- Category: Experimental HCV Drugs
- Published on Thursday, 17 April 2014 00:00
- Written by Liz Highleyman
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 results presented at the 49th EASL International Liver Congress 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 patients with a duration as short as 8 weeks. Sofosbuvir/ledipasvir without ribavirin is not as effective against HCV genotype 3, and some data indicate it is susceptible to viral resistance.
As part of its ongoing hepatitis C drug development program, 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 coformulation of sofosbuvir and GS-5816, similar to the sofosbuvir and ledipasvir coformulation it has already submitted for regulatory approval in the U.S. and Europe.
Gregory Everson from the University of Colorado at Denver presented findings from a Phase 2 clinical trial (GS-US-342-0102) looking at the safety and efficacy of sofosbuvir plus GS-5816 taken without ribavirin for 12 weeks in treatment-naive genotype 1-6 chronic hepatitis C patients.
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 favorable IL28B CC gene variant associated with interferon responsiveness.
Participants in this open-label study were randomly assigned to receive 400 mg once-daily sofosbuvir plus either 25 mg or 100 mg once-daily GS-5816 for 12 weeks. They were followed after finishing therapy to determine sustained virological response, or continued undetectable HCV viral load 12 weeks post-treatment (SVR12), which is considered a cure.
- SVR12 rates for genotype 1 patients were 96% using the 25 mg GS-5816 dose and 100% using the 100 mg dose.
- For people with genotype 2 the corresponding rates were 91% and 100%, respectively.
- 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 25 mg and 100 mg 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 25 mg GS-5816 dose and 96% using the 100 mg dose.
- Looking at the patients who did not achieve SVR12, 3 people relapsed after completing treatment: 1 genotype 1 patient taking 25 mg GS-5816, 1 genotype 3 patient taking 25 mg, and 1 genotype 3 patient taking 100 mg.
- In addition, 1 genotype 3 patient was a non-responder during treatment, 1 genotype 2 patient died during follow-up, and 1 genotype 3 patient was found to be re-infected.
- Genetic sequencing revealed that about one-quarter of genotype 1-3 patients had pre-existing resistance-associated NS5A viral variants.
- Among these, virological failure was more likely with 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.
- 4 patients had serious adverse events, 3 of them in the 25 mg GS-5816 dose arms; however, no one discontinued for this reason.
- The most common side effects reported by more than 10% of participants were fatigue, headache, nausea, and constipation.
- No one developed anemia, a sideeffect often seen with ribavirin.
"Sofobuvir + 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.
GT Everson, TT Tran, WJ Towner, 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 European Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O111.
Gilead Sciences. Gilead Announces Phase 2 Results for Two Investigational All-Oral Sofosbuvir-Based Regimens for the Treatment of Chronic Hepatitis C. Press release. April 10, 2014.