In June 2011, Gilead entered into an agreement with Janssen R&D Ireland for the development of a fixed-dose combination of cobicistat and the protease inhibitor darunavir. In October 2011, Gilead also announced an agreement with Bristol-Myers Squibb to develop a fixed-dose combination of cobicistat and atazanavir.
Gilead submitted a New Drug Application to FDA for cobicistat on June 28, 2012. On May 23, 2012, the company’s Marketing Authorisation Application for the product was validated for review by the European Medicines Agency (EMA). Cobicistat is also a component of the Quad, a complete single tablet regimen for HIV combining cobicistat with elvitegravir, emtricitabine and tenofovir disoproxil fumarate. The Quad is currently under U.S. and European regulatory review.
Gilead announced topline results for Study 114 on December 5, 2011.
About Study 114
Study 114 is a randomized, double-blind Phase 3 clinical trial comparing the efficacy and safety of cobicistat-boosted atazanavir versus ritonavir-boosted atazanavir, each administered with Truvada, over a 192-week period at more than 200 study sites in North America, South America, Europe and Asia Pacific. Eligible participants were 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 a once-daily regimen of cobicistat 150 mg, atazanavir 300 mg and Truvada (n=344) or ritonavir 100 mg, atazanavir 300 mg and Truvada (n=348).
The primary endpoint of the study is the proportion of patients achieving HIV RNA levels of less than 50 copies/mL at 48 weeks of treatment, as determined by the FDA-defined snapshot analysis. Secondary objectives evaluated the efficacy, safety and tolerability of the treatment regimens through 96 weeks of treatment.
At baseline, patients in the cobicistat and ritonavir arms had a median HIV RNA of 4.78 log
copies/mL and 4.84 log
copies/mL and mean CD4 cell count of 353 cells/mm
and 351 cells/mm
Mean increases in CD4 cell counts were 213 cells/mm
for cobicistat patients and 219 cells/mm
for ritonavir patients at 48 weeks (p=0.67). Virologic failure rates were low in both arms – 6 percent for patients receiving cobicistat and 4 percent for those receiving ritonavir. Drug resistance was also low – two patients developed an NRTI resistance mutation in the cobicistat arm, and none in the ritonavir arm.
Incidence of laboratory abnormalities (Grade 3-4) was similar in both arms of the study. Laboratory abnormalities (Grade 3-4) occurring in at least one percent of patients in either treatment arm included hyperbilirubinemia, creatine kinase, hematuria, ALT, AST, amylase, glycosuria, hyperglycemia, GGT and neutropenia. Only hyperbilirubinemia (65 percent in the cobicistat arm vs. 57 percent in the ritonavir arm, p=0.023) and creatine kinase (6 percent in both arms) occurred in more than 5 percent of patients in either arm.