FDA Panel Recommends Approval of Quad Regimen


"The FDA's Antiviral Drugs Advisory Committee agreed with the efficacy outcome, and there was little discussion or debate on the efficacy of Quad."

The FDA Antiviral Drugs Advisory Committee (AVAC) voted 13 to 1 in favor of approval for Gilead Inc.'s single-tablet Quad regimen (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) for treatment-naive adult patients with HIV-1 Friday after a daylong deliberation that exhaustively examined the issue of renal impairment.

The AVAC voted Thursday in favor of approving Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP), and Gilead convinced the panel to give the Quad regimen a thumbs' up, as well. (See BioWorld Today, May 11, 2012.)

"Do you have a name for this, yet?" asked committee member Thomas P. Giordano, medical director of HIV Services for the Harris County Hospital District in Houston. "Because I suggest Quadzilla."

The committee closely scrutinized safety data, particularly with respect to renal function, at times deconstructing the data patient by patient to drill down on the exact causes of those adverse events.

In addition to the components of Truvada, Quad also includes elvitegravir (EVG) and cobicistat (COBI). EVG is an inhibitor of HIV integrase strand transfer that prevents the virus from inserting its genetic material into the host cell genome. COBI, a new chemical entity, is a structural analogue of ritonavir that inhibits cytochrome P450 3A (CYP3A), boosting exposure of CYP3A substrates, such as EVG.

Gilead's application is based on 48-week safety and efficacy data from studies designated GS-US-236-0102 and GS-US-236-0103 (informally known as 102 and 103). The studies were virtually identical in design and produced very consistent results. Both have a goal of showing non-inferiority of the Quad regimen using a margin of 12%.

Study 102 is an ongoing, phase 3, randomized, double-blind, double-dummy, active-control trial of Quad versus Gilead's Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) in HIV-1 infected adults naive to antiretroviral therapy (ART).

In Study 103, a phase 3, randomized, double-blind, double-dummy, active controlled trial, Gilead is comparing Quad to atazanavir/ritonavir (ATV/r) plus Truvada in HIV-1 infected ART-naive adults. Study 102 is being carried out in the U.S. and Puerto Rico, and Study 103 is being run at international sites.

In trial 102, the Quad regimen showed 87.6% virologic success compared to 84.1% of subjects in the ATR group. In trial 103, 89.5% of subjects on Quad had virologic success compared to 86.8% of subjects in the ATV/r + TVD group. Both studies met the non-inferiority margin of 12%.

Efficacy Wasn't at Issue

The AVAC agreed with the efficacy outcome, and there was little discussion or debate on the efficacy of Quad. More compelling, however, were questions surrounding the discontinuation of treatment of 11 patients due to renal complications. Adverse events in that category included Fanconi syndrome, renal failure, increased blood creatinine, proteinuria and nocturia.

Because there was no clear explanation for those renal complications, the committee recommended monitoring patients for kidney complications at least every six months.

Nephrology expert Lawrence G. Hunsicker, emeritus medical director of organ transplantation for the University of Iowa College of Medicine, pointed out that reduction of renal filtration was not the only possible adverse effect of renal tubulopathy, which affected four patients. He said there would also be phosphate wasting and impairment of vitamin D metabolism and other changes that would most likely turn up in the bone.

"The focus should be not just on renal insufficiency, but the bone effects of this drug," Hunsicker said. "The earlier you can detect this tubulopathy, the more likely it is you'll be able to discontinue it soon enough to avoid permanent damage."

Early detection is important, he said, because drugs that adversely affect the kidneys are frequently also excreted by the kidneys, so as renal function is lost, the drug builds up in the system and exposure is increased.

If there was consensus on the need for renal monitoring and early detection, there was an equal lack of clarity on how best to carry out that monitoring.

Gilead proposed assessment of creatinine clearance (CrCl) before treatment initiation, with a required minimum of 70 mL/min, plus routine monitoring and discontinuation of treatment if the CrCl falls below 50 mL/min. Gilead also suggested that Quad not be given with concurrent or recent use of nephrotoxic drugs.

Hunsicker, however, disputed that CrCl would be adequate. "I'm not sure that looking at creatinine, or dipstick proteinuria is the best way to do this. I don't have a clear suggestion."

The outcome of that discussion however, was general agreement that the culprit in renal complications was likely tenofovir, a component of Truvada that is already being used and dealt with in the clinic, and that the need for better methods of detecting renal tubulopathy should not be an obstacle in approving Quad.

There were questions, also, about drug-drug interactions, most of which could not be answered by Gilead at the current time. Gilead found that Quad interacts with Ortho Tri-Cyclen Lo (norgestimate and ethinyl estradiol), increasing exposure to norgestimate, and decreasing exposure to ethinyl estradiol. The company has plans for future studies to address interactions with other drugs.

The committee ultimately voted nearly unanimously in favor of approval, having been convinced of the efficacy and safety of Quad. The sole vote against came from Michelle M. Estrella, program director for the nephrology division of Johns Hopkins University School of Medicine.

"There are plenty of alternatives to Quad," Estrella said, "And enough questions with regard to ongoing studies in terms of safety profile that led me to my decision."

Estrella expressed concern that there may be more toxicities beyond the 48-week term of the studies, and that there was "no huge hurry" to approve the drug until ongoing studies were completed.

Estrella also objected to the low representation of women in the study population, which was overwhelmingly male (88% to 92%).

The committee vote was no surprise, and had little effect on Gilead's stock (GILD: NASDAQ). The stock rose $0.59, to close at $51.84 Friday.

"The AdCom vote for approval is in line with consensus," wrote Mark Schoenebaum, an analyst with ISI Group, "and we continue to expect (despite the focus on the kidney effects of the Quad) that the FDA will follow the recommendations of the AdCom and approve the Quad."

Schoenebaum added that even though the approval would be limited initially to treatment-naive patients, the consensus numbers were still achievable, and kidney monitoring requirements would not be an undue burden.

Catherine Shaffer

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