Cobicistat

Gilead Sciences is conducting human studies of a product that could replace ritonavir as an antiretroviral boosting agent in some fixed-dose combinations. Cobicistat, formerly known as GS 9350, is a once-daily, heat-stable compound that can be coformulated with other agents including tenofovir and Gilead’s integrase inhibitor elvitegravir (which, at present, must be boosted with ritonavir to maintain high blood levels).

The advantage of cobicistat is that it enhances pharmacokinetics and does not in itself have antiviral effects. It would not be expected to have the metabolic side-effects found with ritonavir use.

A phase I dose-ranging study has evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of escalating single and multiple doses of the drug in healthy volunteers. Gilead has co-formulated cobicistat in a 'quad' pill with its investigational integrase inhibitor elvitegravir and its co-formulation of tenofovir and emtricitabine (Truvada). Two phase II clinical trials are now evaluating cobicistat and the quad pill formulation in treatment-naive individuals.^1,2,3

Phase II Study 216-0105 found cobicistat comparable to ritonavir as a boosting agent for atazanavir (Reyataz). Treatment-naive participants began taking either 150mg cobicistat or 100mg ritonavir (Norvir), combined with tenofovir/emtricitabine (Truvada) and atazanavir. At 24 weeks, 84% of people taking cobicistat and 86% of those taking ritonavir had viral loads below 50 copies/ml. A similar proportion of people in both arms dropped out early (8 vs 10%, respectively).

Phase II Study 236-0104 randomly assigned participants to one of two combination regimens. One was the new quad pill, containing elvitegravir with cobicistat as a booster, plus tenofovir (Viread) and emtricitabine (Emtriva). In the comparator arm, participants received the Atripla pill containing efavirenz (Sustiva, Stocrin) plus tenofovir and emtricitabine.

After 24 weeks, 90% of participants in the quad group and 83% in the Atripla group reached a viral load below 50 copies/ml, according to an intent-to-treat analysis. Although not designed to be a non-inferiority trial, the study did show that the quad pill was non-inferior to Atripla.

CD4 cell count increases were similar in both arms in both studies. The major concern with cobicistat was a small increase in blood creatinine levels, a sign of possible kidney impairment. Creatinine rose by 0.14 mg/dl with the quad pill vs 0.04 mg/dl with Atripla in Study 236-0104.

Gilead expects to move into Phase III trials of cobicistat and the quad pill later this year. Co-formulation deals with other companies could potentially include Bristol Myers-Squibb’s atazanavir (Reyataz) and Tibotec’s darunavir (Prezista), if once-daily dosing of darunavir with cobicistat boosting proves successful.