Gilead Sciences announces Quad regimen Phase II clinical trial results for HIV infection treatment

Gilead Sciences, Inc. (Nasdaq:GILD) today announced Phase II clinical trial results showing that its investigational fixed-dose, single-tablet "Quad" regimen of elvitegravir, cobicistat and Truvada^® (emtricitabine and tenofovir disoproxil fumarate) for the treatment of HIV infection maintained a high rate of virologic suppression through 48 weeks, exhibiting antiretroviral activity comparable to that of Atripla^® (efavirenz 600 mg/emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg). At week 48, the proportion of patients who achieved HIV RNA (viral load) less than 50 copies/mL was 90 percent in the Quad arm and 83 percent in the Atripla arm (using an analysis where missing equals failure). These data are being featured in a late-breaker poster presentation today at the 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Boston (Abstract #H-938b).

“We are pleased with the robustness of these 48-week Phase II results as we continue to make rapid progress with our Phase III clinical program for the Quad”

The 48-week data from this Phase II study (Study 236-0104) extend the positive 24-week results announced in February 2010 at the Conference on Retroviruses and Opportunistic Infections (CROI). Safety, tolerability and discontinuation rates were similar between both arms of the study, but fewer central nervous system (CNS) adverse events, including abnormal dreams/nightmares, dizziness and anxiety were observed in patients receiving the Quad compared to those receiving Atripla.

"The advent of the single-tablet regimen helped advance the care of people living with HIV, but additional options are needed, particularly for those who experience side effects with existing drug combinations," said Richard Elion, MD, principal investigator and Clinical Research Director, Whitman-Walker Clinic in Washington, D.C. "These positive Phase II data suggest that the Quad could be an important new option for people with HIV."

Results from a separate study also being presented by Dr. Elion at ICAAC show that cobicistat-boosted atazanavir plus Truvada has similar efficacy and safety to ritonavir-boosted atazanavir plus Truvada at 48 weeks. Changes to estimated glomerular filtration rates observed among patients early in the study remained stable through week 48 and were comparable to the changes observed among patients receiving ritonavir. Gilead is continuing to study cobicistat as an alternative stand-alone boosting agent for other antiretroviral medications in addition to its role in the Quad.

"We are pleased with the robustness of these 48-week Phase II results as we continue to make rapid progress with our Phase III clinical program for the Quad," said Norbert W. Bischofberger, PhD, Gilead's Executive Vice President, Research and Development and Chief Scientific Officer. "Our first Phase III study of the Quad versus Atripla was recently fully enrolled, and the second study of the Quad versus a protease-based regimen is now closed for screening. We look forward to sharing the results of these two important pivotal studies in 2011."

The Quad Study 236-0104

Study 236-0104 is a double-blind, multicenter, randomized (2:1), active-controlled 48-week clinical trial evaluating the safety and efficacy of the Quad>3 at baseline. Weeks 24 and 48 are the primary and secondary time points, respectively, for efficacy, which is measured as the proportion of patients with HIV RNA less than 50 copies/mL. Secondary objectives include the safety and tolerability of the two treatment regimens through 48 weeks.

At baseline, study participants in the Quad arm had a mean viral load of 4.59 log₁₀ copies/mL and a median CD4 cell count of 354 cells/mm³. Patients in the Atripla arm of the study had a mean viral load of 4.58 log₁₀ copies/mL and a median CD4 cell count of 436 cells/mm³ at baseline.

At 48 weeks, 90 percent of patients in the Quad arm and 83 percent of patients in the Atripla arm achieved the study's primary objective of HIV RNA levels of less than 50 copies/mL, using an analysis where missing equals failure (difference in stratum-weighted response rate between Quad and Atripla = +8.4%; 95% CI: -8.8% to 25.6%). In addition, when using an analysis where missing values are excluded, 96 and 95 percent of patients in the Quad and Atripla arms, respectively, achieved HIV RNA levels of less than 50 copies/mL after 48 weeks.

Patients taking the Quad experienced a mean increase in CD4 cell count of 240 cells/mm³, compared to a mean increase of 162 cells/mm³ among Atripla patients at 48 weeks.

Discontinuation rates and adverse events were similar in both arms of the study. Three patients discontinued treatment in each arm of the study; one of them, an Atripla patient, discontinued treatment due to an adverse event (suicidal ideation), whereas no patients discontinued the Quad due to an adverse event. The rates of adverse events were similar between treatment arms, although fewer CNS adverse events were observed among Quad patients. The most commonly observed treatment-emergent adverse events occurring in greater than 5 percent of patients in either treatment arm were abnormal dreams/nightmares, fatigue, dizziness, diarrhea, somnolence, headache, anxiety, nausea, abdominal distension and rash. Two Grade 3 or 4 adverse events were reported among Quad patients (pneumonia and anogenital warts), and two among Atripla patients (B-cell lymphoma with lymphadenopathy and neutropenia).

There was a similar incidence of laboratory abnormalities (Grades 2-4) across both arms of the study. Laboratory abnormalities occurring in greater than 5 percent of patients in either treatment arm included hyperamylasemia, hypercholesterolemia, creatine kinase, neutropenia and proteinuria. Mean changes in cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were small and similar in both arms of the study.

Cobicistat Study 216-0105

Study 216-0105 is a double-blind, multicenter, randomized (2:1), active-controlled 48-week clinical trial evaluating the safety and efficacy of cobicistat-boosted atazanavir>3 at baseline. Weeks 24 and 48 are the primary and secondary time points, respectively, for efficacy, which is measured as the proportion of patients with HIV RNA less than 50 copies/mL. Secondary objectives include the safety and tolerability of the two treatment regimens through 48 weeks.

At baseline, study participants in the cobicistat arm had a mean viral load of 4.56 log₁₀ copies/mL and a median CD4 cell count of 341 cells/mm³. Patients in the ritonavir arm of the study had a mean viral load of 4.69 log₁₀ copies/mL and a median CD4 cell count of 367 cells/mm³ at baseline.

At 48 weeks, 82 percent of patients in the cobicistat group and 86 percent of those in the ritonavir group met the primary objective of achieving HIV RNA levels of less than 50 copies/mL, using an analysis where missing equals failure (difference in stratum-weighted response rate between cobicistat and ritonavir = -4.6%; 95% CI: -21.7% to 12.5%). In addition, when using an analysis where missing values are excluded, 91 and 96 percent of patients in the cobicistat and ritonavir arms, respectively, achieved HIV RNA levels of less than 50 copies/mL after 48 weeks.

Patients taking a cobicistat-boosted regimen experienced a mean increase in CD4 cell count of 230 cells/mm³, compared to a mean increase of 206 cells/mm³ among patients taking a ritonavir-boosted regimen at 48 weeks.

Discontinuation rates were similar between study arms. Two cobicistat patients discontinued treatment due to adverse events (vomiting and rash) as did one ritonavir patient (ocular icterus). The most commonly observed treatment-emergent adverse events occurring in greater than 5 percent of patients in either treatment arm were diarrhea, nausea, fatigue and flatulence. There were two Grade 3 or 4 adverse events among cobicistat-treated patients (hyperbilirubinemia and rash) and none among patients in the ritonavir arm.

There was a similar incidence of laboratory abnormalities (Grades 2-4) across both arms of the study. Laboratory abnormalities (Grades 2-4) occurring in greater than 5 percent of patients in either treatment arm included hyperbilirubinemia, hyperamylasemia, hypercholesterolemia, creatine kinase, hypophosphatemia and hematuria. Mean changes in cholesterol, LDL, HDL and triglycerides were similar in both arms of the study.

Small increases in serum creatinine (a value used to estimate kidney function) with cobicistat with resulting decreases in estimated creatinine clearance (by Cockroft-Gault) were observed at the early time points in the Phase II study, but stabilized through week 48 and were comparable to patients in the ritonavir arm. At 48 weeks, the mean increase from baseline in serum creatinine was 0.15 mg/dL among cobicistat patients and 0.13 mg/dL among ritonavir patients. The mean decrease in estimated glomerular filtration rate at 48 weeks was 13.3 mL/min and 13.8 mL/min among cobicistat and ritonavir patients, respectively.