AASLD 2013: Faldaprevir All-oral Regimen Shows 100% Early Sustained Response for HCV 1a

An interferon-free regimen of faldaprevir, deleobuvir, and PPI-668 led to 4-week post-treatment sustained virological response (SVR4) in all treatment-naive patients with hard-to-treat HCV subtype 1a in an ongoing Phase 2 trial, according to a late-breaking poster presentation at the 64th AASLD Liver Meeting this month in Washington, DC.

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

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

SOUND-C3 enrolled 12 treatment-naive chronic hepatitis C patients who had harder-to-treat HCV subtype 1a but were non-cirrhotic and had the favorable IL28B CC gene pattern associated with interferon responsiveness. 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 a rapid decline in HCV RNA after starting therapy, the HCV subtypes diverged with continued treatment. At the end of treatment, 100% of subtype 1b patients had undetectable viral load, compared with 58% of 1a patients. At 4 weeks 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 -- considered a cure.

Among people with subtype 1a, there were 4 viral breakthroughs during treatment and 5 post-treatment relapses. Among those with subtype 1b, 2 people discontinued early due to adverse events, of whom 1 relapsed and 1 achieved SVR12.

In an effort to improve cure rates for people with the harder-to-treat HCV subtype, Jay Lalezari from Quest Clinical Research in San Francisco and colleagues conducted another Phase 2 trial testing the same dose of faldaprevir, 400 or 600 mg twice-daily deleobuvir, and Presidio Pharmaceuticals' NS5A inhibitor PPI-668 at a dose of 200 mg 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 favorable IL28B CC variant; people with liver cirrhosis were excluded.

Half of the participants were still undergoing treatment at the time of data analysis, but one-third (13 people) completed 4 weeks of post-treatment follow-up. SVR4 is too soon to declare a cure, as relapse may still happen after this point; regulatory authorities consider SVR12 to indicate a cure.

Results

• Again, rapid viral suppression occurred in all treatment arms, with 97% reaching HCV RNA <25 IU/mL by week 4 of treatment.
• Among patients followed for 4 weeks post-treatment, 100% achieved SVR4 across all arms.
• 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, with 1 serious adverse event and 1 person discontinuing early due to gastrointestinal symptoms.
• People taking ribavirin were more likely to experience moderate adverse events, while those using the ribavirin-free regimen had mostly 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.

11/21/13

References

J Dufour, M Buti, V Soriano, et al. Interferon-free Treatment with Faldaprevir, Deleobuvir (BI 207127) and Ribavirin in SOUND-C3: 95% SVR12 in HCV-GT1b. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract 1102.

JLalezari, L Holland, E Glutzer, et al. Rapid and Consistent Virologic Responses in a Phase 2 Trial of a New All-Oral Combination of Faldaprevir, Deleobuvir, and PPI-668, with and without Ribavirin, in Patients with HCV Genotype-1a Infection. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. AbstractLB-20.

Other Source

Boehringer Ingelheim. Boehringer Ingelheim's interferon-free hepatitis C treatment portfolio strengthened by promising Phase II data. Press release. November 2, 2013.