Vanihep (vaniprevir) / Merck (MSD) - LARVOL DELTA

Transcriptome Analyses Reveal the Aroma Terpeniods Biosynthesis Pathways of Primula forbesii Franch. and the Functional Characterization of the PfDXS2 Gene. (PubMed, Int J Mol Sci) - "Finally, 1-deoxy-d-xylulose 5-phosphate synthase gene of P. forbesii (PfDXS2, MK370094), the first key enzyme gene in the 2-c-methyl-d-erythritol 4-phosphate (MEP) pathway of terpenoids, was cloned and functionally verified using virus-induced gene silencing (VIGs)...This report is the first to present molecular data related to aroma metabolites biosynthesis pathways and the functional characterization of any P. forbesii gene. The data on RNA sequencing provide comprehensive information for further analysis of other plants of the genus Primula."

Journal

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

Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture. (PubMed, Cell Rep) - "This conundrum is resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PL). HCV drugs that inhibit PL synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir's antiviral activity as much as 10-fold, while those that only inhibit M do not synergize with remdesivir."

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

Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance (ACS Chem Biol) - PMID: 23594083; "Macrocyclic inhibitors were generally more potent ...the P1-P3 macrocyclic inhibitors were less susceptible to drug resistance than the linear and P2-P4 macrocyclic analogues. In addition, the heterocyclic moiety at P2 largely determined the inhibitor resistance profile, susceptibility to drug resistance, and the extent of modulation by the helicase domain."

Preclinical • Hepatitis C Virus

Population and clonal analysis of resistance associated amino acid variants (RAVS) in viruses from patients enrolled in a Phase 2B study of MK-7009 (vaniprevir) (HEP DART 2011) - P2b, N=150; 28 patients experienced virologic failure that received MK7009. Of these 22/28 (79%) had viruses with RAVs observed at positions R155, A156 and/or D168; RAVs at R155, A156 and D168 were detected in genotype 1a infected non-SVR patients, while RAVs at D168 were detected in genotype 1b infected patients by population sequencing

P2 data • Hepatitis C Virus

Study to evaluate different regimens of vaniprevir (MK7009) for the treatment of chronic genotype 1 hepatitis C virus infection in treatment-naive patients (MK-7009-019)(withdrawn) (clinicaltrials.gov) - P2, N=0; Withdrawn; N=530 ->0

Enrollment • Hepatitis C Virus

Vaniprevir plus peginterferon alfa-2b and ribavirin in treatment-experienced Japanese patients with hepatitis C virus genotype 1 (GT1b) infection: phase 3 studies. (PubMed) - J Gastroenterol Hepatol - "Vaniprevir + PR is an effective, well-tolerated treatment for Japanese patients with HCV GT1 infection who failed previous interferon-based treatment."

Journal • Biosimilar • Hepatitis C Virus • Immunology

Preclinical and clinical properties of vaniprevir (VANIHEP(®) Capsules 150 mg), a novel therapeutic agent for hepatitis C. (PubMed) - No abstract available.

Journal • Biosimilar • Hepatitis C Virus • Immunology • Inflammation

Vaniprevir plus peginterferon alfa-2a and ribavirin in treatment-experienced Japanese patients with hepatitis C virus genotype 1 infection: A randomized phase II study (J Gastroenterol) - P2, N=90; NCT00880763; Sponsor: Merck; "Rates of RVR were significantly higher with vaniprevir compared with placebo (86, 95, and 76% in the vaniprevir 100-, 300-, and 600-mg arms versus 20% with control; p<0.001 for all comparisons). Rates of SVR, an exploratory analysis, in the vaniprevir 100-, 300-, 600-mg, and control arms were 95, 100, 100, and 72%, respectively."

P2 data • Hepatitis C Virus

Vaniprevir (MK-7009) in treatment-experienced genotype (GT) 1 HCV-infected patients demonstrates time-dependent pharmacokinetics (PK) (APASL 2013) - Presentation time: 08.06.2013, 08:30-17:30; P2, N=285; NCT00704405; Sponsor: Merck; "For both the 300mg and 600mg BID dose groups, mean trough concentrations (C12hr) of vaniprevir decreased from Day 3 to Week 4, with similar C12hr values from Weeks 4 to 48 ...decrease in exposures coincides with the rapid reduction in HCV RNA within the first 4 weeks of dosing in most patients."

P2 data • Hepatitis C Virus

Comparative resistance analysis between cirrhotic and non-cirrhotic treatment experienced patients who failed treatment with a combination of vaniprevir (MK-7009) and pegylated interferon and ribavirin (P/R) (EASL 2014) - Presentation time: 12.04.2014, 09:00-18:00; Abstract #P1228; P2, N=46; NCT00704405; Sponsor: Merck; “Non-cirrhotic and cirrhotic patients displayed similar distributions of mutations with R155K or D168 mutations principally linked to failure. For both groups, the presence of baseline mutations at other positions did not affect SVR”

P2 data • Hepatitis C Virus

Combination of vaniprevir with peginterferon and ribavirin significantly increases the rate of sustained viral response in treatment-experienced patients with chronic HCV genotype 1 infection and cirrhosis (Clin Gastroenterol Hepatol) - PMID: 24120953; P2b, N=285; NCT00704405; Sponsor: Merck; "In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9/15 (60.0%), 9/13(69.2%), 8/15 (53.3%), and 10/13 (76.9%), compared with 2/14 (14.3%) in the control group....Cirrhotic patients with null or partial responses to prior therapy achieved SVRs less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs."

P2b data • Hepatitis C Virus

Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: Safety, antiviral activity, resistance, and pharmacokinetics (Antiviral Res) - PMID: 23747481; P1b, N=40; NCT00518622; Sponsor: Merck; "After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log10 IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg bid ...AEs) were diarrhea (n = 5) and nausea (n = 5)."

P1 data • Hepatitis C Virus

A phase 2b study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment (AASLD 2011) - Presentation time: Nov 07 8:00 AM - 5:30 PM; P2b, N=211; MK-7009 when combined with PR achieves significant improvement in SVR compared to PR control in this population of experienced pts and compares favorably with other first generation protease inhibitors; MK-7009 is generally safe for use for up to 48 wks of therapy

P2b data • Hepatitis C Virus

Projected long-term impact of MK-7009 (vaniprevir) for previously treated chronic HCV genotype 1 infection (APASL 2013) - Presentation time: 08.06.2013, 08:30-17:30; P2, N=285; NCT00704405; Sponsor: Merck; "Compared with Control, MK-7009-based regimens were projected to reduce the lifetime cumulative incidence of DC from an average of 17.1% to an average range of 3.7­-7.3% ...subgroup analyses, the respective average incidence of HCC among prior null responders to Peg-IFN and RBV (about 26% of all patients) was found to be 5.1-14.3% under MK-7009 compared with 25.9% in Control."

P2 data • Hepatitis C Virus

Impact of IL28B genotype on virologic response in prior treatment failure patients who received MK-7009 in combination with peginterferon and ribavirin (EASL 2012) - Presentation time: 21.04.2012, 09:00-18:00; P2, N=211; All MK-7009 regimens showed statistically significantly superior SVR24 rates compared to control in the main study: 71%, 85%, 67%, and 78% in the MK-7009 regimens 1 through 4 versus 19% in control

P2 data • Hepatitis C Virus

Fine-Needle Aspiration for the Evaluation of Hepatic Pharmacokinetics of Vaniprevir: A Randomized Trial in Patients With Hepatitis C Virus Infection. (PubMed, Clin Pharmacol Ther) - P1; "The shape of liver FNA and CNB concentration-time profiles were comparable. In conclusion, FNA may be effective for serial tissue sampling to assess hepatic drug exposure in patients with liver disease."

Clinical • Journal • PK/PD data