Capravirine discontinued, but Pfizer's HIV R&D won't stop

The global HIV pipeline is relatively strong, with 27 drugs currently in clinical development. However, it is unlikely that any major treatment advances will be experienced before 2009/10. The only drugs that had looked likely to reach the market before then were Boehringer Ingelheim's tipranavir and Pfizer's capravirine. While tipranavir was approved by the FDA in June 2005, Pfizer has discontinued development of capravirine.

Preclinical studies of capravirine seemed promising, indicating a unique resistance profile, with potent antiviral activity against different strains of HIV. However, the drug's clinical development proved complex, with trials being suspended in 2001 after an animal toxicology study showed that high-dose administration was associated with an inflammation of the blood vessels.

Problems with toxicity

Rather than abandon capravirine's development, Pfizer elected to conduct additional safety trials to evaluate its safety profile at doses matching those administered to humans. However, phase II efficacy data plunged the future development of the drug into doubt, as it was shown that there was no statistically significant difference in the rates of treatment failure between capravirine and placebo.

Prior to Pfizer's withdrawal of capravirine, research by Datamonitor had found that, overall, few physicians were enthusiastic about the drug.

"I think it's got activity, but the weaknesses are [that] it's got be dosed with ritonavir," says a opinion leader. "The data wouldn't support its use. I think the other strength is it's been shown in vitro at least to have activity against resistant virus. Another weakness is we don't have a true resistance profile for capravirine. I really don't think it's going to go forward."

A German opinion leader commented: "The weakness of capravirine is that it does not have a very good toxicity profile and the even bigger weakness is that it doesn't add antiviral efficacy of any convincing nature…the strength would be in vitro data suggesting that, in the presence of certain NNRTI mutations that it would possibly exert a significant antiviral effect, but that doesn't really come out of the data."

Race to the market

Given these data, the decision to return the rights to capravirine to Shionogi was unsurprising. Moreover, Pfizer has a second developmental antiretroviral, maraviroc, which could potentially change the HIV treatment paradigm. Currently in a race with GSK's GW873140 and Schering-Plough's SCH-417690 to be the first CCR5 inhibitor to reach the market, the outlook for maraviroc is considerably brighter than capravirine. Indeed, Datamonitor forecasts that the CCR5 inhibitors could generate between $700-800 million by 2015.

Maraviroc is currently in Phase III clinical trials, which compares favorably to GW873140 and SCH-417690 which are in Phase II studies. Datamonitor's research found that, in the absence of any real product differentiators, a key success factor will be the market entry status of the CCR5s, with the first to market gaining the greatest market share. As such, maraviroc looks well-positioned to continue Pfizer's foray into HIV therapy.

"Which one is going to best, I don't know. And they're all going to come out around the same time. I think the answer to which one wins is which one gets out first. It's likely that the results are going to be very similar between all of them," concludes a opinion leader.