Sofosbuvir + new GS-5816 NS5A inhibitor is effective against hepatitis C genotypes 1-6

Published: 17 April 2014
Gregory Everson speaking at the International Liver Congress 2014. Photo by Liz Highleyman, hivandhepatitis.com.

A new experimental NS5A inhibitor, GS-5816, was shown to be safe and effective when used in an interferon- and ribavirin-free dual regimen with sofosbuvir (Sovaldi) for people with hepatitis C genotypes 1 through 6, according to phase 2 trial results presented at the 49th annual meeting of the European Association for the Study of the Liver (EASL) last week in London.

Gilead Science's recently approved hepatitis C virus (HCV) nucleotide polymerase inhibitor sofosbuvir has demonstrated good efficacy in combination with ribavirin against HCV genotype 2. Sofosbuvir plus ledipasvir, Gilead's first-generation NS5A replication complex inhibitor, cures most hepatitis C genotype 1 with a treatment duration as short as 8 weeks. Sofosbuvir/ledipasvir without ribavirin is not as effective against HCV genotype 3, however, and some data indicate it is susceptible to viral resistance.

As part of its ongoing hepatitis C drug development programme, Gilead is also testing a next-generation NS5A inhibitor, GS-5816, which demonstrated potent activity against HCV genotypes 1 through 6 in early studies. The company is developing a co-formulation of sofosbuvir and GS-5816, similar to the sofosbuvir and ledipasvir co-formulation it has already submitted for regulatory approval in Europe and the US.

Gregory Everson of the University of Colorado at Denver presented findings from a phase 2 clinical trial looking at the safety and efficacy of sofosbuvir plus GS-5816 taken without ribavirin for 12 weeks in treatment-naive people with genotype 1-6 chronic hepatitis C.

This study included 154 previously untreated hepatitis C patients without liver cirrhosis. About 60% were men, most were white and the mean age was approximately 50 years. Nearly 30% had HCV subtype 1a, which is considered most difficult to treat. In addition, 7% had HCV subtype 1b, 14% had genotype 2, 35% had genotype 3, 9% had genotype 4, a single individual had genotype 5 and 6% had genotype 6. About one-third had the favourable IL28B CC gene variant associated with interferon responsiveness.

Participants in this open-label study were randomly assigned to receive 400mg once-daily sofosbuvir plus either 25mg or 100mg once-daily GS-5816 for 12 weeks. They were followed after finishing therapy to determine sustained virological response, or continued undetectable HCV viral load at 12 weeks post-treatment  (SVR12), which is considered a cure.

SVR12 rates for people with genotype 1 were 96% using the 25mg GS-5816 dose and 100% using the 100mg dose. For people with genotype 2, the corresponding rates were 91% and 100%, respectively, while the cure rates for genotype 3 were 93% in both dose arms.

Turning to the less common genotypes – where the numbers were too small to draw meaningful conclusions – genotype 4 SVR12 rates were 100% and 86%, respectively, in the 25mg and 100mg dose groups. The single genotype 5 patient and all genotype 6 patients in both dose arms were cured. Across all genotypes, overall SVR12 rates were 95% using the 25mg dose and 96% using the 100mg dose.

Looking at the patients who did not achieve SVR12, three people relapsed after completing treatment: one person with genotype 1 taking 25mg GS-5816, one person with genotype 3 taking 25mg and one person with genotype 3 taking 100mg. In addition, one person with genotype 3 was a non-responder during treatment, one person with genotype 2 died during follow-up and one person with genotype 3 was found to be re-infected.

Genetic sequencing revealed that about one-quarter of people with genotype 1-3 had pre-existing resistance-associated NS5A viral variants. Among them, virological failure was more likely using the lower GS-5816 dose (5% vs 2%). However, most people with pre-existing variants were cured.

Treatment with sofosbuvir and GS-5816 was generally safe and well-tolerated. Four people had serious adverse events, three of them in the 25mg dose arms. However, no one discontinued for this reason. The most common side-effects reported by at least 10% of participants were fatigue, headache, nausea and constipation. No one developed anaemia, a side-effect often seen with ribavirin.

"Sofosbuvir + GS-5816 for 12 weeks resulted in SVR12 rates >90% in all HCV genotypes (1-6)," the researchers concluded. "The presence of pre-treatment NS5A variants was not predictive of failure to achieve SVR12”.

Everson noted that a combination of sofosbuvir and GS-5816 is now being tested in two harder-to-treat groups, previously treated hepatitis C patients and people with cirrhosis.

Reference

Everson G et al. Safety and efficacy of treatment with the interferon-free, ribavirin-free combination of sofosbuvir + GS-5816 for 12 weeks in treatment naive patients with genotype 1-6 HCV infection. 49th Annual Meeting of the European Association for the Study of the Liver (EASL), abstract O111, London, 2014.

Hepatitis information

For more information on hepatitis visit infohep.org.

Infohep is a project we're working on in partnership with the European Liver Patients Association (ELPA).

Visit infohep.org >