Gilead ’s Quad single tablet regimen for HIV non-inferior to Atripla® in pivotal Phase 3 study

Gilead Sciences, Inc. (Nasdaq: GILD) today announced full Phase 3 clinical trial results from pivotal Study 102 demonstrating that the Quad, a once-daily single tablet regimen of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate for the treatment of HIV-1 infection, is non-inferior to Atripla®(efavirenz/emtricitabine/tenofovir disoproxil fumarate) after 48 weeks of therapy in treatment-naïve adults. Atripla is currently the most-prescribed HIV treatment regimen in the United States. The Study 102 findings were presented today in an oral session (Abstract #101) at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) taking place in Seattle.

“These data show that the Quad is as effective as a current standard of care in HIV therapy. The safety profile of Quad was also comparable to that of Atripla, and was better tolerated in terms of key neurological side effects,” said Paul Sax, MD, Clinical Director of the HIV Program and Division of Infectious Diseases at Brigham and Women’s Hospital, Boston, and principal investigator of Study 102. “Based on these results, I believe the Quad could represent a potentially important new treatment regimen for a wide range of HIV patients initiating therapy.”

The study found that at 48 weeks of treatment, 88 percent of Quad patients compared to 84 percent of Atripla patients achieved HIV RNA (viral load) less than 50 copies/mL, based on the U.S. Food and Drug Administration (FDA) snapshot algorithm (95 percent CI for the difference: -1.6 percent to +8.8 percent; predefined criterion for non-inferiority was a lower bound of a two sided 95 percent CI of -12 percent). While the frequency of grade 3-4 adverse events and laboratory abnormalities were comparable between study arms, the Quad demonstrated a lower incidence than Atripla with regard to central nervous system (CNS) side effects, lipids and rash. Discontinuation rates due to adverse events were comparable in both arms of the study.

The Phase 3 clinical program for Quad includes two studies (Studies 102 and 103) that each evaluate the Quad regimen versus a standard of care among HIV-1 infected antiretroviral treatment-naïve adults. Gilead announced topline results for Studies 102 and 103 on August 15, 2011 and September 19, 2011, respectively. Gilead submitted a U.S. New Drug Application for Quad on October 27, 2011, and the FDA has set a target review date under the Prescription Drug User Fee Act of August 27, 2012. On November 24, 2011, the company submitted a Marketing Authorisation Application for the product to the European Medicines Agency, whose review may be complete by the end of 2012.

Study 102

Study 102 is a randomized (1:1), double-blind Phase 3 clinical trial comparing the efficacy, safety and tolerability of the Quad (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (n=348) versus Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (n=352) among HIV-infected treatment-naïve adults with HIV RNA levels greater than or equal to 5,000 copies/mL. The primary endpoint of the study is the proportion of patients achieving HIV RNA levels less than 50 copies/mL at 48 weeks of treatment, per the FDA snapshot algorithm. Secondary objectives will evaluate the efficacy, safety and tolerability of the treatment regimens through 192 weeks of treatment.

At baseline, patients in the Quad arm had a median HIV RNA of 4.75 log10 copies/mL and mean CD4 cell count of 391 cells/mm3. Patients in the Atripla arm had a median HIV RNA of 4.78 log10 copies/mL and mean CD4 cell count of 382 cells/mm3. Across both arms, 33 percent of patients had HIV RNA greater than 100,000 copies/mL, and 13 percent of patients had CD4 counts less than or equal to 200 cells/mm3.

Among patients with baseline HIV RNA greater than 100,000 copies/mL, 84 percent and 82 percent of Quad and Atripla patients, respectively, achieved viral load less than 50 copies/mL based on the FDA snapshot algorithm. Mean increases in CD4 cell counts were 239 cells/mm3 for Quad patients and 206 cells/mm3 for Atripla patients (p=0.009). Virologic failure rates were equal (7 percent) in both arms.

Four percent of Quad patients and 5 percent of Atripla patients discontinued treatment due to adverse events. The most common adverse events occurring in greater than 10 percent of patients in either treatment arm included diarrhea, nausea, abnormal dreams, upper respiratory infections, headache, fatigue, insomnia, depression, dizziness and rash. Among adverse events occurring in at least 10 percent of patients, neuropsychiatric side effects were less common among Quad patients, including abnormal dreams (15 percent for Quad vs. 27 percent for Atripla), dizziness (7 vs. 24 percent) and insomnia (9 vs. 14 percent). Rash was also less likely to occur among Quad patients (6 percent for the Quad vs. 12 percent for Atripla). Nausea (mostly grade 1) was more frequent among Quad patients compared to Atripla (21 percent vs. 14 percent, respectively).

There was a similar incidence of laboratory abnormalities (grades 3-4) across both arms of the study. Laboratory abnormalities (grades 3-4) occurring in greater than five patients in either treatment arm included creatine kinase, AST, ALT, GGT, neutrophils, amylase and hematuria. Increases in total cholesterol and LDL were lower for the Quad (+10 mg/dL total cholesterol and +10 mg/dL LDL) compared to Atripla (+19 mg/dL total cholesterol and +17 mg/dL LDL) at week 48 (total cholesterol, p<0.001; LDL, p=0.001). The median increases in serum creatinine were 0.14 mg/dL for Quad and 0.01 mg/dL for Atripla.

Study 102 is ongoing in a blinded fashion. After week 192, subjects will continue to take their blinded study drug until treatment assignments have been unblinded, at which point all subjects will be given the option to participate in an open-label rollover extension and receive the Quad single tablet regimen. Additional information about the study can be found at www.clinicaltrials.gov.

About the Quad

The Quad contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir; cobicistat, a “boosting” agent that enables elvitegravir once-daily dosing; and Truvada®, which is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate.

Elvitegravir is an integrase inhibitor. Unlike other classes of antiretroviral agents, integrase inhibitors interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead’s agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights.

Cobicistat is Gilead’s proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. In addition to studying the agent as part of the Quad, Gilead is also examining cobicistat’s potential in boosting commercially available HIV protease inhibitors.

The Quad, elvitegravir and cobicistat are investigational products and their safety and efficacy have not yet been established.