AASLD 2013: Faldaprevir Triple Therapy Effective Across Patient Subgroups

The experimental hepatitis C virus (HCV) protease inhibitor faldaprevir in combination with pegylated interferon and ribavirin was effective across a range of subgroups of patients with genotype 1 infection -- including prior relapsers and non-responders -- in the STARTVerso clinical trials program, according to research presented at the recent AASLD Liver Meeting in Washington, DC.

Faldaprevir is an experimental oral HCV protease inhibitor. Its safety and efficacy has been examined in 3 Phase 3 clinical trials, 2 of which involved treatment with faldaprevir or placebo in combination with pegylated interferon and ribavirin. The STARTVerso1 study recruited people in Europe and Japan and the study population in STARTVerso2 was drawn from the U.S., Korea, and Taiwan.

All study participants were treatment-naive (had not taken hepatitis C treatment before) and had HCV genotype 1. Both studies had the same design. Participants were randomized into 3 arms: placebo plus pegylated interferon/ribavirin for 24 weeks, 120 mg once-daily faldaprevir plus pegylated interferon/ribavirin for 12 or 24 weeks, or 240 mg once-daily faldaprevir plus pegylated interferon/ribavirin for 12 weeks. People randomized to the faldaprevir arms who achieved early virological response stopped all therapy at week 24. The primary endpoint of the studies was a sustained virological response 12 weeks after completion of therapy (SVR12).

Primary results showing the safety and efficacy of faldaprevir triple therapy for treatment-naive patients were presented to the International Liver Congress (EASL 2013) in April.

In the latest study, investigators pooled data from STARTVerso1 and STARTVerso2. Investigators wished to see how faldaprevir performed across patient subgroups and which baseline characteristics were associated with treatment outcomes.

Results consistently showed that the addition of faldaprevir improved treatment outcomes across subgroups, and that white and Asian people were more likely to achieve SVR than individuals of African-American or black ethnicity. Several well-established baseline characteristics were also associated with treatment outcomes.

The characteristics of the participants were similar in both studies. Approximately 20% of participants were from Asia with 40% each from Europe and North America. Nearly three-quarters (71%) were white, 20% were Asian, and 7% were black. The mean age was 49 years. Just under half (47%) of participants had harder-to-treat HCV genotype 1a infection and between 36% and 41% had the favorable IL28B CC gene variant. Liver cirrhosis was present in approximately 10% of patients and the mean baseline HCV RNA load was 6.4 log copies IU/mL.

Sustained virological response was achieved by 50% of people in the placebo arm and by 72% and 73% treated with 120 mg and 240 mg faldaprevir, respectively.

In Europe, 77% of people taking faldaprevir achieved SVR, as did 88% of participants in Asia. However, outcomes were poorer in North America, with only 60% to 63% of people treated with the 2 faldaprevir doses having a successful outcome. The investigators noted that there was a higher rate of treatment discontinuation in North America for reasons other than failure of therapy. They believe this was related to management of side effects.

Several baseline characteristics were also significantly associated with increased chances of achieving sustained virolgical response. These included baseline HCV RNA, IL28B CC compared to CT or TT gene variants, infection with HCV genotype 1b compared to genotype 1a, younger age, white or Asian ethnicity compared to black ethnicity, and absence of cirrhosis.

The investigators therefore concluded that faldaprevir with pegylated interferon and ribavirin is effective for the treatment of HCV genotype 1 infection across a range of patient subgroups.

Treatment-Experienced Patients

Faldaprevir plus pegylated interferon/ribavirin is also a safe and effective treatment for people who did not respond to a previous course of HCV treatment, according to related study. Nearly three-quarters (70%) of people who relapsed after a previous course of HCV therapy had a successful treatment outcome, as did half of individuals with previous partial response and 33% who had a null response to earlier therapy.

The randomized, multicenter, placebo-controlled STARTVerso3 trial enrolled 3 categories of participants:

• Relapsers: People who had undetectable HCV RNA (<25 IU/mL) after 48 weeks of treatment but detectable viral load within the next 24 weeks of post-treatment follow-up;
• Partial responders: People with a 2 log decrease in HCV RNA by week 12 of therapy, but who did not have undetectable viral load at the end of treatment;
• Null responders: People who did not have at least a 2 log drop in HCV RNA by week 12 of treatment.

A total of 677 people were recruited to the study and their randomization was stratified according to previous treatment response.

People who had relapsed or had a partial response were randomized into 3 study arms:

• Placebo plus pegylated interferon/ribavirin;
• Faldaprevir 240 mg once-daily for 12 weeks and placebo for a further 12 weeks taken with pegylated interferon/ribavirin;
• Faldaprevir 240 mg once-daily for 24 weeks plus pegylated interferon/ribavirin.

All patients with previous null response received faldaprevir and were randomized into 2 study arms:

• Faldaprevir 240 mg once-daily for 12 weeks and placebo for a further 12 weeks taken with pegylated interferon/ribavirin;
• Faldaprevir 240 mg once-daily for 24 weeks plus pegylated interferon/ribavirin.

Previous relapsers or partial responders who achieved early treatment response -- HCV RNA <25 copies IU/mL at week 4 and undetectable at week 8 of therapy -- were eligible to stop treatment at week 24.

The primary endpoint of the study was again sustained virological response 12 weeks after completion of therapy. Data were also collected on early treatment response rates, sustained virological response at post-treatment week 24 (SVR24), and adverse events.

The overall results clearly showed the efficacy of faldaprevir. Outcomes among people who had previously relapsed showed that 14% of individuals receiving placebo had a sustained virological response compared to 70% of patients in both faldaprevir arms, a significant difference. Most patients (86%-87%) who previously relapsed had an early treatment response.

Analysis of patients with previous partial response showed that 3% of individuals receiving placebo had a sustained treatment response compared to 58% of patients who received 12 weeks of therapy with faldaprevir and 47% of those who treated with the drug for 24 weeks.

One-third of previous null responders experienced 12-week sustained virological response, and outcomes did not differ between the faldaprevir treatment strategies.

Treatment outcomes 24 weeks after completion of therapy continued to show the benefits of faldaprevir. None of the common HCV resistance mutations had an impact on the chances of achieving a successful treatment outcome.

Several well-established baseline characteristics were associated with treatment outcomes, and overall response rates were better among people without cirrhosis who had HCV genotype 1b and the favorable IL28B CC polymorphism.

Adverse events were reported for 95% of patients in the placebo arms and by 97%-99% patients randomized to receive faldaprevir triple therapy. Moderate adverse events occurred in 48% of placebo patients compared to 58%-59% of faldaprevir recipients. Serious adverse events were rare in the placebo arm (1%) but more common among patients in the faldaprevir arms (8%-10%). However, only 5%-6% of faldaprevir recipients discontinued treatment. Rates of laboratory abnormalities were similar for the 2 faldaprevir strategies.

The investigators concluded that the addition of faldaprevir to standard HCV therapy is associated with "clinically meaningful" improvements in treatment outcomes among treatment-experienced patients. Extending the duration of treatment with the drug to 24 weeks did not confer any additional benefits.

11/27/13

References

EM Yoshida, T Asselah, C Moreno, et al. Subgroup analyses and baseline predictors of response with faldaprevir plus pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic hepatitis C genotype-1 infection: a pooled analysis of STARTVerso 1 and 2. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract1114.

IM Jacobson, T Asselah, P Ferenci, et al. STARTVerso3: A randomised, double-blind, placebo-controlled phase III trial of faldaprevir in combination with pegylated interferon alfa2a plus ribavirin in treatment-experienced patients with chronic HCV genotype-1 infection. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract1100.

Other Source

Boehringer Ingelheim. Phase III data show Boehringer Ingelheim's faldaprevir was highly effective in a broad range of patients with genotype-1 hepatitis C. Press release. November 2, 2013.