GS-5816: a DAA with pan-genotypic HCV activity

Posted on July 19, 2015

The availability of a safe, highly effective, pangenotypic regimen for the treatment of HCV infection would have a major impact on global disease prevalence, as it would be suitable for treatment of all infected persons regardless of genotype. Results of a new phase 1 study demonstrate the safety and potent pan-genotypic HCV activity of GS-5816, a novel inhibitor of the HCV nonstructural NS5A protein. GS-5816 administered at doses ranging from 5 to 150 mg for 3 days was well tolerated with no evidence of drug or dose-related side effects. Rapid reductions in HCV RNA were observed at all doses across all HCV genotypes evaluated. GS-5816 has demonstrated additive or synergistic activity when evaluated in vitro in combination with other DAAs including sofosbuvir. This study supports further development of GS-5816 in combination with sofosbuvir to achieve the objective of a safe and highly effective, pangenotypic treatment for HCV infection.

Hepatitis C virus is classified into six major genotypes with variable geographic distribution. While genotype 1 HCV infection is highly prevalent in high income countries, there is a medical need for the development of direct-acting antivirals (DAAs) with pan-genotypic activity, as nongenotype 1 infection accounts for >50% of infection globally. Between 6 November 2012 and 24 January 2014, Eric Lawitz, MD, AGAF, CPI, and colleagues conducted a phase 1, randomized, double-blind, placebo-controlled, multicenter, dose-ranging study of GS-5816, a novel inhibitor of the HCV nonstructural NS5A protein, which has shown pan-genotypic HCV activity in vitro. The encouraging results of this trial were recently published in the Journal of Viral Hepatitis (Lawitz E, et al. J Viral Hepat. 2015 Jul 16 [Epub ahead of print]). The aim of this exploratory study was to evaluate the safety, pharmacokinetics and antiviral activity of once-daily GS-5816 at doses ranging from 5 to 150 mg for 3 days in patients aged 18–65 years with treatment naïve, chronic, genotype 1–4 HCV infection.

  • Within each of 11 cohorts, patients were randomized in a 4:1 ratio to GS-5816 or placebo except for the cohort of patients with genotype 4 HCV infection, who were not randomized, and all patients received GS–5816
  • Patients were excluded if coinfected with hepatitis B virus or human immunodeficiency virus, had prior treatment with a HCV NS5A inhibitor, evidence of cirrhosis or hepatocellular carcinoma, history of clinical hepatic decompensation (e.g. ascites, jaundice, encephalopathy or variceal hemorrhage) or any other clinically significant condition other than chronic HCV infection

Demographic and baseline characteristics of the 87 randomized patients in this study were similar across placebo and GS-5816 dose groups. Most patients were male (78%) and White (68%); nearly one-third (31%) were Black or African American. Baseline viral load was similar across treatments with a mean HCV RNA of 6.43 log10 IU/mL. Twenty-one of the 87 patients (24%) reported at least one adverse event between Day 1 and Day 17 of the short-term follow up: 18 of 70 (26%) of the GS-5816-treated patients and 3 of 17 (18%) of the placebo-treated patients.

  • No deaths or serious adverse events were reported from Day 1 through the last study visit at Week 48 (long-term follow-up visits occurred at 12, 24, and 48 weeks)
  • All adverse events were considered mild or moderate in severity, and headache was the most frequently reported adverse event (6/87 patients, 7%)
  • One patient treated with GS-5816 150 mg was withdrawn on the first day of treatment because of mild nausea
  • There was no trend in adverse events relative to GS-5816 dose
  • There were no clinical relevant changes in clinical laboratory values, vital signs, physical examinations or ECGs

Administration of three consecutive daily doses of GS-5816 at all evaluated doses (5–150 mg) resulted in rapid reductions in HCV RNA at all doses across all HCV genotypes evaluated. There were no meaningful changes in HCV RNA in any of the placebo-treated patients. All patients had HCV RNA return to baseline levels during the follow-up period.

  • Dose ranging was performed in genotype 1a and genotype 3 HCV-infected patients to identify a potential dose–response to GS-5816
    • Initial viral decline was similar across all dose groups in both genotypes
    • Genotype 1a patients administered GS-5816 5 mg for 3 days had an earlier viral rebound after treatment than patients receiving higher doses of GS-5816
  • Pretreatment NS5A resistance-associated polymorphisms were detected in 31% (22/70) of patients. Genotype 1 and 3 HCV-infected patients without pretreatment NS5A resistance-associated polymorphisms had greater declines in HCV RNA than patients with resistance-associated polymorphisms.

GS-5816 was rapidly absorbed with pharmacokinetics similar to those seen in healthy volunteers and confirmed that GS- 5816 is suitable for once-daily dosing in patients with HCV infection. The pangenotypic activity demonstrated by GS-5816 in patient with genotype 1a, 1b, 2, 3 and 4 HCV infection contrasts with other NS5A inhibitors in clinical development that have been shown to lack antiviral activity against some viral genotypes. The study authors conclude the following: “Regimens containing an NS5A inhibitor have demonstrated excellent tolerability and high antiviral efficacy in Phase 3 studies and represent a major advance in the treatment of genotype 1 HCV infection. However, genotype 2–6 HCV infection is responsible for >50% of HCV infections globally and represents the majority of infections in some regions with the highest disease prevalence such as Pakistan, India, Egypt and Russia. The availability of a safe, highly effective, pangenotypic regimen for the treatment of HCV infection would have a major impact on global disease prevalence as it would be suitable for treatment of all infected persons regardless of genotype. In addition, pangenotypic regimens offer the additional advantage of obviating the need for HCV genotyping, the cost of which can be a barrier to treatment in resource limited settings. GS-5816 has demonstrated additive or synergistic activity when evaluated in vitro in combination with other DAAs including sofosbuvir. The safety and the potent pangenotypic activity observed in this study support further development of GS-5816 in combination with sofosbuvir to achieve the objective of a safe and highly effective, pangenotypic treatment for HCV infection.”


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