses suggest CypD inhibitionmay promote cell death pathways which act as tumor suppressors."

Preclinical • Diabetes • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • BIRC5 • PPIF

Repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents. (PubMed, Drug Discov Today) - "Because CypA acts as a proviral component in hepatitis C virus, coronavirus and HIV, its inhibitors have been suggested as potential treatments for these infections. Here, we review the structure of cyclosporin A and sanglifehrin A analogs as well as synthetic micromolecules inhibiting CypA; and we discuss their broad-spectrum antiviral efficacy in the context of the virus lifecycle."

Journal • Review • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the Dystrophin-Deficient D2.B10-Dmd /J Mouse. (PubMed, Oxid Med Cell Longev) - "We also tested whether drug treatment with a specific blocker of mitochondrial permeability transition pore opening (Debio-025), or ACE inhibition (Perindopril), had any effect on dystrophy-related cardiomyopathy...At 18 weeks, compared to DBA/2, D2-mdx hearts displayed greater ventricular collagen, lower cell density, greater cell diameter, and greater protein expression levels of IL-6, TLR4, BAX/Bcl2, caspase-3, PGC-1α, and notably monoamine oxidases A and B. Remarkably, these adaptations in D2-mdx mice were associated with preserved resting left ventricular function similar to DBA/2 mice. Compared to vehicle, although Perindopril partly attenuated the increase in heart weight and collagen at 18 weeks, the drug treatments had no marked impact on dystrophic cardiomyopathy."

IO biomarker • Journal • Preclinical • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Heart Failure • Immunology • Muscular Dystrophy • Myositis • BAX • BCL2 • CASP3 • IL6 • TLR4

The Potential Use of Cyclosporine Ultrafine Solution Pressurised Metered-Dose Inhaler in the Treatment of COVID-19 Patients. (PubMed, Recent Adv Drug Deliv Formul) - "Ultrafine pMDI formulation of cyclosporine or Debio 025 should be investigated for the inhalation therapy of COVID-19."

Clinical • Journal • Immunology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Transplantation

[VIRTUAL] CYCLOPHILIN D KNOCKOUT SIGNIFICANTLY PREVENTS HCC DEVELOPMENT IN A STREPTOZOTOCIN-INDUCED MOUSE MODEL OF DIABETES-LINKED NASH (AASLD 2021) - "We previously reported that multiple pan-cyclophilin inhibitor (CypI) compounds - CRV431, NV556 and Debio-025/Alisporivir - decreased features of NASH and HCC in mice . CypI represent a novel class of safe compounds for the potential treatment of diabetes- and Western diet-induced HCC development in mouse models . These data show for the first time that mice without CypD are significantly protected from HCC development, suggesting CypD inhibition is at least partly responsible for the anti-tumor effects of CypI antagonists . Similar studies investigating other cyclophilin family members are ongoing ."

Preclinical • Diabetes • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • PPIF

Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis. (PubMed, Int J Mol Sci) - "At the same time, alisporivir suppressed mitochondrial biogenesis, assessed by the expression of Ppargc1a, and altered the dynamics of organelles, inhibiting both DRP1-mediated fission and MFN2-associated fusion of mitochondria. The article discusses the effects of alisporivir administration and cyclophilin D inhibition on mitochondrial reprogramming and networking in DMD and the consequences of this therapy on skeletal muscle health."

Journal • Preclinical • Duchenne Muscular Dystrophy • Genetic Disorders • Immunology • Inflammation • Muscular Dystrophy • PPIF

Phase II Research Against Covid-19 Launched in France With Debiopharm's Antiviral Alisporivir (PRNewswire) - "Debiopharm...announced today the first patient dosed in an investigator-initiated, randomized phase II, open-label clinical trial for its antiviral alisporivir (Debio 025). The study will be conducted by the AP-HP to assess the efficacy and safety of the cyclophilin inhibitor in the treatment of early stage, hospitalized COVID-19 patients not requiring medical ventilation nor exhibiting signs of acute respiratory distress syndrome....If phase II results show the results required to advance to phase III, Debiopharm will seek to partner with a larger global pharmaceutical company or public healthcare organization for rapid patient access."

Trial status • Infectious Disease • Novel Coronavirus Disease

CYCLOVID: Evaluation of Alisporivir for the Treatment of Hospitalised Patients With Infections Due to SARS-CoV-2 (COVID-19) (clinicaltrials.gov) - P2; N=100; Not yet recruiting; Sponsor: Assistance Publique - Hôpitaux de Paris

Clinical • New P2 trial • Infectious Disease • Novel Coronavirus Disease

Inhibition of SARS-CoV-2 infection by the cyclophilin inhibitor Alisporivir (Debio 025). (PubMed, Antimicrob Agents Chemother) - "Alisporivir (Debio 025) is a nonimmunosuppressive analogue of cyclosporine with potent cyclophilin inhibition properties. Alisporivir inhibited a post-entry step of the SARS-CoV-2 lifecycle. These results justify that a proof-of-concept Phase 2 trial be rapidly conducted with alisporivir in patients with SARS-CoV-2 infection."

Journal • Novel Coronavirus Disease

SARS-CoV-2 pandemic : Time to revive the cyclophilin inhibitor alisporivir. (PubMed, Clin Infect Dis) - "This Viewpoint summarizes the strong scientific arguments supporting the use of alisporivir, a non-immunosuppressive analogue of cyclosporine A with potent cyclophilin inhibition properties that has reached Phase 3 clinical development, for the treatment of COVID-19. They include the strong cyclophilin dependency of the lifecycle of many coronaviruses, including SARS-CoV and MERS-CoV, and preclinical data showing strong antiviral and cytoprotective properties of alisporivir in various models of coronavirus infection, including SARS-CoV-2. Alisporivir should be tested without delay on both virological and clinical endpoints in patients with or at-risk of severe forms of SARS-CoV-2 infection."

Journal • Immunology • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Review article: HCV genotype 3 - the new treatment challenge (Aliment Pharmacol Ther) - "New therapies with protease inhibitors have focused on genotype 1 largely and have demonstrated enhanced responses, but have limited activity against genotype 3. Thus far, in clinical trials, NS5B and NS5A inhibitors have performed more poorly in genotype 3, while a cyclophilin inhibitor, alisporivir, has shown promise."

Review • Hepatitis C Virus

Exane BNP Paribas Healthcare Conference (Novartis) - Anticipated filing for HCV infection in 2013

Anticipated filing • Hepatitis C Virus

BC556, A potent, pan-genotypic, high barrier to resistance, second generation cyclophilin inhibitor for treatment of chronic HCV infection (EASL 2012) - Presentation time: 20.04.2012, 09:00-18:00; BC556 is a highly potent inhibitor of in vitro HCV replication across all viral genotypes tested (average EC50 in HCV replicons 0.02 µM) and is approximately 4-fold more potent than alisporivir

Pharmacokinetics • Hepatitis C Virus

Pharmacokinetics, Pharmacodynamics and Safety of DEB025 Plus Ribavirin in Chronic Hepatitis C Genotype 2 and 3 Treatment naïve Patients (clinicaltrials.gov) - P2; N=146; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Recruiting -> Active, not recruiting

Enrollment closed • Biosimilar • Hepatitis C Virus

3-year Follow-up Study to Assess the Viral Activity in Hepatitis C Patients Who Failed Feeder DEB025/Alisporivir Study (clinicaltrials.gov) - P3; N=105; Terminated; Sponsor: Novartis Pharmaceuticals; Completed ➔ Terminated; Study was prematurely terminated.

Trial termination • Biosimilar • Hepatitis C Virus • Immunology • Infectious Disease

Alisporivir (ALV) plus peginterferon/ribavirin (PR) achieves high SVR12 rates among null responders, IL28BCT/TT and cirrhotic hcvg1 patients (FUNDAMENTAL study interim analysis) (EASL 2013) - Presentation time: 25.04.2013, 09:00-18:00; Abstract 1421; P3, N=461; FUNDAMENTAL (NCT01318694); Sponsor: Novartis; “In overall ITT, ALV+PR had superior SVR12 to PR (p< 0.001) in all groups (45% ALV600QD+PR, 54% ALV800QD+PR, 67% ALV400BID+PR, vs 15% PR).”

P3 data • Hepatitis C Virus

Pharmacokinetics, Pharmacodynamics and Safety of DEB025 Plus Ribavirin in Chronic Hepatitis C Genotype 2 and 3 Treatment naïve Patients (clinicaltrials.gov) - P2; N=147; Completed; Sponsor: Debiopharm International SA; Active, not recruiting ➔ Completed

Trial completion • Biosimilar • Hepatitis C Virus • Immunology

Alisporivir with pegIFN/RBV in protease inhibitor (PI) treatment failure patients with chronic hepatitis C (clinicaltrials.gov) - P3, N=150; Not yet recruiting -> Recruiting

Enrollment open • Hepatitis C Virus

Debiopharm Group regains full rights to alisporivir program (Debiopharm Press Release) - P2, N=NA; "Debiopharm Group™...today announced that it has updated its arrangement with Novartis to regain full rights to Alisporivir (DEB025) currently completing two Phase 2 studies of interferon-free treatment in Hepatitis C...This arrangement allows for the transfer, at Debiopharm's election, of ongoing Alisporivir Phase 2 clinical trials to Debiopharm and transfers all rights for HCV and other indications."

Licensing / partnership • Hepatitis C Virus

Add-on therapy of pitavastatin and eicosapentaenoic acid improves outcome of peginterferon plus ribavirin treatment for chronic hepatitis C (J Med Virol) - P=NA, N=NA; PMID: 23161429; "In both groups, sustained virological response rates were significantly higher in patients with genotype TT of IL-28B (rs8099917) than in those with non-TT genotype. Among the patients with non-TT genotype, sustained virological response rates were markedly higher in the add-on than standard group. Addition of pitavastatin and EPA to peg-IFN/ribavirin treatment improved sustained virological response in patients infected with HCV-1b."

Clinical data • Hepatitis C Virus

Efficacy and safety study of DEB025/alisporivir combined to standard therapy (peg-IFN and ribavirin) in chronic hepatitis C genotype 1 naïve patients (clinicaltrials.gov) - P3, N=1,081; Sponsor: Novartis; Active, not recruiting -> Completed.

Trial completion • Hepatitis C Virus

Two-way Interaction Between Alisporivir and EDP239 (clinicaltrials.gov) - P1; N=42; Completed; Sponsor: Enanta Pharmaceuticals; Recruiting -> Completed

Trial completion • Biosimilar • Hepatitis C Virus • Immunology • Inflammation

Pharmacokinetics, Pharmacodynamics and Safety of DEB025/Alisporivir in Combination With Ribavirin Therapy in Chronic Hepatitis C Genotype 2 and 3 Patients Who Have Previously Failed Interferon Therapy or Are Intolerant or Unable to Take Interferon (clinicaltrials.gov) - P2; N=52; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Recruiting -> Active, not recruiting

Enrollment closed • Biosimilar • Hepatitis C Virus

Enanta Pharmaceuticals’ HCV NS5A inhibitor EDP-239 advances into combination studies with alisporivir (DEB025) (Enanta Press Release) - P1, N=42; NCT02173574; Sponsor: Novartis; "Enanta...announced that Novartis has advanced EDP-239...into drug combination studies with alisporivir (DEB025)....The phase 1 combination study conducted by Novartis is investigating the pharmacokinetics, safety, and tolerability of alisporivir (DEB025) and EDP-239 when co-administered to healthy adult subjects and is scheduled to enroll 42 healthy subjects."

New P1 trial • Hepatitis C Virus

Modeling early viral kinetics with alisporivir: Interferon-free treatment and SVR predictions in HCV G2/3 patients (EASL 2013) - Presentation time: 26.04.2013, 09:00-18:00; Abstract 823; P2, N=249; NCT01215643; Sponsor: Novartis; “The model predicts 73% SVR following 400 mg ALV BID + 400 mg RBV BID for 24 weeks. The predicted SVR rate following response-guided therapy was 79%.”

P2 data • Hepatitis C Virus