Renal safety issues are expected to dominate at the Antiviral Drugs Advisory Committee’s May 11 review of Gilead Sciences Inc.’s Quad single-tablet HIV treatment regimen, given FDA reviewers’ concerns about the combined renal effects of two of the drug’s four components.

In briefing documents released on May 9, FDA raises concerns about the disproportionate number of renal adverse events and laboratory abnormalities in the pivotal trials attributable to two of Quad’s components, tenofovir and the novel boosting agent cobicistat. FDA seeks the committee’s views on Quad’s renal safety profile and whether Gilead’s proposed renal monitoring recommendations go far enough toward mitigating and preventing injury.

FDA briefing documents provide only a brief summary of the clinical efficacy results, an indication of the agency’s comfort level with the data.

Although FDA’s review documents raise no major questions about the four-drug combination’s efficacy, the agency does point to the need for further exploration on some issues, such as drug-drug interactions.

The agency also notes that the small percentage of females enrolled in the pivotal trials may have limited the ability to identify potential safety signals in this population.

Two Novel Agents Joined With Truvada

Gilead filed its NDA for Quad (elvitegravir/cobicistat/emtricitabine/tenofovir) on Oct. 27, 2011, seeking an indication for treatment of HIV-infected adults who are antiretroviral naïve or have no known substitutions associated with resistance to the individual component drugs Also see "Gilead Clarifies Quad Will Come First, Over Detailing For Triple Combo Complera" - Pink Sheet, 28 October, 2011..

Quad is not the proposed brand name but, rather, the moniker by which the four-in-one pill is widely known. If approved, Quad would become the first fixed-dose combination containing an HIV integrase strand-transfer inhibitor (elvitegravir) for use once daily in HIV treatment.

Quad contains two novel components – elvitegravir and the “boosting” agent cobicistat – and the dual nucleoside/nucleotide reverse transcriptase inhibitor backbone of emtricitabine and tenofovir (Gilead’s Truvada).

On May 10, the antiviral drugs committee will consider an HIV pre-exposure prophylaxis indication for Truvada, a meeting that is expected to focus on the Risk Evaluation and Mitigation Strategy elements needed to reduce the risk of viral resistance and encourage strict adherence to the recommended dosing schedule ([A#14120508003]).

FDA’s background briefing documents for the Quad meeting provide only a brief summary of the clinical efficacy results, suggesting the agency has a solid level of comfort with the data. In two similarly designed pivotal trials, Quad was deemed to be non-inferior on the primary endpoint of virologic success (HIV-1 RNA <50 copies/ml="" at="" week="" 48)="" against="" two="" currently="" available="" treatment="" regimens:="">Bristol-Myers Squibb Co.’s Atripla (efavirenz/emtricitabine/tenofovir) and atazanavir/ritonavir plus Truvada.

In Study 236-0102, 87.6% of Quad subjects had virologic success, compared to 84.1% of subjects receiving Atripla. In Study 236-0103, the virologic success rate in the Quad group was 89.5%, compared to 86.8% in the atazanavir/ritonavir plus Truvada group. In both studies, the Quad arm met the pre-specified non-inferiority margin of 12%.

Subgroup analyses revealed no substantive differences in efficacy based on gender, race, age, region, baseline HIV-1 RNA level or baseline CD4 count. However, the agency noted that the percentage of women enrolled across study arms was low, ranging from 8%-12%. In a general summary that appears later in the briefing document, FDA said: “Given the relatively small percentage of women enrolled, our ability to identify potential safety signals in this population may be limited.”

Turning to the issue of resistance, FDA said the Phase III studies helped to characterize the emergence of HIV-1 integrase and reverse transcriptase resistance in treatment-naïve subjects receiving Quad, but that more investigation in this area was needed. Patients failing treatment with Quad are likely to also be cross-resistant to raltegravir and other integrase inhibitors, and some patients failing Quad will fail with resistance to two classes of drugs, FDA said. Although cobicistat has no direct antiviral effect, “the suggestion of higher proportion of failure isolates with protease substitutions will require further evaluation.”

FDA review documents also touch on a potential drug-drug interaction with oral contraceptives, and they say the sponsor will need to address the potential for drug-drug interactions not previously evaluated, such as with the anti-addiction drugs methadone or buprenorphine/naloxone or the hepatitis C direct-acting antivirals boceprevir (Merck & Co. Inc.’s Victrelis) and telaprevir (Vertex Pharmaceuticals Inc.’s Incivek).

Renal Effects And Monitoring Recommendations

The bulk of FDA’s briefing document relates to safety, particularly renal effects, Gilead’s view on their cause and the company’s monitoring recommendations.

Gilead’s briefing documents note that tenofovir has been associated with renal effects, including renal failure, Fanconi syndrome, proximal renal tubulopathy and other events. Tenofovir-associated renal toxicity “is thought to be mainly due to an effect on proximal renal tubules,” the company said.

Cobicistat inhibits active tubular secretion of creatinine, thereby leading to small elevations in serum creatinine. However, the boosting agent does not affect glomerular function. Consequently, small increases in serum creatinine are expected after initiating Quad therapy, resulting in decreases of approximately 15 mL/min in estimated glomerular filtration rate but not actual GFR, according to Gilead.

The company has proposed several renal safety measures, including assessing creatinine clearance in all patients prior to starting therapy. Quad should not be initiated in patients with creatinine clearance below 70 mL/min, which was the cutoff used in the Phase III studies. Routine monitoring of creatinine clearance and serum phosphorous should performed during therapy in patients with renal impairment or at risk for renal impairment, and therapy should be discontinued in patients for whom the estimated GFR rate falls below 50 mL/min.

FDA’s review notes that the incidence of serious adverse events related to renal and urinary disorders was higher in the Quad group (0.4%) than in either of the comparator groups (both 0.0%) in the clinical trials. In the pooled Phase III studies, eight subjects receiving Quad discontinued study drug due to renal AEs, four of whom developed proximal renal tubular dysfunction. By comparison, there was one study discontinuation due to renal AE in the comparator group and no instances of proximal renal tubular dysfunction.

The frequency of probable proximal tubulopathy leading to study drug discontinuation was greater in the Quad pooled Phase III trials than might be expected solely due to tenofovir based on results of previous clinical trials of treatment-naïve patients that included tenofovir in the study treatment regimen, FDA said.

The agency also noted that overall incidence of graded creatinine elevations and graded proteinuria was higher in the Quad group than in either comparator arm.

The renal adverse events seen in the Phase III trials lead FDA to question whether “two discrete processes may be at work: a non-pathologic decrease in eGFR as the Applicant maintains and a bona fide increased risk of renal dysfunction.”

“The disproportionate number of renal adverse events leading to study drug discontinuation (including proximal tubulopathies) in the EVG/COBI/FTC/TDF [Quad] group combined with a higher frequency of graded serum creatinine and urine protein abnormalities raise a question as to whether two discrete processes may be at work: a non-pathologic decrease in eGFR as the Applicant maintains and a bona fide increased risk of renal dysfunction,” FDA said. “The difficulty arises in assessing for and rapidly discriminating between these two events, as a modest elevation in creatinine and modest decline in eGFR is anticipated with the use of EVG/COBI/FTC/TDF, but prolonged use in the setting of renal injury should be avoided.”

Questions For The Panel

Acknowledging that Quad’s safety profile “was generally acceptable,” the agency nevertheless poses several safety-related questions to the committee.

In the first discussion question, the panel is asked to comment on Quad’s safety profile, “focusing on proximal tubulopathy and other renal adverse events leading to subject discontinuation.”

The second question is the day’s only one requiring a vote, and it asks whether the available data support approval.

The third question asks the committee to discuss whether there are additional measures, beyond those proposed by Gilead, needed to improve renal safety in patients receiving Quad. It specifically asks for comment on three bullet points:

“Would additional laboratory monitoring (e.g. urine dipstick testing for protein and glucose) potentially improve renal safety? Does use in patients with baseline glycosuria and proteinuria warrant separate recommendations?
“Would renal safety be enhanced by monitoring renal function in all patients as opposed to only patients with renal impairment or at risk of renal impairment?
“Should laboratory cutoffs be provided to help distinguish the effect of cobicistat on serum creatinine and creatinine clearance from genuine renal dysfunction? If yes, please comment on specific parameters, including, but not limited to the Applicant’s current proposal.”

Finally, FDA asks the panel to comment on any post-marketing studies needed to further define the risks or optimal use of Quad.

Renal Safety In The Spotlight At FDA Panel Review Of Gilead’s Quad

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