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EASL 2015: Merck HCV Combination Effective after Failure of First Generation Direct-Acting Antivirals

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Treatment for 12 weeks with grazoprevir and elbasvir, 2 direct-acting antivirals being development by Merck, plus ribavirin, cured 95% of people with hepatitis C who had experienced failure of a previous combination containing an HCV protease inhibitor, Xavier Forns of the University of Barcelona Hospital Clinic reported the at the European Association for the Study of the Liver (EASL) 50th International Liver Congress this week in Vienna.

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Merck’s combination of direct-acting antivirals consists of grazoprevir (a NS3/4 protease inhibitor) and elbasvir (a NS5A inhibitor). The combination is being studied as a once-daily single-tablet regimen, with or without ribavirin. The 2 drugs are active against multiple hepatitis C virus genotypes.

The C-SALVAGE study was designed to investigate the efficacy of grazoprevir/elbasvir in people with genotype 1 hepatitis C monoinfection who had failed to achieve a cure after a previous course of antiviral treatment containing pegylated interferon and either Vertex's telaprevir (Incivek or Incivo), Merck's boceprevir (Victrelis), or Janssen's simeprevir (Olysio).

Protease inhibitor activity after first failure in this drug class is not well understood. There is some evidence that resistance to protease inhibitors persists, but until the C-SALVAGE study was carried out it was unclear to what extent Merck’s protease inhibitor-based regimen might be successful in the population of people who had failed to benefit from a first- or second-generation protease inhibitor.

For Merck, it is important to establish that a regimen containing grazoprevir can cure hepatitis C in the vast majority of people who failed to benefit from the earlier protease inhibitors. In the cases of people previously treated with boceprevir and telaprevir, up to half of patients with more advanced liver disease may have failed to achieve a cure, leaving a substantial unmet need.

This study recruited 79 patients, of whom 42% were women and 34% had cirrhosis. 38% had HCV genotype 1a infection. The study excluded participants with decompensated cirrhosis or hepatocellular carcinoma (liver cancer), and people coinfected with HIV.

The majority of participants had received prior treatment with telaprevir (54%); simeprevir was less common (10%). 30% of participants had experienced virological non-response or viral breakthrough during prior protease inhibitor treatment. The remainder had experienced viral breakthrough during the post-protease inhibitor period of pegylated interferon therapy, or viral relapse after completion of all treatment.

A high frequency of resistance mutations associated with prior protease inhibitor treatment was identified at baseline by sequencing of the NS3 region of HCV. Of 73 patients with sequencing data available, 41% had at least 1 protease resistance mutation.

Overall, 96.2% of participants achieved a sustained virological response 12 weeks after completing treatment (SVR12), with no substantial differences according to the protease inhibitor to which they were exposed previously.

All but 1 participant completed the 12-week course of treatment, while that 1 patient discontinued therapy due to a serious adverse event. None of the 5 serious adverse events reported during the study (bacterial pharyngitis, laryngeal squamous cell carcinoma, asthma, appendicitis, and urinary tract infection) were considered to be associated with the study drugs.

During treatment 18% of participants had a ribavirin dose reduction due to adverse events such as anemia. In all cases, these patients achieved SVR12.

4/23/15

Reference

X Forns, S Gordon, E Zuckerman, et al. C-SALVAGE: Grazoprevir (GZR; MK-5172), Elbasvir (EBR; MK-8742) and Ribavirin (RBV) for Chronic HCV-genotype 1 (GT1) Infection after Failure of Direct-acting Antiviral (DAA) 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract O001.