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Faldaprevir + Deleobuvir All-oral Regimen Works Well Against Genotype 1b HCV

An interferon-free combination of the direct-acting antivirals faldaprevir and deleobuvir with ribavirin cured hepatitis C in a majority of patients treated for 12 to 40 weeks, but outcomes were significantly better for people with HCV genotype 1b, researchers reported in the August 15, 2013, New England Journal of Medicine.

The advent of direct-acting antiviral agents (DAAs) active against hepatitis C virus (HCV) has brought about a new treatment paradigm. DAAs will initially be approved for use in combination with interferon-based therapy, but many patients and providers are waiting for all-oral regimens that work without pegylated interferon and its difficult side effects.

Stefan Zeuzem from Johann Wolfgang Goethe University in Frankfurt and an international team of colleagues conducted the Phase 2b SOUND-C2 trial to test all-oral regimens containing Boehringer Ingelheim's HCV protease inhibitor faldaprevir (formerly BI 201335) plus the non-nucleosideNS5B HCV polymerase inhibitor deleobuvir(formerly BI 207127), with or without ribavirin.

This open-label study included 362 previously untreated genotype 1 chronic hepatitis C patients. A majority were men, almost all were white, and the mean age was about 50 years. About 10% had liver cirrhosis, about one-quarter had the favorable IL28B CC gene pattern, and approximately two-thirds had easier-to-treat HCV subtype 1b, though proportions varied across study arms.

Participants were randomly allocated to 5 treatment arms:

• Faldaprevir 120 mg once-daily + deleobuvir 600 mg 3-times-daily + ribavirin for 16 weeks (TID16W);
• Faldaprevir 120 mg once-daily + deleobuvir 600 mg 3-times-daily + ribavirin for 28 weeks (TID28W);
• Faldaprevir 120 mg once-daily + deleobuvir 600 mg 3-times-daily + ribavirin for 40 weeks (TID40W);
• Faldaprevir 120 mg once-daily + deleobuvir 600 mg twice-daily + ribavirin for 28 weeks (BID28W);
• Faldaprevir 120 mg once-daily + deleobuvir 600 mg 3-times-daily, with no ribavirin (TID28W-NR).

The primary endpoint was sustained virological response, or continued undetectable viral load, at 12 weeks after completion of treatment (SVR12). Results were previously reported at the AASLD Liver Meeting last November, and have now been peer-reviewed for publication.

Results

• Overall SVR12 rates ranged from about 40% to 70% for the various regimens:

o   TID16W: 59%;

o   TID28W: 59%;

o   TID40W: 52%;

o   BID28W: 69%;

o   TID28W: 39%.

• The response rate was significantly lower in the ribavirin-sparing arm compared with the groups that used ribavirin.
• Among participants who used ribavirin, sustained response rates did not differ significantly according to treatment duration.
• Triple therapy with twice-daily deleobuvir dosing performed a bit better than 3-times-daily, but the difference was not statistically significant.
• In an analysis by HCV genotype, SVR12 rates ranged from 56% to 85% for subtype 1b, compared with just 11% to 47% for genotype 1a.
• Response rates were also better for people with the IL28B CC gene pattern (58%-84%) compared with non-CC patterns (33% to 64%) -- notable because IL28B is involved in interferon responsiveness and these were interferon-free regimens.
• SVR12 rates were similar for patients with and without liver cirrhosis.
• Faldaprevir, deleobuvir, and ribavirin were generally safe and well-tolerated.
• The most common side effects were skin rash, photosensitivity, nausea, vomiting, and diarrhea.
• 9% of participants experienced severe adverse events and 12% discontinued treatment for this reason.

Based on these findings, the study authors concluded, "The rate of a sustained virologic response 12 weeks after the completion of therapy was 52% to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin."

These results informed the regimens used in the pivotal Phase 3 HCVerso trials -- now fully enrolled, according to Boehringer Ingelheim -- which are evaluating once-daily faldaprevir, twice-daily deleobuvir, and ribavirin taken for 16 or 24 weeks in people with HCV subtype 1b.

8/21/13

Reference

S Zeuzem, V Soriano, T Asselah, et al. Faldaprevir and Deleobuvir for HCV Genotype 1 Infection. New England Journal of Medicine 369(7):630-639. August 15, 2013.