A second-generation hepatitis C protease inhibitor, faldaprevir, cured up to 80% of previously untreated people with genotype 1 hepatitis C virus (HCV) infection when combined with pegylated interferon and ribavirin, Professor Peter Ferenci of the Medical University of Vienna reported on Saturday at the International Liver Congress (EASL 2013) in Amsterdam.
The findings came from the phase III STARTVerso study which randomised 656 people with chronic hepatitis C infection to receive at least 12 weeks of faldaprevir or placebo, in combination with pegylated interferon and ribavirin.
The results of STARTVerso, together with two other phase III study results, 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 Prof. Mark Thursz said that he expected faldaprevir, another second-generation protease inhibitor simeprevir, and sofosbuvir, a NS5B nucleotide polymerase inhibitor, to “totally cannibalise” the market niche for hepatitis C therapy currently occupied by the first-generation protease inhibitors boceprevir (Victrelis) and telaprevir (Incivo).
STARTVerso randomised participants to receive one of two doses of faldaprevir (120mg once daily or 240mg once daily) or placebo for at least 12 weeks, in combination with pegylated interferon and ribavirin.
At 12 weeks, participants in the 120mg arm were randomised to continue faldaprevir treatment to week 24, or to a placebo, and all participants continued pegylated interferon and ribavirin to week 24. At week 24, people who had achieved HCV RNA <25 IU/ml at week 4 and HCV RNA <25 IU/ml and undetectable at week 8 (Early Treatment Success) were eligible to stop all treatment. The remainder received pegylated interferon and ribavirin to week 48.
In the 240mg arm, all participants stopped faldaprevir at week 12 but continued pegylated interferon and ribavirin to week 24. All participants in this arm who achieved Early Treatment Success (ETS) were able to stop treatment at week 24. The remainder received pegylated interferon and ribavirin to 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.
Depending on their treatment assignment, up to 80% of people who received faldaprevir achieved a sustained virologic response 12 weeks after stopping treatment (SVR12). There was no difference in efficacy between the two doses of faldaprevir but the lower dose (120mg) was better tolerated.
Around two-thirds of study participants had genotype 1b hepatitis C infection.Between 58 and 65% had a CT or TT IL28B genotype, indicating the likelihood of a poorer response to interferon-based treatment. Participants were predominantly Caucasian (78%) and in the earlier stages of liver disease (METAVIR score F1-F2) (81-84%) according to study arm. Six per cent of participants had cirrhosis.
Final results showed that by intent-to-treat analysis 80% of patients in the faldaprevir 240mg arm and 79% in the 120mg arm achieved SVR12, compared with 52% in the pegylated interferon/ribavirin arm (p< 0.001).
A total of 88% achieved early treatment success and were eligible to stop all treatment at week 24. Of these patients 89% in the 240mg group and 86% in the 120mg group achieved SVR12. There was a pronounced difference in SVR rates in the 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 120mg and 72% in the 240mg achieved SVR12. 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 240mg group (76 vs 83%) favouring genotype 1b. The difference was more pronounced in the faldaprevir 120mg 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 genotype. Those with the favourable CC genotype had the best responses (90 and 95% in the 120mg and 240mg 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 120mg recipients and 5% of faldeprevir 240mg 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 240mg group.
12% of these patients experienced gastrointestinal symptoms compared with 7% in the faldaprevir 120mg group and 3% in the control group who were taking pegylated interferon and ribavirin with placebo.
Mild to moderate rash was also observed in more patients taking faldaprevir compared with the placebo group. 32-33% of patients taking 120mg or 240 mg faldaprevir respectively experienced rash, compared with 22% in the placebo group. Severe rash was rarely observed, occurring in two patients in each study arm (6 cases overall). None of the rash events observed in this trial were life-threatening, and all events resolved.
A higher frequency of jaundice in faldaprevir-treated patients (3% in the 240mg group) was accompanied by a higher frequency of bilirubin elevations (53% of patients in the 240mg group experienced bilirubin elevations, compared to 12% in the 120mg group). These increases were transient and bilirubin levels returned to normal after week 16.
There was no difference in the incidence of anaemia between the study arms up to week 24. People in the faldaprevir arms were less likely to require ribavirin dose reductions.
The 240mg dose offered no clear advantages over the 120mg dose, Professor Ferenci concluded, although the finding of lower response rates in genotype 1a in the 120mg dose group may leave that conclusion open to question.
Ferenci P et al. Faldaprevir plus pegylated interferon alfa-2A and ribavirin in chronic HCV genotype-1 treatment-naïve patients: final results from STARTVerso1, a randomised double blind placebo-controlled phase III trial. 48th International Liver Congress, Amsterdam, abstract 1416, 2013.