A favorable adverse event profile in two head-to-head trials with other HIV treatment regimens could help Gilead Sciences Inc.’s four-active-ingredient HIV treatment Quad (elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate) in its review by FDA's Antiviral Drugs Advisory Committee May 11, and in marketing if the drug is approved.

Quad has two unapproved ingredients; cobicistat is a novel boosting agent and elvitegravir is an investigational integrase inhibitor. But the one-to-one randomized, blinded, active-controlled design of the two pivotal Phase III trials, both of which are meant to show non-inferiority, is as orthodox as can be in this field. The comparator in one of the trials, Gilead’s own Atripla (efavirenz, emtricitabine and tenofovir disoproxil fumarate) was approved by FDA in July 2006 on the basis of a non-inferiority study Also see "Atripla Approved As First Once-Daily, Single-Tablet HIV Therapy" - Pink Sheet, 12 July, 2006..

Gilead's comments at the time of the NDA filing of Quad last year suggest that if FDA approves it, the company's recently approved triple combination Complera (emtricitabine, tenofovir and rilpivirine), for which it partnered with Johnson & Johnson’s Janssen R&D Ireland, will wind up with lower priority while marketing for Atripla will cease Also see "Gilead Clarifies Quad Will Come First, Over Detailing For Triple Combo Complera" - Pink Sheet, 28 October, 2011..

In HIV treatment, side effect and resistance profiles are pivotal to product differentiation, so the better adverse event profile vis-à-vis Atripla and the comparable AE profile versus atazanavir/ritonavir plus emtricitabine/Tenofovir combination should help Gilead promote the drug.

Strong Phase III Results

Results from the two pivotal Phase III studies were presented at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle earlier this month, and the abstracts are available online. In the first trial, Study 102, Quad was compared with Atripla as initial therapy for HIV infection in 700 treatment-naïve HIV subjects, who were randomized 1:1 to Quad or Atripla once daily, plus matching placebos. The primary endpoint was the proportion of subjects with HIV RNA of less than 50 copies/mL at week 48, per the FDA snapshot algorithm (with a 12% pre-specified non-inferiority margin).

This endpoint was met, with Quad proving non-inferior to Atripla, in that 88% and 84% of subjects, respectively, had viral suppression at week 48 by snapshot algorithm (difference +3.6%, 95% CI: -1.6% to +8.8%). Response rates were similar among subjects with baseline HIV RNA of more than 100,000 copies/mL (Quad 84%, Atripla 82%).

Drug discontinuation rates for adverse events were similar in the two arms: 3% for Quad and 5% for Atripla. Nausea was significantly more frequent in Quad than in Atripla (21% vs. 14%), but dizziness (7% vs. 24%), abnormal dreams (15% vs. 27%), insomnia (9% vs. 14%), and rash (6% vs. 12%) were significantly less common in Quad, as were total cholesterol and LDL increases at week 48.

In Study 103, which is still ongoing, 708 treatment-naïve HIV-1+ subjects were randomized 1:1 to receive either Quad or atazanavir/ritonavir plus emtricitabine/tenofovir. Primary endpoints were safety and the proportion of subjects with HIV RNA at less than 50 copies/mL at week 48 (FDA snapshot algorithm, 12% pre-specified non-inferiority margin) in the intent-to-treat population.

Again, the primary objective was met; Quad was non-inferior to the comparator, with 90% and 87% of subjects, respectively, having HIV RNA of less than 50 copies/mL at week 48 (difference +3.0%, 95% CI: -1.9% to 7.8%). Among subjects with HIV RNA of 100,000 or more copies/mL, response rates were similar (Quad 85%, comparator 82%).

Discontinuation rates for adverse events were similar at 4% for Quad and 5% for the comparator. Adverse events associated with elevated bilirubin levels were significantly higher in the comparator, and no adverse event that occurred in 5% or more of subjects was significantly higher in Quad. In both trials, Gilead took care to recruit minorities (37% non-white subjects in Study 102 and 26% in Study 103).

The user fee deadline is Aug. 27, following a standard review period although the company had requested priority status.

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