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Sofosbuvir with GS-5816 shows pan-genotypic activity
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LONDON — Combination therapy with sofosbuvir and the investigational compound GS-5816 yielded 12-week sustained viral response rates in patients with hepatitis C virus genotypes, according to findings presented by Gregory T. Everson, MD, of the University of Colorado in Denver.
Everson described GS-5816 as an HCV NS5A inhibitor that demonstrated pan-genotypic activity in a previous 3-day monotherapy study.
Gregory T. Everson
The current study is a phase 2 investigation of GS-5816 (Gilead) with sofosbuvir (Sovaldi, Gilead) in treatment-naive genotype 1 to 6 HCV-infected patients without cirrhosis.
The analysis included 55 patients with genotype 1 disease; 54 patients with genotype 3; and 45 patients with genotypes 2, 4, 5 and 6. Patients with genotype 2 through 6 were included as one group.
“In the genotype 1 population, the patients were predominantly subtype 1a,” Everson said.
All patients received sofosbuvir 400 mg daily. Patients in each group were then randomly assigned 25 mg or 100 mg GS-5816. Overall, 77 patients received the 25-mg dose of the investigational drug and 77 patients received the 100-mg dose. Sustained virologic response at 12 weeks (SVR12) served as the primary efficacy outcome. COBAS TaqMan (Roche) was used to measure HCV RNA lower limit of quantitation. Safety endpoints included adverse events, discontinuations and laboratory abnormalities. The researchers also measured viral kinetics and resistance.
There was one virologic failure in the 25-mg arm of GS-5816 and no failures in the 100-mg arm.
Patients in the 25-mg group with genotype-1 disease achieved an SVR12 rate of 96%. The rate was 91% for genotype 2; 93% for genotype 3; and 100% for genotypes 4, 5 and 6.
Among those who received the 100-mg dose, the SVR12 rates were 100% for genotypes 1 and 2, 93% for genotype 3, 86% for genotype 4 and 100% for genotypes 5 and 6.
“Generally, this was a well-tolerated regimen,” Everson said. “About 70% had [adverse events] on treatment, but they were mostly mild and of low grade.”
Everson said six patients had grade 3 or 4 laboratory abnormalities that included hyperglycemia, asymptomatic transient lipase elevations and transient creatinine elevations. “There were no grade 3 or 4 abnormalities with regard to neutrophil or platelets in the absence of ribavirin,” he added.
“The combination of sofosbuvir with GS-5816 for 12 weeks resulted in SVR12 of greater than 90% in all HCV genotypes,” Everson said. “Failure occurred more often in patients who received the 25-mg dose [of GS-5816] compared with the higher dose.
The presence of pre-treatment resistant variants to NS5A did not predict failure to the new treatment. This study provides evidence that this combination is reasonable to pursue in future studies.”
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Disclosure: Infectious Disease News could not confirm any relevant financial disclosures at the time of publication. Dr. Everson has been a principal investigator of research grants provided by Gilead Sciences to the University of Colorado Denver for the conduct of clinical trials. He has also served on Advisory Boards for Gilead Sciences.