May 11, 2012
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FDA Advisory Committee votes in favor of four-drug preventive HIV tablet

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The FDA Antiviral Drugs Advisory Committee voted 13-1 in favor of a new drug application for a fixed-dose combination tablet of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate.

The application was submitted by Gilead Sciences and came in the wake of results of two ongoing phase 3 trials: GS-US-236-0102 and GS-US-236-0103.

These studies assessed the non-inferiority of the tablet compared with emtricitabine/tenofovir/efavirenz (Atripla, Gilead; study 236-0102) and atazanavir/ritonavir plus dual nucleoside/nucleotide reverse transcriptase inhibitor backbone (Truvada; study 236-0103). Noninferiority was measured using the FDA-approved margin of 12%.

Trial results

In trial 236-0102, the study drug was linked to an 87.6% virologic success rate compared with an 84.1% rate among those randomly assigned Atripla. In study 236-0103, the study drug was associated with an 89.5% virologic success rate vs. an 86.8% rate among patients receiving Truvada.

The application is for an indication in patients with HIV-1 who are treatment-naive and/or have no known resistance to the individual components of the combination tablet.

Primary efficacy endpoint was the proportion of patients with HIV-1 RNA viral loads of less than 50 copies/mL at 48 weeks, which was defined as virologic success. The researchers used an FDA-defined snapshot analysis algorithm to determine the results.

Adverse event profiles indicated that “gastrointestinal disorders” — specifically, renal complications — and “psychiatric disorders” were the most common causes of discontinuation of the four-drug pill.

Renal complications

Because renal issues were the focus of much of the debate, Michelle M. Estrella, MD, MHS, assistant professor and associate fellowship program director of the nephrology division at Johns Hopkins University School of Medicine, and Lawrence G. Hunsicker, MD, professor of medicine and emeritus medical director of organ transplantation in the nephrology division at the University of Iowa College of Medicine, carried much of the debate.

Estrella was the lone nay vote. “At this point in time, there are plenty of alternatives to the drug for the treatment of treatment-naive individuals,” she said. “Most of the data reporting on safety profile were within 48 weeks of follow-up, while the renal toxicity we saw was beyond 48 weeks. There is no huge hurry in approving this drug until outstanding studies are completed.”

Estrella said women and those at risk for chronic renal disease were under-represented in the study population, and she would like to see data that account for those demographic concerns.

Hunsicker voted in favor of the approval, but also expressed concerns about renal toxicity: “The evidence for efficacy is strong,” he said. “The toxicities are related largely to Truvada, which is part of many other regimens anyway. The addition of the other drugs doesn’t add substantially to the toxicity. But, I do believe we need to do further studies.”

Most of the other panelists cited strong efficacy results as the reason for an affirmative vote.

Yoshihiko Murata, MD, PhD, assistant professor of medicine in the division of infectious diseases at the University of Rochester School of Medicine and Dentistry, served as acting chair of the committee. He summarized the areas where further study or monitoring is needed.

“Regarding whether additional laboratory monitoring would improve renal safety, our renal colleagues (Estrella and Hunsicker) said that the specific measures would need to be studied,” he said. “We had an emphatic ‘yes’ regarding monitoring renal function in all patients.”

Hunsicker said, specifically, that early detection of tubulopathy is the most important strategy for monitoring renal complications.

Several panelists suggested areas where further study could be improved. Most said longer-term follow-up is necessary, along with studies involving more women, studies with renal and bone parameters and studies investigating drug-drug interactions between the four-drug tablet and other ART medications.

In a final summary of the discussions, Murata said drug-drug interactions with anti-hepatitis C virus medications should be evaluated, along with protease inhibitor resistance and metabolic profile changes while on therapy.

Although the FDA is not required to take the advice of the advisory committee, it usually does.