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Gilead 4-Drug Hepatitis C Combo Shows Modest Efficacy in Phase 2 Trial

An interferon-free regimen containing 3 direct-acting antiviral drugs plus ribavirin cured about 60% of genotype 1 hepatitis C patients treated with the highest dose for 24 weeks, according to study findings reported in the February 5 advance edition of Hepatology -- only a modest cure rate compared with some other new regimens with cure rates approaching 100%.

The advent of direct-acting antiviral antivirals (DAAs) that target different steps of the hepatitis C virus (HCV) lifecycle have ushered in a revolution in treatment, but many patients and providers are awaiting all-oral regimens without difficult-to-tolerate interferon.

Two next-generation DAAs -- Janssen's HCV protease inhibitor simeprevir (Olysio) and Gilead Science's polymerase inhibitor sofosbuvir (Sovaldi) -- were approved this past December. Both demonstrated high cure rates in combination with pegylated interferon and ribavirin, as well as with each other. Sofosbuvir plus ribavirin alone is effective for many people, especially those with easier-to-treat HCV genotypes 2 or 3, but adding antivirals from other classes raises efficacy.

David Wyles from the University of California at San Diego and colleagues evaluated a 4-drug all-oral combination containing the NS5A inhibitor ledipasvir (formerly GS-5885), the NS3 protease inhibitor vedroprevir (GS-9451), the non-nucleoside polymerase inhibitor tegobuvir (GS-9190), and ribavirin.

This Phase 2 study enrolled 140 previously untreated genotype 1 chronic hepatitis C patients without liver cirrhosis. They were randomly assigned to receive ledipasvir at doses of 30 or 90 mg once-daily plus 200 mg once-daily vedroprevir, 30 mg twice-daily tegobuvir, and 1000-1200 mg/day weight-based ribavirin. In the 90 mg group, patients who experienced rapid virological response, defined as undetectable HCV RNA during treatment weeks 2-10, were randomized again to either stop treatment at 12 weeks or continue for 24 weeks.

Results

• Sustained virological response rates at 12 weeks post-treatment (SVR12) were 63% for patients receiving 90 mg ledipasvir for 24 weeks, 54% for those receiving 90 mg ledipasvir for 12 weeks, and 48% for those treated with 30 mg ledipasvir for 24 weeks.
• Among patients in the 90 mg arm who experienced rapid response during weeks 2-10, SVR12 rates were 68% in the 12-week group and 81% in the 24-week group.
• Virological breakthrough during treatment was more common among people with harder-to-treat HCV subtype 1a, and was associated with resistance-associated mutations for all 3 DAAs.
• Among people who relapsed after finishing treatment, all but 1 had resistance mutations for 1 or 2 of the DAAs.
• The 4-drug combination was generally safe and well-tolerated.
• The most common side effects were fatigue, headache, nausea, diarrhea, and skin rash.

"In patients with HCV genotype 1, an interferon-free regimen containing [ledipasvir/vedroprevir/tegobuvir/ribavirin] was well tolerated and led to SVR12 in up to 63% of patients," the study authors concluded.

These results are unimpressive compared with data from studies of sofosbuvir plus ledipasvir or the newer NS5A inhibitor GS-5816, or AbbVie's "3D" combination, which have demonstrated SVR12 rates in the 90% to 100% range.

Gilead has indicated that it has discontinued studies of tegobuvir, but vedroprevir is still listed in its hepatitis C development pipeline. Gilead recently requested Food and Drug Administration approval of a coformulation containing sofosbuvir plus ledipasvir, and it is also working on a sofosbuvir/GS-5816 combination pill.

2/14/14

Reference

DL Wyles, M Rodriguez-Torres, E Lawitz, et al. All-Oral Combination of Ledipasvir, Vedroprevir, Tegobuvir, and Ribavirin in Treatment-Naive Patients with Genotype 1 HCV Infection. Hepatology. February 5, 2014 (Epub ahead of print).