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Alisporivir/PEG-IFN a-2a plus ribavirin yields high virologic response rates for HCV genotype 1
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In a phase 2 trial, alisporivir with pegylated interferon alfa-2a plus ribavirin yielded superior complete early virologic response rates in patients with hepatitis C genotype 1 infection who failed prior treatment vs. treatment with placebo and pegylated interferon alfa-2a plus ribavirin, according to published study data.
“[Alisporivir] in combination with [pegylated interferon alfa-2a and ribavirin] has been shown to have potent and synergistic anti-HCV activity in treatment-naive patients with HCV genotype 1 and 2/3 infection,” the researchers wrote. “This paper presents the final results of FUNDAMENTAL, a randomized, double-blind, placebo-controlled, phase 2 study undertaken to assess the efficacy and safety of [alisporivir] in combination with [pegylated interferon alfa-2a and ribavirin] in patients with chronic HCV genotype 1 infection in whom prior [pegylated interferon alfa-2a and ribavirin] therapy had failed.”
Researchers randomly assigned 459 patients to a dosage of alisporivir (Debio 025, Debiopharm Group; ALV) at either 400 mg twice daily, 600 mg once daily or 800 mg once daily with PEG-IFN a-2a and ribavirin, or placebo plus PEG-IFN a-2a and ribavirin for 48 weeks. The patients were from 73 study centers across North America and Europe. Of these patients, 43% relapsed, 23% were prior partial responders and 34% were prior null responders to treatment and 457 were actually treated in this study.
In April 2012, the FDA placed a clinical hold on the trial program, according to the research. All patients underwent at least 31 weeks of treatment. Patients in the ALV group completed the remaining weeks of treatment on PEG-IFN a-2a and ribavirin only.
Overall, 57% of all patients completed treatment and 71% of patients who received 400 mg of ALV had the highest rate of completion of all patient groups. Of the patients who received placebo and PEG-IFN a-2a with ribavirin, 57% were blindly switched to an ALV regimen due to failing to meet efficacy criteria, according to the research.
All of the patients treated with ALV had superior rates of complete early virologic response (cEVR) compared with patients in the placebo group. The group with the highest cEVR was patients who received 400 mg of ALV (74% vs. 36% of placebo patients; P < .0001), and showed the greatest decrease in HCV RNA.
The sustained virologic response rate at 12 weeks was 65% in patients who previously relapsed and were treated with ALV vs. 26% of patients who received placebo; SVR12 was 63% in partial responders who received ALV vs. 5% in partial responders who received placebo; SVR12 was 68% in null responders treated with ALV vs. 3% in null responders treated with placebo.
Patients who received more than 40 weeks of treatment with 400 mg of ALV had a greater SVR12 compared with patients treated for the same amount of time with placebo and PEG-IFN a-2a (89% vs. 30%; P = .0053). SVR24 rates were highest in the ALV groups compared with those who received PEG-IFN a-2a with ribavirin alone, regardless of prior treatment response and cirrhosis.
The patients who received 400 mg of ALV also had the lowest rates of viral breakthrough and relapse.
The researchers observed headache, fatigue, anemia, neutropenia and nausea as the most common adverse events in all patient groups. Hypertension was not common, but more common in patients receiving ALV than PEG-IFN a-2a alone.
“ALV … markedly increased responsiveness to [PEG-IFN a-2a plus ribavirin] therapy in HCV genotype 1 nonresponders, including prior null nonresponders and cirrhotics,” the researchers said. “ALV merits further investigation in interferon-free regimens in combination with direct-acting antiviral agents,” the researchers wrote. – by Melinda Stevens
Disclosures: Buti reports receiving fees for serving as an advisory board member for Novartis, MSD, Gilead and Janssen. Please see the study for a full list of all other authors’ relevant financial disclosures.
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