uprifosbuvir (IDX21437) / Merck (MSD) - LARVOL DELTA

Lead-in cohort results from a phase 2 study of a novel 8-week combination regimen of Bemnifosbuvir and Ruzasvir in patients with chronic hepatitis C virus infection (EASL-ILC 2024) - P2 | "In previous studies, the combination of BEM and daclatasvir (n=10), and uprifosbuvir and RZR (n>400), were safe, well- tolerated, and each combination achieved high sustained virologic response (SVR) rates in HCV- infected patients... BEM+RZR for 8 weeks was well tolerated in HCV-infected patients. A high rate of SVR4 (98%) was documented in this preliminary analysis. All patients will continue to be followed to SVR12."

Clinical • P2 data • Fibrosis • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Liver Cirrhosis

LACK OF PHARMACOKINETIC DRUG-DRUG INTERACTION BETWEEN BEMNIFOSBUVIR AND RUZASVIR IN HEALTHY PARTICIPANTS (AASLD 2023) - "Combinations of BEM with daclatasvir, and RZR with uprifosbuvir were safe and well-tolerated, and independently achieved high sustained virologic response rates (SVR) in HCV-infected participants. In vitro, BEM is 10 times more potent than sofosbuvir and retains activity against sofosbuvir-resistant mutations... This study reports the first combination results of BEM and RZR in humans. The study drugs were well tolerated. Plasma PK of BEM and RZR was not altered when co-administered, indicative of a lack of PK DDI between the two drugs, and also the absence of a food effect."

Clinical • PK/PD data • Hepatitis C

Differential activity of nucleotide analogs against tick-borne encephalitis and yellow fever viruses in human cell lines. (PubMed, Virology) - "Remdesivir, uprifosbuvir and sofosbuvir were the most potent drugs against TBEV and YFV in liver cells, but they had reduced activity in neural cells, whereas galidesivir retained uniform activity across cell lines and viruses. Ribavirin, valopicitabine, molnupiravir and GS-6620 exhibited only moderate antiviral activity. We found antiviral activity for drugs previously reported as inactive, demonstrating the importance of using human cell lines and comparative experimental assays when screening the activity of nucs. The relatively high antiviral activity of remdesivir, sofosbuvir and uprifosbuvir against TBEV and YFV merits further investigation in clinical studies."

Journal • Preclinical • CNS Disorders

"sofosbuvir & @Merck’s copycat uprifosbuvir comes to mind :)" (@victoriacyanide)

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods. (PubMed, Chem Sci) - "This concise synthesis was achieved by development of several synthetic (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides."

Journal

Insights into the Control of Drug Release from Complex Immediate Release Formulations. (PubMed, Pharmaceutics) - "The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution."

Journal

Understanding effect site pharmacology of uprifosbuvir, a HCV nucleoside inhibitor: case study of a multidisciplinary modelling approach in drug development. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "This paper presents an example of the practical execution of a MIDD-based, cooperative multidisciplinary modelling approach, creating a model that grows along with the team's integrated knowledge. Insights gained from this process could be used in forming optimal collaborations between disciplines in drug development for other investigative compounds."

Clinical • Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Glecaprevir/pibrentasvir+sofosbuvir: an optimal retreatment strategy in the setting of HCV NS5A resistance. (PubMed, BMJ Case Rep) - "He received ruzasvir and uprifosbuvir for 12 weeks within a clinical trial. Given that this mutation confers resistance to first line salvage options, sofosbuvir and glecaprevir/pibrentasvir was used for 12 weeks and the patient was cured of HCV infection 12 weeks after the end of treatment. This shows that sofosbuvir and glecaprevir/pibrentasvir is a viable, effective option for second line/salvage therapy of HCV infection in the setting of resistance to NS5A inhibitors with the Y93H mutation."

Journal • CNS Disorders • Depression • Fatigue • Hepatitis C Virus • Hepatology • Infectious Disease

Efficacy and Safety of a Two-Drug Direct-Acting Antiviral Agent Regimen Ruzasvir 180 mg and Uprifosbuvir 450 mg for 12 Weeks in Adults with Chronic Hepatitis C Virus Genotype 1, 2, 3, 4, 5, or 6. (PubMed, J Viral Hepat) - P2 | "Treatment-naïve or interferon (with or without ribavirin)-experienced participants with or without compensated cirrhosis were enrolled. The most frequent (≥5% of participants) drug-related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two-drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well-tolerated in participants infected with HCV GT1, GT2, GT4, GT5, and GT6, with a lower efficacy in GT3-infected persons."

Clinical • Journal • Fatigue • Fibrosis • Hepatitis C Virus • Hepatology • Immunology • Infectious Disease

Efficacy and Safety of Ruzasvir 60 mg and Uprifosbuvir 450 mg for 12 Weeks in Adults With Chronic Hepatitis C Virus Genotype 1, 2, 3, 4, or 6 Infection. (PubMed, J Viral Hepat) - P2 | "In clinical trials, the three-drug regimen of ruzasvir (RZR) 60 mg, uprifosbuvir (UPR) 450 mg and grazoprevir 100 mg, with or without ribavirin, has demonstrated promising efficacy and excellent tolerability across a wide range of hepatitis C virus (HCV)-infected individuals. One participant experienced on-treatment alanine aminotransferase/aspartate aminotransferase elevations that resolved without intervention. Data from the present study indicate that the combination of RZR 60 mg plus UPR 450 mg once daily for 12 weeks was well-tolerated overall but was effective only for certain genotypes."

Clinical • Journal • Fatigue • Hepatitis C Virus • Infectious Disease

Effectiveness of current and future regimens for treating genotype 3 hepatitis C virus infection: a large-scale systematic review. (PubMed, BMC Infect Dis) - "On the basis of SVR12, we established that for treating GT3 infections (i) regimens incorporating newer DAAs are more effective than those comprising older DAAs, and (ii) ribavirin may be of less benefit in newer DAA regimens than in older DAA regimens. The analysis provides evidence that DAA regimens can replace Peg-IFN-based regimens for GT3 infection."

Journal • Biosimilar • Fibrosis • Hepatitis C Virus • Immunology • Oncology

After several FDA setbacks, Idenix to begin clinical study of new HCV nuc outside the U.S. (Health News Daily) - “...it will begin Phase I/II study of…IDX21437 in Canada and Belgium, bypassing FDA oversight in the early stages....moving forward in studying its NS5A inhibitor, samatasvir (IDX719), in tandem with...simeprevir...”

Anticipated new P2/3 trial • Hepatitis C Virus

Efficacy and Safety of Grazoprevir (MK-5172) and Uprifosbuvir (MK-3682) With Elbasvir (MK-8742) or Ruzasvir (MK-8408) for Chronic Hepatitis C Virus (HCV) Genotype (GT) 3, GT4, GT5, and GT6 Infection (MK-3682-012) (clinicaltrials.gov) - P2; N=413; Completed; Sponsor: Merck Sharp & Dohme Corp.; Trial primary completion date: Feb 2017 ➔ Sep 2016

Trial primary completion date • Biosimilar • Fibrosis • Hepatitis C Virus • Immunology • Infectious Disease

C-BREEZE 2: Efficacy and Safety of a Two-Drug Direct-Acting Antiviral Agent (DAA) Regimen Ruzasvir 180 mg and Uprifosbuvir 450 mg for 12 Weeks in Adults With Chronic Hepatitis C Virus (HCV) Genotype (GT)1, 2, 3, 4, or 6 (AASLD 2017) - P2; "Background: Ruzasvir (RZR, MK-8408, an NS5A inhibitor) and uprifosbuvir (UPR, MK-3682, an NS5B nucleotide inhibitor) are highly potent HCV DAAs...Treatment-naive or interferon ± ribavirin–experienced participants with or without compensated cirrhosis were enrolled in both cohorts... The two-drug combination of RZR 180 mg + UPR 450 mg for 12 weeks was highly effective and well-tolerated in GT1-, 2-, 3-, or 4-infected participants with or without compensated cirrhosis treated in Cohort 1 of the trial. The presence of baseline NS5A RASs did not impact the response rate. Complete SVR12 results will be presented."

Biomarker • Clinical • Next-Generation Sequencing • Biosimilar • Fibrosis • Hepatitis C Virus • Immunology • Infectious Disease

Robust HCV Genotype 3a Infectious Cell Culture System Permits Identification of Escape Variants With Resistance to Sofosbuvir. (PubMed) - Gastroenterology - "We developed a system for highly efficient culture of HCV genotype 3a. Genotype 1a has a high genetic barrier to resistance for sofosbuvir, whereas resistance to this DAA can be induced in genotype 3a. We therefore isolated HCV genotype 3a variants with reduced sensitivity to sofosbuvir, with increased fitness and with cross-resistance to other NS5B inhibitors. These findings indicate that sofosbuvir escape variants could compromise the effectiveness of nucleotide analogs against HCV. GenBank accession numbers: KX280712-KX280716."

Journal • Biosimilar • Hepatitis C Virus • Immunology • Infectious Disease

Pharmacokinetics of MK-3682B in Participants With Moderate to Severe Renal Insufficiency (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: Merck Sharp & Dohme Corp.

New P1 trial • Biosimilar • Hepatitis C Virus • Immunology • Inflammation • Renal Disease

Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials. (PubMed, Lancet Gastroenterol Hepatol) - P2; "These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection."

Journal • Biosimilar • Fibrosis • Gene Therapies • Hepatitis C Virus • Immunology • Infectious Disease • Ocular Inflammation • Ophthalmology

Merck: J.P. Morgan Healthcare Conference (Merck (MSD)) - Anticipated completion of P2b trial (NCT02332707) of MK-3682 + grazoprevir + elbasvir/MK-8408 for chronic hepatitis C infection in 2016; Anticipated completion of P2b trial (NCT02332720) of MK-3682 + grazoprevir + elbasvir/MK-8408 for chronic hepatitis C infection in 2016; Anticipated initiation of P3 trial of MK-3682 + grazprevir + elbasvir in hepatitis C infection in 2016

Anticipated new P3 trial • Anticipated trial completion date • Hepatitis C Virus

Idenix Pharmaceuticals reports fourth quarter and year ended 2013 financial results (Idenix Press Release) - "In January 2014, Idenix initiated the seven-day proof-of-concept portion of a phase I/II clinical trial for IDX21437....Data are expected in the first half of 2014....Data from the HELIX-2 trial are expected in the second half of 2014....'With the advancement of our two HCV clinical programs, we remain on track to initiate an Idenix-sponsored combination clinical trial of samatasvir and IDX21437 by mid-2014.' 

Anticipated new trial • Anticipated P1/2 data • Anticipated P2 data • Hepatitis C Virus

Idenix Pharmaceuticals reports sustained virologic response rate (SVR4) for phase II all-oral combination study of samatasvir (IDX719), a potent, pan-genotypic HCV NS5A inhibitor, and simeprevir (Idenix Press Release) - P2, N=90; HELIX-1 (NCT01852604); Sponsor: Idenix; "In the treatment-naïve, non-cirrhotic, genotype 1b or 4 HCV-infected patients receiving 50 mg of samatasvir and 150 mg of simeprevir plus ribavirin, 85 percent (n=17/20) remained undetectable for HCV RNA four weeks after completing therapy (SVR4)....The HELIX-1 study results are expected to be presented at a scientific meeting in 2014....we are on track to initiate an Idenix-sponsored combination study of samatasvir and IDX21437 by mid-2014."

Anticipated new trial • Anticipated P2 data • P2 data • Hepatitis C Virus

In Vitro Antiviral Profile of Ruzasvir: A Potent and Pan-genotype Inhibitor of HCV NS5A. (PubMed, Antimicrob Agents Chemother) - "The interaction of ruzasvir with NS3/4A protease inhibitor (grazoprevir) and NS5B polymerase (uprifosbuvir) pro-drug was additive to synergistic with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir."

Journal • Preclinical