Simeprevir boosts response to interferon-based hepatitis C therapy for prior relapsers

Adding the HCV protease inhibitor simeprevir (formerly TMC435) to pegylated interferon and ribavirin cured 79% of prior relapsers, and most were eligible to complete treatment after three months, according to findings from the PROMISE study presented at the Digestive Disease Week meeting (DDW 2013) in Orlando.

The advent of direct-acting antiviral agents (DAAs) has ushered in a new era of hepatitis C treatment. While many people with hepatitis C virus (HCV) and providers eagerly anticipate interferon-free regimens, many people with progressive liver disease cannot wait. Adding the first-generation HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek or Incivo) to pegylated interferon/ribavirin increases response rates, but these drugs have difficult dosing regimens and side-effects of their own. Fortunately, several next-generation DAAs are more effective, easier to take, and better tolerated.

Eric Lawitz from the University of Texas Health Science Center, on behalf of an international team of colleagues, presented findings from PROMISE (TMC435-HPC3007), a Phase 3 trial evaluating the efficacy, safety, and tolerability of simeprevir as an add-on to pegylated interferon/ribavirin for treatment-experienced people with genotype 1 chronic hepatitis C.

PROMISE enrolled 393 people who previously relapsed after a prior course of interferon-based therapy taken for at least 24 weeks. About 65% were men, most were white, and the median age was 52 years. About 40% had harder-to-treat HCV subtype 1a, about 75% had unfavorable IL28B gene patterns, 15% had advanced liver fibrosis (stage F3), and a similar proportion had cirrhosis (stage F4). People with HIV or hepatitis B co-infection were excluded.

Two-thirds of participants were randomly assigned to receive 150mg once-daily simeprevir plus pegylated interferon alfa-2a (Pegasys) and weight-based ribavirin for 12 weeks, followed by pegylated interferon/ribavirin alone for 12 more weeks. At that point (week 24), using a response-guided therapy algorithm based on response at weeks 4 and 12, they either stopped all treatment or continued interferon/ribavirin through week 48. The control arm received pegylated interferon/ribavirin for 48 weeks, with a placebo during the first 12 weeks.

• 77% of participants taking simeprevir triple therapy had rapid virological response (RVR) at week 4, compared with just 3% in the control arm.
• End-of-treatment response rates were high, 97% in the simeprevir arm and 72% in the control arm.
• Overall, 79% of participants receiving simeprevir achieved SVR12, compared with 37% in the control arm.
• Most participants (93%) were eligible to stop treatment at week 24, and within this group, 83% achieved sustained virological response at 12 weeks post-treatment (SVR12), considered a cure.
• Of the 7% who did not meet response-guided therapy criteria and continued treatment through week 48, only 32% achieved SVR12.
• SVR12 rates for people with HCV subtype 1a were 70% with simeprevir compared with 28% in the control arm; corresponding rates for subtype 1b were 86% and 43%.
• People with all IL28B patterns responded better to simeprevir triple therapy, with SVR12 rates ranging from 89% for the favorable CC variant to 79% for the intermediate CT pattern to 65% for the least favorable TT pattern (compared with 53, 34, and 19%, respectively, in the control arm).
• Sustained response rates using simeprevir were similar regardless of whether participants had absent-to-moderate (stage F0-F2) fibrosis (82%), advanced fibrosis (73%), or cirrhosis (74%) (compared with 41, 20, and 26%, respectively, in the control arm).
• 3% of people taking simeprevir and 27% in the control arm experienced on-treatment virological failure, while 19 and 48%, respectively, had post-treatment relapse.
• Overall adverse event rates were similar in the simeprevir and control arms, most commonly side-effects of interferon (fatigue, headache, flu-like symptoms).
• People taking simeprevir were a bit more likely to experience rash (19 vs 14%), itching (24 vs 17%), anaemia (11 vs 6%), and elevated bilirubin (6 vs 2%), but these were mostly mild to moderate.
• Serious adverse events and discontinuations for this reason were rare in both arms.

"In genotype 1 HCV patients who previously relapsed after interferon-based therapy, 79.2% achieved an SVR12 when treated with [simeprevir/pegylated interferon/ribavirin]", the researchers concluded.

"[Simeprevir] was generally safe and well-tolerated", they added. "Shortened therapy duration in [simeprevir]-treated patients led to reduced fatigue severity and a more rapid return to normal activities."

The 79% cure rate in PROMISE was essentially equal to the 80 to 81% SVR12 rates for treatment-naive patients in the Phase 3 QUEST-1 and QUEST-2 trials, which were presented in April at the International Liver Congress (EASL 2013) and again at DDW. In late March, Janssen submitted requests for US and European regulatory approval of simeprevir for use with pegylated interferon/ribavirin.