Why Vicriviroc Failed in Its Phase 3 Trials -- and What It May Mean for Future Studies in HIV Treatment-Experienced People

The morning here in San Francisco brought several of the most eagerly anticipated study presentations of the conference, at least for those interested in developments on the antiretroviral therapy front. I'll keep my entries on these studies relatively light on the data and follow up (either in this blog or elsewhere within our CROI coverage) with more detailed info (and hopefully the slides themselves) later on.

Joseph Gathe, M.D., recapped key phase 3 data from the VICTOR studies, which attempted to assess the safety and efficacy of the CCR5 antagonist vicriviroc when added to "optimized background regimens," or HAART regimens consisting of already-approved drugs that a patient receives based on established criteria for resistance, adverse effects and the like. A total of 721 treatment-experienced patients were involved in this 48-week analysis; they were randomized to receive either an optimized background regimen along with vicriviroc or an optimized background regimen alone.

Bottom line: There were similar rates of treatment discontinuations, virologic suppression, CD4+ cell count gain and adverse events across both arms. In a non-inferiority study, this would be lovely news. But in this case, vicriviroc essentially was unable to show that it added anything worthwhile to the regimens that are already used to treat HIV in treatment-experienced people. And that's why, late last month, Merck & Co., Inc. announced that it would suspend its attempts to win U.S. Food and Drug Administration approval for vicriviroc in treatment-experienced patients, but would continue in its attempts to develop the drug for first-line therapy.

The critical issue with vicriviroc, according to Gathe, was not that the drug itself wasn't potent enough. It was that the optimized background regimens were just too damn good, thus diluting the ability for the trial to see whether vicriviroc could add anything to them. He noted that, among study participants who had three or more active drugs in their background regimen (meaning drugs that were actively suppressing HIV), there was virtually no difference in terms of virologic efficacy between the vicriviroc arm and the non-vicriviroc arm. However, when participants had two or fewer active drugs in their background regimen, vicriviroc suddenly shined: 70% of those receiving vicriviroc achieved viral suppression, compared to 55% of those who received only their optimized background regimen. Since 64% of study participants had three or more active background drugs, Gathe argued that vicriviroc's antiretroviral capabilities were overshadowed by those already-effective regimens.

If you concur with Gathe's logic, these findings raise a disturbing conundrum for the future development of new antiretroviral options for HIV treatment-experienced people. If we've reached a point where we're blessed to have a large number of drugs that (when used in combination) are highly effective at suppressing HIV, how do we gauge the value of new drugs coming through the pipeline? Do we need to redefine success in these trials? Should researchers go out of their way to enroll only people who are seriously running low on their treatment options (and is such a thing even realistic for crafting a study with enough participants to be considered trustworthy)? Should they dare to consider the ethically stinky prospect of withholding "fully optimized" background therapy in a trial to make it easier to gauge the ability of an investigational drug to help heavily treatment-experienced people? Or do we accept that we've reached a saturation point with our current crop of antiretrovirals, and demand a higher bar for efficacy before adding any new drugs to the armamentarium?