Anxious not to be left behind in the move towards once-daily HIV treatment, Boehringer-Ingelheim announced yesterday that it is beginning recruitment to an international study of an extended-release, once-daily formulation of its antiretroviral drug nevirapine (Viramune).
Once-daily use of nevirapine has been in doubt since the 2003 results of the 2NN study, which showed a higher risk of liver toxicity in those who received the once-daily dose when compared with those who received the drug twice daily, the current license recommendation.
Subsequent studies have not clarified matters:
- A literature review published in 2007 showed a trend towards higher rates of rash across studies in patients taking the drug once-daily.
- A randomised study in France found no adherence advantage to once-daily treatment with nevirapine.
- A large (n=289) randomised study in Spain found no significant difference in the rate of grade 3 or 4 liver toxicity over 72 weeks of follow-up between those who switched to nevirapine once-daily and those who remained on twice-daily dosing (Podzamczer).
The disadvantages of once-daily nevirapine dosing are due in part to the very high drug levels that result from once daily dosing, and an extended release formulation is intended to smooth out the peak level of the drug by releasing the drug more slowly than two 200mg standard tablets taken together.
The VERXVE study will compare twice daily dosing with once-daily dosing of a new, extended release formulation comprising one nevirapine tablet. All participants will receive Truvada alongside nevirapine.
VERXVE is a 48-week study that will recruit around 1000 treatment-naive patients in North and South America, Europe, Australia and South Africa, and results are expected in 2010.
The study will also need to put to rest concerns regarding the efficacy of combinations which combine nevirapine and tenofovir. The DAUFIN study, reported in 2007, found a high risk of failure using the combination of tenofovir, 3TC and nevirapine, while an Italian study found a high failure rate in recipients of Truvada (tenofovir and FTC) plus twice daily nevirapine who had high viral load.
The potential licensing of a new once-daily formulation will have an additional commercial advantage for Boehringer-Ingelheim: its patent exclusivity on the current formulation of nevirapine expires in Europe in 2010 and the United States in 2011, at which point generic manufacturers could begin to sell cheaper versions of the drug. A new extended release formulation of the drug would be patented as a new product, and so would be protected from generic competition.
Podzamczer D et al. Low hepatotoxicity in patients randomized to switching to nevirapine QD vs continuing with nevirapine BID. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 960, 2008.