Faldaprevir all-oral regimen shows 100% response rate for people with HCV 1a in interim analysis

An interferon-free regimen of faldaprevir, deleobuvir and PPI-668 led to a 4-week post-treatment sustained virological response (SVR4) in treatment-naive patients with hard-to-treat HCV subtype 1a in an ongoing phase 2 trial, according to a late-breaking poster presented at The Liver Meeting 2013, the 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD) last month in Washington, DC.

The advent of direct-acting antiviral agents (DAAs) has brought about a revolution in hepatitis C treatment. These novel drugs have also revealed some previously unrecognised characteristics of hepatitis C virus (HCV), including the differential responsiveness and barriers to resistance of HCV subtypes 1a and 1b.

The addition of PPI-688 to regimens vastly improves the efficacy of regimens containing faldaprevir and deleobuvir, which used to have lower response rates in genotype 1a patients compared with 1b.

The phase 2b SOUND-C3 trial, also described in a poster at The Liver Meeting, tested an all-oral triple combination of the HCV protease inhibitor faldaprevir (formerly BI 201335) at a dose of 120mg once daily, the non-nucleoside polymerase inhibitor deleobuvir (BI-207127) at a dose of 600mg twice daily and weight-based ribavirin, all taken for 16 weeks.

SOUND-C3 enrolled 12 people with chronic hepatitis C, who had not taken treatment before (treatment naive) and who had harder-to-treat HCV subtype 1a but did not have liver cirrhosis and had the favourable IL28B CC gene pattern. Also included were 20 people with easier-to-treat subtype 1b, of whom 20% had liver cirrhosis and only 15% had the IL28B CC variant.

Although all participants experienced rapid decline in HCV RNA after starting therapy, the HCV subtypes diverged with continued treatment. At the end of treatment, 100% of people with subtype 1b had undetectable viral load, compared with 58% of people with subtype 1a. At week 4 after completion of treatment, SVR4 rates were 100% and 33%, respectively. At 12 weeks post-treatment, the difference was even greater, with 95% of 1b patients but only 17% of 1a patients achieving SVR12, or a cure.

Among people with subtype 1a, there were four viral breakthroughs during treatment and five post-treatment relapses. Among those with subtype 1b, two people discontinued treatment early due to adverse events, of whom one relapsed and one achieved SVR12.

In an effort to improve cure rates for people with the harder-to-treat HCV subtype 1a, Jay Lalezari from Quest Clinical Research in San Francisco and colleagues conducted another phase 2 trial testing the same dose of faldaprevir, 400 or 600mg twice-daily deleobuvir and Presidio Pharmaceuticals' NS5A inhibitor PPI-668 at a dose of 200mg once daily, with or without weight-based ribavirin, for 12 weeks.

This study enrolled 37 previously untreated chronic hepatitis C patients with HCV subtype 1a. A majority (70%) were men, 78% were white and 36% had the favourable IL28B CC variant; people with liver cirrhosis were excluded.

Again, rapid viral suppression occurred in all treatment arms, with 97% reaching HCV RNA <25 IU/ml by week 4 of therapy. Half of the participants were still undergoing treatment at the time of data analysis, but one-third (13 people) completed four weeks of post-treatment follow-up. Among these patients, 100% achieved SVR4 across all arms. This is too soon to declare a cure, as relapse may still happen after this point (regulatory authorities consider SVR12 a cure).

A majority of participants (20 people) had potential resistance-associated mutations or polymorphisms at baseline, but this did not appear to compromise treatment efficacy. All 12 patients with the NS3 Q80K variant responded well to treatment.

Treatment was generally safe and well-tolerated. There was one serious adverse event and one person discontinued due to gastrointestinal symptoms. People taking ribavirin were more likely to experience moderate adverse events while those using the ribavirin-free regimen mostly had mild side-effects. Bilirubin elevation was common, attributable to faldaprevir's inhibition of a hepatic enzyme, but there was no evidence of liver toxicity.

"Treatment of a difficult-to-treat patient population (HCV GT-1a, predominantly IL28B CT or TT) with a new oral combination regimen of PPI-668 + faldaprevir + deleobuvir has consistently produced rapid virologic responses, with or without ribavirin," the researchers concluded. "Based on preliminary data, the ribavirin-free cohort appears to have a better tolerability profile with similar antiviral efficacy compared to the ribavirin-containing cohorts."

The faldaprevir/deleobuvir/ribavirin triple regimen continues to be evaluated in the ongoing phase 3 HCVerso trial. Results from that study and final results from the PPI-668 study are expected in the second quarter of 2014.