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EASL 2013: Second-generation Protease Inhibitor Faldaprevir Cures up to 80% of Genotype 1 Hepatitis C

A second-generation HCV protease inhibitor, faldaprevir (formerly BI 201335), cured up to 80% of previously untreated people with genotype 1 hepatitis C virus infection when combined with pegylated interferon and ribavirin, Peter Ferenci of the Medical University of Vienna reported on Saturday at the EASL International Liver Congress (EASL 2013) in Amsterdam. A response gap was observed, however, between HCV subtypes 1a and 1b.

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The findings came from the Phase 3 STARTVerso study, which randomized 656 people with chronic hepatitis C to receive 1 of 2 doses of faldaprevir (120 mg once-daily or 240 mg once-daily) or placebo, for at least 12 weeks, in combination with pegylated interferon and ribavirin.

At 12 weeks, participants in the 120 mg arm were randomized to continue faldaprevir through to week 24, or switch to a placebo, while all patients continued pegylated interferon and weight-based ribavirin to week 24. At week 24, patients who had achieved HCV RNA < 25 IU/ml at week 4 and undetectable viral load at week 8 (Early Treatment Success, or ETS) were eligible to stop all treatment. The remainder received pegylated interferon and ribavirin through week 48.

In the 240 mg arm, all participants stopped faldaprevir at week 12 but continued pegylated interferon and ribavirin through week 24. All participants in this arm who achieved Early Treatment Success were able to stop treatment at week 24. The remainder received pegylated interferon and ribavirin through week 48.

In the control arm, all participants received pegylated interferon and ribavirin plus placebo for 24 weeks, followed by a further 24 weeks of pegylated interferon and ribavirin alone.

Around two-thirds of study participants had genotype 1b hepatitis C infection, and between 58% and 65% had unfavorable non-CC IL2B gene variants, indicating the likelihood of poorer response to interferon-based treatment. Participants were predominantly Caucasian (78%) and 81%-84% were in the earlier stages of liver disease (Metavir score F1-F2); 6% of participants had cirrhosis.

Depending on their treatment assignment, up to 80% of patients who received faldaprevir achieved a sustained virological response 12 weeks after stopping treatment (SVR12). There was no significant difference in efficacy between the 2 doses of faldaprevir, but the lower dose was better tolerated.

Final results showed that by intent-to-treat analysis, 80% of patients in the faldaprevir 240 mg arm and 79% in the 120 mg arm achieved SVR12, compared with 52% in the pegylated interferon/ribavirin arm.

A total of 88% of patients achieved early treatment success and were eligible to stop all treatment at week 24. Of these patients, 89% in the 240 mg group and 86% in the 120 mg group achieved SVR12.

There was a pronounced difference in SVR rates among faldaprevir-treated patients between those with detectable or undetectable HCV RNA at week 4. Among those with HCV RNA below the limit of quantification but still detectable at week 4, 77% in the 120 mg arm and 72% in the 240 mg arm achieved SVR 12. Among those with undetectable HCV RNA at week 12, 91% and 94%, respectively, achieved SVR12.

There was a modest difference in response rates between HCV genotype 1a and 1b in the faldeparevir 240 mg group (76% vs 83%), favoring genotype 1b. The difference was more pronounced in the faldaprevir 120 mg group (69% vs 84%). This difference in SVR12 rates was not explained by higher rates of null or partial response, but by higher rates of viral breakthrough during treatment and post-treatment viral relapse.

Responses also differed according to IL28B gene pattern. Patients with the favorable CC genotype had the best responses (90% and 95% in the 120 mg and 240 mg groups, respectively), compared to 70% and 69% for those with the CT genotype, and 76% and 79% for the TT genotype.

Adverse events leading to treatment discontinuation occurred in 4% of placebo recipients, 4% of faldaprevir 120 mg recipients and 5% of faldeprevir 240 mg recipients. Serious adverse events occurred in 7% of faldaprevir recipients. The only adverse events that occurred more frequently in faldaprevir-treated patients were gastrointestinal, and these occurred with highest frequency in the 240 mg group.

A higher rate of jaundice among faldaprevir-treated patients (3% in the 240 mg group) was accompanied by a higher frequency of elevated bilirubin; 53% of patients in the 240 mg arm experienced bilirubin elevations, compared to 12% in the 120 mg group. These increases were transient and bilirubin levels returned to normal after week 16.

There was no difference in the incidence of anemia between the study arms up to week 24. Patients in the faldaprevir arms were less likely to require ribavirin dose reductions, although they did receive erythropoietin (EPO) more frequently.

The 240 mg faldaprevir dose offered no clear advantages over the 120 mg dose, Ferenci concluded, although the finding of lower response rates in genotype 1a patients in the 120 mg dose group may leave that conclusion open to question.

The results of STARTVerso, together with those of 2 other Phase 3 trials, are likely to be submitted later this year to support the licensing of faldaprevir in the United States and European Union. Faldaprevir is being developed by Boehringer-Ingelheim for use with pegylated interferon and ribavirin, and also for use in interferon-free regimens.

Speaking at a press conference on the opening day of the International Liver Congress, EASL Secretary-General Mark Thursz said that he expected faldaprevir, another second-generation protease inhibitor simeprevir (formerly TMC435), and sofosbuvir (formerly GS-7977), a NS5B nucleotide polymerase inhibitor, to "totally cannibalize" the market niche for hepatitis C therapy currently occupied by the first-generation protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek or Incivo).

4/29/13

Reference

P Ferenci, T Asselah, GR Foster, et al. Faldaprevir plus pegylated interferon alfa-2A and ribavirin in chronic HCV genotype-1 treatment-naive patients: final results from STARTVerso1, a randomised double blind placebo-controlled phase III trial. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam, April 24-28, 2013. Abstract 1416.

Other Source

Boehringer Ingelheim. Boehringer Ingelheim’s Faldaprevir-Based Treatment Regimen Achieved Viral Cure in up to 80 Percent of Patients with Hepatitis C in Phase 3 Pivotal Trial. Press release. April 23, 2013.