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

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.