Arlansa (narlaprevir) / Merck (MSD), R-Pharm - LARVOL DELTA

Preliminary results of non-interventional study to assess virological effectiveness, safety, and tolerability of NVR/RTV+SOF combination in HCV infected persons living with HIV (APASL 2025) - "Background Narlaprevir (NVR) is a NS3 protease inhibitor of HCV used for hepatitis C therapy in combination with ritonavir (RTV) and other direct-acting antivirals. In this analysis to date, the effectiveness of NVR/RTV + sofosbuvir (SOF) once-daily for 12 weeks was assessed in a large population of Russian people who are infected with HCV (genotype 1) and living with HIV (PLHIV)...Conclusion Genotype-specific treatments for HCV are being actively employed in national plan for eliminating HCV infection in Russia. NVR/RTV + SOF in HIV/HCV co-infection was highly effective and tolerable in clinical practice, drug use is a potential barrier to reach HCV elimination in PLHIV."

Clinical • Observational data • Fibrosis • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation

The anti-SARS-CoV-2 activity of novel 9, 10-dihydrophenanthrene derivatives: an insight into molecular docking, ADMET analysis, and molecular dynamics simulation. (PubMed, Sci Afr) - "Then, through molecular docking simulations, we used the crystal structure of the main protease of SARS-CoV-2 (3CLpro/Mpro) in a complex with the covalent inhibitor "Narlaprevir" (PDB ID: 7JYC). We also supported our molecular docking predictions with an extended molecular dynamics simulation of a docked ligand-protein complex. We hope that the results obtained in this study can be used as good anti-SARS-CoV-2 inhibitors."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Recent Advances in Covalent Drug Discovery. (PubMed, Pharmaceuticals (Basel)) - "The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be 'undruggable'. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Targeted Protein Degradation • EGFR

Efficacy and Safety of All-Oral Combination of Narlaprevir/Ritonavir and Sofosbuvir in Treatment-naïve Patients With Chronic Hepatitis C Genotype 1 (clinicaltrials.gov) - P2 | N=85 | Completed | Sponsor: R-Pharm | Unknown status ➔ Completed

Trial completion • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Comparative evaluation of the effectiveness of narlaprevir in the composition of interferon and interferon-free treatment regimens for patients with chronic hepatitis C (PubMed, Ter Arkh) - "Real clinical practice indicates that the use of narlaprevir in the non-interferon mode is not inferior in efficiency to the interferon-containing treatment regimen and demonstrates a more favorable safety profile."

Journal • Fibrosis • Gastroenterology • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • IFNA1

Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease. (PubMed, Nat Commun) - "Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. Protonation states of the ionizable residues in the M active site adapt to the inhibitor, which appears to be an intrinsic property of M. Structural comparisons of the hybrid inhibitors with PF-07321332 reveal unconventional F···O interactions of PF-07321332 with M which may explain its more favorable enthalpy of binding. BBH-1, BBH-2 and NBH-2 exhibit comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro. (PubMed, Antimicrob Agents Chemother) - "Linear PI boceprevir, telaprevir and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among macrocyclic PI, simeprevir had the highest (EC50 15 μM) and glecaprevir the lowest (EC50 >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir and deldeprevir in between. Acyclic PI asunaprevir and faldaprevir had EC50 of 72 and 23 μM, respectively...Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform development and application of protease inhibitors for optimized antiviral treatments of COVID-19."

Journal • Preclinical • Gastrointestinal Cancer • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Lung Cancer • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor

Targeting SARS-CoV-2 M3CLpro by HCV NS3/4a Inhibitors: In Silico Modeling and In Vitro Screening. (PubMed, J Chem Inf Model) - "Here we use the X-ray crystal structure of M3CLpro in complex with boceprevir to study the dynamic changes of the protease upon ligand binding...Specifically, asunaprevir, narlaprevir, paritaprevir, simeprevir, and telaprevir all showed inhibitory effects on M3CLpro. Molecular docking and MD simulations were then performed to investigate the effects of these ligands on M3CLpro and to provide insights into the chemical environment of the ligand binding site. Our findings and observations are offered to help guide the design of possible potent protease inhibitors and aid in coping with the COVID-19 pandemic."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Structural basis for the inhibition of the SARS-CoV-2 main protease by the anti-HCV drug narlaprevir. (PubMed, Signal Transduct Target Ther) - No abstract available

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV2 main protease. (PubMed, PLoS One) - "narlaprevir, and telaprevir. This work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than boceprevir and suitable for rapid repurposing."

Journal • Hepatitis C Virus • Hepatology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Malleability of the SARS-CoV-2 3CL M Active-Site Cavity Facilitates Binding of Clinical Antivirals. (PubMed, Structure) - "The enzyme active-site cavity reveals a high degree of malleability, allowing aldehyde leupeptin and hepatitis C clinical protease inhibitors (telaprevir, narlaprevir, and boceprevir) to bind and inhibit SARS-CoV-2 3CL M. Narlaprevir, boceprevir, and telaprevir are low-micromolar inhibitors, whereas the binding affinity of leupeptin is substantially weaker. Repurposing hepatitis C clinical drugs as COVID-19 treatments may be a useful option to pursue. The observed malleability of the enzyme active-site cavity should be considered for the successful design of specific protease inhibitors."

Clinical • Journal • Hepatitis C Virus • Hepatology • Infectious Disease • Novel Coronavirus Disease

Efficacy and safety of narlaprevir/ritonavir and daclatasvir non interferon combination in population of Russian patients with chronic hepatitis C (PubMed, Ter Arkh) - "Efficacy of treatment with a combination of narlaprevir/ritonavir and daclatasvir in treatment - naïve patients with HCV genotype 1b was close to 90%. This combination was found to be safe and well - tolerated."

Clinical • Journal • Hepatitis C Virus • Infectious Disease

Once daily narlaprevir (NVR; SCH 900518) and ritonavir (RTV) in combination with peginterferon alfa-2b/ribavirin (PR) for 12 weeks plus 12 weeks PR in treatment-naïve patients with HCV genotype 1 (G1): SVR results from NEXT-1, a Phase 2 Study (AASLD 2011) - Presentation time: Nov 07 8:00 AM - 5:30 PM; P2, N=111; NEXT-1; A 12 week course of once daily NVR/RTV with PR followed by PR for 12 weeks produced SVR rates up to 85% in patients with HCV genotype 1 infection and was effective in all demographic groups

P2 data • Hepatitis C Virus

Preliminary results of Phase II study: 100% SVR rates following twelve-week treatment with narlaprevir ritonavir and sofosbuvir combination in patients with HCV Genotype 1 infection (APASL 2020) - No abstract available

Clinical • P2 data

Efficacy and Safety of All-Oral Combination of Narlaprevir/Ritonavir and Sofosbuvir in Treatment-naïve Patients With Chronic Hepatitis C Genotype 1 (clinicaltrials.gov) - P2; N=85; Recruiting; Sponsor: R-Pharm

New P2 trial

Narlaprevir/ritonavir and daclatasvir combination in treatment-naı¨ve patients with chronic hepatitis C genotype 1b infection (APASL 2019) - "Narlaprevir/ritonavir plus daclatasvir was effective and well tolerated in CHC genotype 1b patients. NS3 baseline resistance polymorphisms at positions 54, 56 and 132 affected SVR12 rates."

Clinical