November 6, 2013

Fixed-Dose HCV Combo OK With Ribavirin Substitute

Meeting Coverage

Published: Nov 5, 2013 | Updated: Nov 5, 2013

Coverage of Hepatitis C Virus is supported in part by an independent educational grant from AbbVie Pharmaceuticals.

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

WASHINGTON -- A fixed-dose combination of two investigational hepatitis C (HCV) drugs needs a boost in patients with advanced fibrosis or cirrhosis, a researcher said here.

But the boost doesn't have to be the old standby for HCV therapy, ribavirin, according to Edward Gane, MD, ofAuckland Clinical Studies in Auckland, New Zealand.

Instead, results in a small clinical trial were much the same when another investigational drug, dubbed GS-9669, was added to the combination of sofosbuvir and ledipasvir, Gane reported at the annual meeting of the American Association for the Study of Liver Diseases.

In the ELECTRON trial, Gane and colleagues are testing a single-pill combination of sofosbuvir, a nucleotide polymerase inhibitor, and ledipasvir, which blocks the nonstructural NS5A protein.

For this analysis, he reported outcomes in previously treated patients with genotype 1 HCV and advanced fibrosis or cirrhosis, who were given 12 weeks of the fixed-dose combination alone or with either ribavirin or GS-9669, a NS5B non-nucleoside inhibitor.

The primary endpoint was the proportion of patients who had undetectable virus 12 weeks after the end of therapy (SVR12).

Initially, Gane said, the researchers had tested the fixed-dose pill in 20 patients with or without ribavirin, but results were disappointing without ribavirin with SVR12 rates of 70% versus 100%.

So they enrolled another 51 patients and randomly assigned them to 12 weeks of the fixed dose combination along with either ribavirin or GS-9669.

The results here were better, Gane reported, as the SVR12 rate was 100% in both groups.

Importantly, patients receiving GS-9669 did not have the typical drop in hemoglobin that is associated with ribavirin.

Clinical adverse events were "common and mostly mild," Gane said, mainly headache, fatigue, and nausea. Lab abnormalities were also mild and grades 3 and 4 abnormalities were mostly associated with ribavirin.

In another sub-study, researchers tested the effect of the combination, along with ribavirin, in 25 treatment-naïve genotype 1 patients for only 8 weeks of treatment.

One advantage of many of the all-oral regimens under investigation is that they are quickly beneficial, with treatment duration of usually 12 or 24 weeks.

In contrast, treatment with the current standard of care -- pegylated interferon, ribavirin, and a protease inhibitor -- can be as long as 48 weeks.

In another study to be presented here, Gane said, 8 weeks of sofosbuvir, ledipasvir, and ribavirin was as efficacious as 12 weeks.

But a 6-week treatment period was too short, he said, and led to an "unacceptable relapse rate."

Both at 12 and 8 weeks, Gane said, the three drugs yielded 100% SVR12 rates, but after the 6-week course only 68% of patients reached that endpoint.

The analyses begin to fill in the picture of how the fixed-dose combination might be used, commented Gary Davis, MD, of Baylor University Medical Center in Waco, Texas, who was not involved in the study but who moderated the session at which it was presented.

But the studies remain small so they don't know how much stock can be put in them, he toldMedPage Today.

Sofosbuvir recently got the nod from an FDA advisory panel, which recommended its approval, either with interferon and ribavirin or ribavirin alone, depending on the patient.

But ledipasvir and GS-9669 remain under clinical investigation.

The study was supported by Gilead Sciences. Gane reported financial links with Roche, AbbVie, Novartis, Tibotec, Gilead, Janssen Cilag, Vertex, and Achillion. Several authors are employees of Gilead.

Davis reported financial links with Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech, Gilead, Johnson&Johnson, Merck & Co, Novartis, Pharmasset, and Vertex.

Primary source: American Association for the Study of Liver Diseases
Source reference: Gane E, et al "Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: the ELECTRON trial" AASLD 2013; Abstract 73.


Also See: Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial

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