Protease inhibitors that are active against NS3/4a are a fertile area of research. Boehringer Ingelheim’s compound faldaprevir is currently in Phase III trials.1 In one 24-week trial in 429 treatment-naïve patients with genotype-1 hepatitis C infection, subjects were given standard peg-interferon and ritonavir therapy plus placebo, or standard therapy plus either 120mg or 240mg of faldaprevir either with or without a three day lead-in of standard therapy alone, or standard therapy plus the higher dose of faldaprevir.2
Those given the higher dose of faldaprevir achieving a maintained RVR at week four and undetectable at week eight were re-randomised at week 24, and subsequently stopped treatment or received standard therapy for a further 24 weeks. The SVR rate for the placebo group was 56%, compared with 72% in both groups receiving standard therapy lead-in, and 84% for those who received the higher dose with no lead-in. Slightly higher rates of adverse events were seen in those given faldaprevir, but tolerability and safety remained acceptable.
It has also been investigated in patients who had previously failed to respond to standard therapy.3 A total of 290 patients who had either completely failed or achieved only a partial response were given 48 weeks of standard therapy, in combination with 240mg of faldaprevir once a day either with or without a three-day standard therapy lead-in, or 240mg twice a day with a lead-in.3 Those in the once-daily dosing lead-in group who achieved a maintained RVR at eight weeks were re-randomised to stop all treatment at week 24, or continue with standard therapy up to 48 weeks. A SVR was achieved in up to 50% of prior partial responders, and up to 35% of prior non-responders. A significantly higher number of the re-randomised patients who continued with therapy achieved a SVR.
In a further, Phase III, randomised, double blind, placebo-controlled trial, a total of 652 treatment-naïve patients with HCV infection were given 24 weeks of standard therapy in combination with placebo, or either 12 or 24 weeks of add-on treatment of once daily doses of either 120mg or 240mg of faldaprevir.4 Early treatment success in this case was deemed to be HCV RNA levels below 25 iU/ml after four weeks, and undetectable at eight weeks, and their combination therapy was stopped after 12 weeks. Those without early treatment success, and those receiving placebo, continued for the full 24 weeks of the study. The incidence of serious adverse events was similar across treatment arms, and in total 88% of those patients given one of the faldaprevir doses were able to stop all treatment after 24 weeks.
1. M. Llinàs-Brunet et al. J. Med. Chem. 2010, 53, 6466
2. M.S. Sulkowski et al. J. Hepatol. 2013, 57, 2143
3. M.S. Sulkowski et al. J. Hepatol. 2013, 57, 2155
4. P. Ferenci et al. J. Hepatol. 2013, 58 (Suppl. 1), Abst. 1416