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pharmacokinetic enhancer of atazanavir 300 mg once daily or darunavir 800 mg once daily as part of antiretroviral combination therapy in human immunodeficiency virus-1 (HIV-1) infected adults

* On April 21, 2014, Gilead Sciences has announced that the FDA has accepted the company’s refiling of two New Drug Applications (NDA) for cobicistat, a pharmacoenhancing or “boosting” agent that increases blood levels of the protease inhibitors atazanavir and darunavir to enable once-daily dosing of these medicines in HIV therapy, and elvitegravir, an integrase inhibitor for the treatment of HIV-1 infection in treatment-experienced adults. The FDA has set target review dates under the Prescription Drug User Fee Act (PDUFA) of October 3, 2014 for cobicistat and October 4, 2014 for elvitegravir. Gilead submitted NDAs for cobicistat and elvitegravir in June 2012. In April 2013, the company received Complete Response Letters from the FDA. In its communications, the agency stated that it could not approve the cobicistat and elvitegravir applications in their current forms, citing deficiencies in documentation and validation of certain quality testing procedures and methods that were observed during inspections. Gilead has worked with the FDA to address the questions raised in the Complete Response Letters.
Cobicistat and elvitegravir are components of Gilead’s Stribild® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), a once-daily single tablet regimen for the treatment of HIV-1 infection. Stribild was approved in the United States in August 2012.
Cobicistat is approved under the tradename Tybost® and elvitegravir is approved under the tradename Vitekta® in Europe, Canada and Australia.

* On September 25, 2013, Gilead Sciences has announced that the European Commission has granted marketing authorization for once-daily Tybost™ (cobicistat 150 mg tablets). Tybost™ is indicated as a boosting agent for the HIV protease inhibitors atazanavir 300 mg once daily and darunavir 800 mg once daily as part of antiretroviral combination therapy in adults with HIV-1 infection.  The EU approval of Tybost is supported by 48-week data from a pivotal Phase 3 study (Study 114), which found that Tybost was non-inferior to ritonavir when administered with an antiretroviral regimen of atazanavir plus Truvada® (emtricitabine 200 mg and tenofovir disoproxil (as fumarate) 245 mg) in HIV-infected treatment-naïve adults. Approval is also supported by pharmacokinetic data demonstrating that Tybost boosts blood levels of atazanavir and darunavir similar to ritonavir. Tybost should only be co-administered with atazanavir or darunavir. In Study 114, Tybost was well tolerated and most adverse events were mild to moderate. The most common adverse reactions (incidence greater than or equal to 10 percent, all grades) were jaundice, ocular icterus and nausea.

Tybost™ is a component of Gilead’s Stribild® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg), a once-daily complete single tablet regimen for the treatment of HIV-1 infection that was approved in the United States in August 2012 and in the European Union in May 2013. Gilead submitted a new drug application to the U.S. Food and Drug Administration (FDA) for Tybost as a single agent in June 2012 and received a Complete Response Letter in April 2013. Gilead is working on resubmitting the application to the FDA. Tybost is approved as a single agent in Canada.

* On 25 July 2013, the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the granting of a marketing authorisation for Tybost®, 150 mg, Film-coated tablet intended for use as a pharmacokinetic enhancer of the human immunodeficiency virus-1 (HIV-1) protease inhibitors atazanavir and darunavir in adults.

The benefits with Tybost® are its ability to inhibit CYP3A-mediated metabolism and to enhance the systemic exposure of CYP3A substrates (such as atazanavir or darunavir) that have limited oral bioavailability and a short half-life due to CYP3A-dependent metabolism.
The most common side effects with cobicistat-boosted atazanavir are associated with elevated bilirubin levels. A pharmacovigilance plan for Tybost® will be implemented as part of the marketing authorisation.