November 14, 2014
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Two studies show promise for 8-week treatment with GS-5816

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BOSTON — Pangenotypic NS5A inhibitor GS-5816 in combination with sofosbuvir-containing regimens demonstrated encouraging results in a number of patient cohorts, according to findings presented here.

Edward J. Gane, MD, of Auckland Clinical Studies in New Zealand, presented findings from the ELECTRON 2 study, which investigated GS-5816 as part of four treatment regimens: sofosbuvir (Sovaldi, Gilead Sciences) plus GS-5816 (Gilead Sciences) 25 mg with or without ribavirin, and sofosbuvir plus GS-5816 100 mg with or without ribavirin. All regimens were administered for 8 weeks.

“This combination has been tested for 12 weeks,” Gane said. “GS-5816 has demonstrated picomolar potency against HCV genotypes 1 through 6 and against all common NS5A RAVs. Pharmacokinetic data support once-daily dosing.”

Eligible participants were treatment naïve individuals with genotype 3 disease without cirrhosis. The population was predominantly male and almost all were genotype 3a.

Sustained virological response at 12 weeks (SVR12) served as the primary outcome measure. The study also included safety endpoints.

SVR12 rates were 100% among 27 patients who received the 25 mg regimen without ribavirin; 88% among 24 patients who received 25 mg regimen with ribavirin; 96% among 27 patients who received 100 mg without ribavirin; and 100% among 26 patients who received the 100 mg regimen with ribavirin.

“We didn’t see any difference in viral kinetics by adding ribavirin or increasing the dose of GS-5816,” Gane said.

There were four treatment failures and two virologic failures across the four treatment arms, according to Gane. One patient discontinued at day 14 due to an adverse event, and there were two virologic relapses.

“The regimen was generally well tolerated,” Gane said of the safety outcomes.

Adverse event rates were 67% for the 25 mg without ribavirin group, 79% for the 25 mg ribavirin group, 81% for the 100 mg without ribavirin group and 85% for the 100 mg with ribavirin group.

“The most common laboratory abnormality was a decrease in hemoglobin,” Gane said. “But this was restricted to the two arms containing ribavirin.”

Fatigue and headache were the most commonly reported adverse events. “These events had no particular association with any one arm,” Gane said. “Most were mild, a few were moderate.”

“This combination is now being coformulated as a fixed-dose tablet and is going through to phase 3 development,” Gane said.

Additional 8-week results

Tram T. Tran, MD, of Cedars-Sinai Medical Center, Los Angeles, presented another data set involving 8 weeks of therapy with GS-5816. All patients received daily sofosbuvir 400 mg in addition to GS-5816 25 mg with or without ribavirin, or GS-5816 100 mg with or without ribavirin.

For patients with genotype 1 disease, SVR12 rates for the 25 mg cohort were 87% without ribavirin and 83% with ribavirin. For the 100 mg group with genotype 1 disease, SVR12 rates were 90% without ribavirin and 81% with ribavirin.

“Genotype 1 patients had similar SVR12 regardless of presence or absence of NS5A resistance-associated variants,” Tran said.

In patients with genotype 2 disease, 25 mg GS-5816 was associated with a 77% SVR rate with ribavirin and an 88% rate without ribavirin. Both 100 mg groups with genotype 2 disease reached 88% SVR.

“Ribavirin did not make a difference in terms of relapse rates in the 100 mg dose,” Tran said.

“No patients on therapy had virologic failure,” she added.

For genotype 2 patients, pre-treatment for NS5A RAVs yield lower response rates than those without pre-treatment for NS5A RAVs, according to Tran.  “This suggests not the emergence of resistance but perhaps that the duration of treatment was insufficient,” she said.

There were four serious adverse events that Tran suggested were not likely related to medication.

Fatigue, headache and nausea were the only adverse events that occurred in more than 10% of patients. – by Rob Volansky

For more information:

Gane EJ. Abstract 79. Presented at: The Liver Meeting; Nov. 7-11, 2014; Boston.

Tran TT. Abstract 80. Presented at: The Liver Meeting; Nov. 7-11, 2014; Boston.

Disclosure: Gane and colleagues report associations with a number of pharmaceutical and device companies. Tran and colleagues also report associations with a number of pharmaceutical and device companies.