Renal toxicity concerns failed to keep Gilead Sciences Inc.’s HIV treatment Quad from sailing through an FDA advisory committee review May 11. Although the panel rendered a lopsided vote in favor of approval, it nevertheless suggested a variety of areas for post-marketing study to better define the four-in-one, fixed-dose combination’s efficacy and safety profile.

In a 13-1 vote, the Antiviral Drugs Advisory Committee said the available data support approval of Quad (elvitegravir/cobicistat/emtricitabine/tenofovir) as a complete regimen for treatment of HIV-1 infection in treatment-naïve adults.

Panel members generally said efficacy had been demonstrated and the potential renal toxicities associated with two of the drug’s components, tenofovir and cobicistat, were real but could be managed with enhanced renal monitoring.

“I thought this was a more convenient combo containing a new mechanism of action component with demonstrated efficacy,” committee member Jeffrey Glenn, Stanford University, said.

The lone dissenting vote was one of the panel’s two nephrologists, temporary voting member Michelle Estrella, Johns Hopkins University, who said she would have liked to have seen more and longer-term safety data, particularly on renal effects, and more clinical data in women.

Assessing the best means for detecting early renal injury related to Quad was one of several areas recommended by the panel for further study post-approval. Committee members also called for more studies on drug-drug interactions and use in combination with other HIV treatments.

Unique Place In HIV Drug Regulation

Given the panel’s overwhelming endorsement, Quad appears on track to hold a unique place in the history of HIV drug regulation.

All currently available, fixed-dose combination treatments for HIV were approved on the basis of demonstrating bioequivalence to the individual component drugs taken together and after approval of the individual drugs, FDA Division of Antiviral Products Medical Team Leader Linda Lewis told the committee. In contrast, the Quad four-drug combination was submitted for FDA review before the single-drug NDAs for the combination’s two novel components, the integrase strand-transfer inhibitor elvitegravir and the “boosting” agent cobicistat.

FDA appeared to harbor no major efficacy concerns about Quad – as evidenced by the fact that discussion of the Phase III efficacy results amounted to only two of 50 slides in the FDA clinical reviewer’s presentation at the meeting.

In two similarly designed Phase III studies, Quad was shown to be non-inferior to Gilead/Bristol-Myers Squibb Co.’s Atripla (efavirenz/emtricitabine/tenofovir) and atazanavir/ritonavir plus Gilead’s Truvada (emtricitabine/tenofovir) Also see "Renal Safety In The Spotlight At FDA Panel Review Of Gilead’s Quad" - Pink Sheet, 9 May, 2012..

Safety, particularly renal effects, was the primary focus of FDA’s background briefing document and the agency’s presentation at the committee.

Tenofovir has been associated with adverse renal effects. Gilead asserts that cobicistat can cause a modest elevation in serum creatinine and a decrease in estimated creatinine clearance due to inhibition of tubular creatinine secretion. However, the company maintains that actual glomerular filtration rate is not affected.

FDA clinical reviewer Adam Sherwat discussed data from the pooled Phase III studies, in which eight subjects receiving Quad discontinued study drug due to renal AEs, four of whom developed proximal renal tubular dysfunction. He also presented high-level safety data from a Phase III trial of single-ingredient cobicistat, in which five subjects receiving the investigational drug experienced proximal tubulopathy.

Gilead proposed various measures aimed at reducing the renal risks associated with Quad use. These included assessing creatinine clearance in all patients prior to starting therapy and not initiating treatment in patients with creatinine clearance below 70 mL/min. Routine monitoring of creatinine clearance and serum phosphorous should be performed during therapy in patients with renal impairment or at risk for renal impairment, Gilead said in its background briefing document.

The company said confirmed increases in serum creatinine of >0.4mg/dL should require close monitoring because cobicistat causes expected increases in serum creatinine <0.4 mg/dl.="" furthermore,="" therapy="" should="" be="" discontinued="" in="" patients="" for="" whom="" the="" estimated="" gfr="" rate="" falls="" below="" 50="" ml/min,="" and="" concurrent="" use="" of="" nephrotoxic="" drugs="" should="" be="">

FDA suggested additional renal monitoring measures may be warranted.

Sherwat said consideration should be given to extending renal monitoring to all Quad patients because in the Phase III studies it was not possible to wholly predict who would develop proximal tubulopathy based solely on risk factors. Furthermore, HHS guidelines recommend renal laboratory monitoring for all patients receiving tenofovir.

Monitoring of urine protein and glucose levels by dipstick testing also should be considered, Sherwat said. HHS guidelines currently recommended such testing every six months for all patients receiving tenofovir and more frequently for patients with increased risk of renal insufficiency, he said.

Unlike creatinine measurements, urine protein and glucose measurements would not be confounded by cobicistat’s impact on creatinine secretion, Sherwat said, and abnormal glucose and protein findings were shown to pre-date drug discontinuation due to tubulopathy in the Phase III trials.

Detecting Renal Injury Early

Nephrologists on the panel stressed the importance of detecting renal toxicities early, and they generally supported FDA’s proposal that renal function be monitored for all patients, not just for those with renal impairment or at risk for impairment. They also suggested that additional renal function tests, such as assessments of protein and glucose levels in the urine, could be helpful for getting ahead of adverse renal effects.

One of the nephrologists, temporary voting member Lawrence Hunsicker, University of Iowa, said post-marketing studies should evaluate the best means for detecting renal injury early. “The earlier that you can detect this tubulopathy, the more likely it is that you’re going to be able to discontinue the drug soon enough to avoid any real permanent damage,” he said.

He also called for longer-term follow-up in post-marketing studies on renal and bone parameters because major adverse effects associated with proximal tubulopathy will be reflected in the skeleton. Gilead also should investigate possible genomic markers that may predispose individuals to the risk of proximal tubulopathy when using Quad, he said.

Committee members proposed additional post-marketing studies on drug-drug interactions, including oral contraceptives and hepatitis C drugs. Studies also should look at use of Quad with salvage drug regimens in treating HIV.

Panelists called for more studies in women given that the two Phase III trials enrolled a low percentage of females (ranging from 8%-12% across study arms). Gilead said it is planning to conduct a study in 510 treatment-naïve women. The company also is running a trial in renally impaired patients.

Quadzilla’s A Good Name

One committee member could not resist turning the discussion about post-marketing studies into a comment about the lack of an official brand name for Quad, which is the unofficial nickname for the four-in-one product.

“I think you need a study to figure out what you’re going to call this thing,” committee member Thomas Giordano, Michael E. DeBakey VA Medical Center, said, to laughter in the meeting room. “Do you have a name? If you don’t, I propose Quadzilla.”

Gilead’s Quad Makes It Through FDA Panel Review Despite Renal Safety Concerns

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