—Gilead's SOF with GS-5816—an investigational inhibitor of the HCV NS5A protein with picomolar antiviral activity across all HCV genotypes
Elsewhere on the site
2015 News & Updates
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
- 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
- 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.”
2015-2013 AASLD & EASL Coverage @ NATAP
GS-5816 / GS9857 Genotypes 1-6
Safety and Efficacy of Treatment with Sofosbuvir + GS-5816 ± Ribavirin for 8 or 12 Weeks in Treatment-Naïve Patients with Genotype 1-6 HCV Infection......
Safety and Efficacy of Treatment With Interferon-Free, Ribavirin-Free Combination of Sofosbuvir + GS-5816 for 12 Weeks in Treatment-Naïve Patients With Genotypes 1-6 HCV Infection......
Once-Daily Sofosbuvir With GS-5816 for 8 Weeks With or Without Ribavirin in Patients With HCV Genotype 3 Without Cirrhosis Result in High Rates of SVR12: The ELECTRON-2 Study......
High Efficacy of Treatment With Sofosbuvir + GS-5816 ± Ribavirin for 12 Weeks in Treatment-Experienced Patients With Genotype 1 or 3 HCV Infection.......
Clinically Relevant Interactions Between GS5816 HCV NS5A Inhibitor and Probe Drugs.....
Evaluation of Transporter and Cytochrome P450-Mediated Drug-Drug Interactions Between Pan-Genotypic HCV NS5A Inhibitor GS-5816 and Phenotypic Probe Drugs.....
The ASTRAL Studies: Evaluation of SOF/GS-5816 Single-Tablet Regimen for the Treatment of Genotype 1-6 HCV Infection.......
GS-9857 Pangenotypic Protease Inhibitor + SOF/GS5816 for 6/8 Weeks......
GS-5816, a Once-Daily NS5A Inhibitor, Demonstrates Potent Antiviral Activity in Patients With Genotype 1-4 HCV Infection in a 3 Day Monotherapy Study......
GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier......
Gilead Announces Phase 2 Data for Investigational All-Oral Regimen of Sofosbuvir Plus GS-5816 for the Treatment of Chronic Hepatitis C......
Gilead Expands Hepatitis C Generic Licensing Agreements to Include Investigational Pan-Genotypic Agent
Gilead Announces Sofosbuvir Plus GS-5816 SVR12 Rates Across Multiple HCV Genotypes --