Staff Writer

The second pivotal Phase III trial (Study 103) of the HIV Quad regimen (elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate) under development by Gilead Sciences Inc. met the expectations of the company and most analysts by demonstrating noninferiority – though not superiority – at week 48 compared to ritonavir-boosted atazanavir plus Truvada (emtricitabine/tenofovir disoproxil fumarate).

The findings, based on the proportion of patients who achieved HIV viral load of less than 50 copies/mL, will propel Quad to a new drug application filing by year-end – ahead of schedule, according to officials at Foster City, Calif.-based Gilead.

The company plans to request a priority review for Quad, which could allow for FDA approval in mid-2012.

Quad contains the four Gilead compounds in a once-daily, single-tablet regimen. If approved, it would represent the first HIV single-tablet regimen containing an integrase inhibitor.

Two studies in the Phase III program for Quad are evaluating the regimen vs. a standard of care among HIV-1 infected antiretroviral treatment-naïve adults.

Designed as a randomized, double-blind trial comparing the efficacy, safety and tolerability of Quad vs. ritonavir-boosted Reyataz (atazanavir, Bristol-Myers Squibb Co.) plus Truvada over a 96-week period, Study 103 is being conducted at 210 sites in North America, South America, Europe and Asia. Eligible participants are HIV-infected treatment-naïve adults with HIV RNA levels greater than or equal to 5,000 copies/mL.

Trial participants were randomized (1:1) to receive Quad (n = 353) or ritonavir and atazanavir plus Truvada (n = 355).

The study's primary endpoint analysis indicated that 90 percent of patients in the Quad arm compared to 87 percent in the ritonavir-boosted atazanavir plus Truvada arm (95 percent CI for the difference: -1.9 percent to 7.8 percent) achieved HIV RNA of less than 50 copies/mL through week 48.

The predefined criterion for noninferiority was a lower bound of a two-sided 95 percent CI of -12 percent, according to Norbert Bischofberger, Gilead's executive vice president of research and development and chief scientific officer, who outlined the results during a conference call with investors Monday afternoon.

"To our knowledge, the 90 percent response rate in the Quad arm is the highest reported to date in any large randomized Phase III clinical study of an antiretroviral regimen, and it speaks to the potency, safety and tolerability of an integrase-based single-tablet regimen," Bischofberger said.

The discontinuation rate due to adverse events was higher in the ritonavir-boosted atazanavir arm (5.1 percent) compared to Quad (3.1 percent), driven largely by elevated bilirubin levels observed in the ritonavir-boosted atazanavir arm. Other adverse events and laboratory abnormalities were similar between the two arms.

Top-line data from Study 103 mirror those reported for Study 102 – a randomized, double-blind trial comparing Quad to the company's Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg). Gilead reported last month that Study 102 met its primary objective of noninferiority at week 48. (See BioWorld Today, Aug. 16, 2011.)

Bischofberger and the company's president and chief operating officer, John Milligan, did not provide additional details or take questions during the conference call, citing plans to submit the Study 103 data for presentation at an undisclosed scientific conference early next year. The company also declined a request from BioWorld Today for additional comment on the study findings and Quad's positioning in the HIV landscape.

However, Milligan told investors the company would accelerate the timelines for studies in which patients are switched from regimens containing non-nucleoside reverse transcriptase inhibitors or protease inhibitors to Quad to determine benefits to patients. Those studies are scheduled to begin recruiting before year-end.

Speaking from the 2011 Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago, Milligan also said the company's single-tablet formulation Complera, (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) – the Atripla successor that was approved by the FDA last month – has enjoyed a "very positive" response from treating physicians. (See BioWorld Today, Aug. 12, 2011.)

Highlighting findings from a late-breaking poster presentation, Milligan said an open-label study of virologically suppressed HIV patients who had received Atripla for at least three months indicated that 100 percent of those switched to Complera maintained HIV RNA levels of less than 50 copies/mL at 12 weeks. Complera, dubbed Btripla, was well tolerated, Milligan added.

The results suggested that HIV patients can switch from a multidose to single-dose regimen without compromising their virologic response or interrupting their daily therapy, Milligan added.

Complera is considered only a bridge to Quad, which analysts see as the next potential blockbuster for Gilead, with projected annual sales of up to $4 billion.

Although some analysts indicated this summer they were seeking better than noninferiority from the Quad pivotal trials, most seemed satisfied with the top-line Study 103 results.

"We acknowledge some may have been hoping for a demonstration of statistically significant superiority in this second study," Brian Abrahams, analyst at Wells Fargo Securities LLC, wrote in a research update. "However, we believe the numerically favorable efficacy trends, along with potentially better tolerability versus Atripla and better tolerability/convenience versus PI-based regimens, will drive significant adoption. Additionally, we believe GILD will be able to further differentiate Quad through soon-to-be initiated switching studies, helping contribute to its future commercial success."

Cohen and Co. analyst Phil Nadeau predicted that Gilead's HIV business "will generate income following the expiration of the tenofovir patents."

With Gilead trading below the discounted cash flow value of its franchises, "we believe that its fundamentals are underappreciated by investors," Nadeau added, projecting shares to outperform the market by 15 percent to 20 percent over the next 12 months.

Voicing the only note of caution, Jefferies & Co. analyst Thomas Wei wrote that Quad's failure to show superiority to protease inhibitor Reyataz plus Truvada doesn't jeopardize FDA approval but does "open the door for competition from dolutegravir (GSK572)" – a next-generation integrase inhibitor from GlaxoSmithKline plc, of London, and Shionogi & Co. Ltd., of Osaka, Japan.

Although Study 103 will allow Gilead to seize some share from protease inhibitors, the Street may have overstated Quad's impact, Wei concluded.

Both Phase III Quad studies are continuing in a blinded fashion through 96 weeks, when secondary objectives of efficacy, safety and tolerability will be evaluated. Following week 96, patients will continue to take their blinded study drug until treatment assignments have been unblinded, at which point all patients will be given the option to participate in an open-label rollover extension and receive the Quad single-tablet regimen.

Gilead's shares (NASDAQ:GILD) closed Tuesday at $40.84, up 79 cents.