Provided by NEJM Journal Watch
June 26, 2013
Atif Zaman, MD, MPH reviewing Sulkowski MS et al. Hepatology 2013 Jun.
In a phase IIb study, faldaprevir plus peginterferon and ribavirin achieved high sustained virologic response rates and was well tolerated in treatment-naive patients.
Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor with antiviral activity in vitro. In the current industry-sponsored, phase IIb trial, investigators assessed its efficacy in achieving sustained virologic response (SVR) in combination with peginterferon (PEG; 180 µg weekly) and ribavirin (RBV; 1000–1200 mg daily) in 429 treatment-naive patients infected with HCV genotype 1. Participants were randomized in a 1:1:2:2 ratio to receive one of the following regimens (each followed by 24 weeks of PEG/RBV only):
- Placebo once daily plus PEG/RBV for 24 weeks;
- Faldaprevir once daily (120 mg) plus PEG/RBV for 24 weeks with a 3-day lead-in of placebo plus PEG/RBV;
- Faldaprevir once daily (240 mg) plus PEG/RBV for 24 weeks with a 3-day lead-in of placebo plus PEG/RBV;
- Faldaprevir once daily (240 mg) plus PEG/RBV for 24 weeks.
Extended rapid virologic response was defined as undetectable viral load at week 4 that was sustained at weeks 8 and 20.
SVR at 24 weeks (primary endpoint) was 56%, 72%, 72%, and 84%, respectively, in the placebo group, 120-mg faldaprevir group, 240-mg faldaprevir group with lead-in, and 240-mg faldaprevir group without lead-in. In the latter group, SVR rates were similar between patients receiving 24 and 48 weeks of therapy who achieved extended rapid virologic response (93% and 92%) and between patients with genotypes 1a and 1b (82% and 84%) but differed between IL28B genotypes CC and non-CC (100% vs. 71%). Adverse events of mild gastrointestinal symptoms, jaundice, rash, and photosensitivity were more common with faldaprevir than with placebo. Discontinuation attributed to adverse events was lower in the placebo group (1%) than in the faldaprevir groups (4%–11%). Virologic breakthrough was low and similar between groups; however, in the faldaprevir groups, the breakthroughs were associated with selection of NS3 R155K or D168V variants.
These faldaprevir regimens achieved high response rates (even in subgroups with hepatitis C virus genotype 1a or IL28B genotypes CT or TT) and were well tolerated with low rates of resistance. Sustained virologic response rates were similar to those currently seen with boceprevir and telaprevir regimens. The main advantage of faldaprevir would be dosing convenience, tolerability, and efficacy in certain subpopulations.
Disclosures for Atif Zaman, MD, MPH at time of publication Speaker’s bureau Bristol-Myers Squibb; Genentech; Gilead; Kadmon; Merck; Salix; Vertex
Sulkowski MS et al. Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype1 HCV: SILEN-C1 trial. Hepatology 2013 Jun; 57:2143. (http://dx.doi.org/10.1002/hep.26276)