Gilead Sciences, a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need, has reported two-year (96-week) results from two pivotal phase III studies (Studies 102 and 103) evaluating the company’s newest single tablet HIV regimen, Stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), among treatment-naïve patients with HIV-1 infection. These results were presented today in an oral session at the 11th International Congress on Drug Therapy in HIV Infection (HIV11) in Glasgow, United Kingdom.

Data show that Stribild was non-inferior after two years of treatment to two standard of care HIV regimens, Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) in Study 102 and a protease-based regimen of ritonavir-boosted atazanavir plus Truvada (emtricitabine and tenofovir disoproxil fumarate) in Study 103.

“In these studies, Stribild demonstrated a robust clinical profile, including sustained efficacy, safety and resistance results over two years of treatment,” said Jürgen Rockstroh, MD, Professor of Medicine, University of Bonn, Germany and a lead investigator for Study 103. “Stribild was also associated with a lower incidence of certain central nervous system side effects compared to Atripla, and had a favorable triglycerides profile versus the atazanavir-based regimen.”

Stribild combines four compounds in one daily tablet: elvitegravir, an integrase inhibitor; cobicistat, a pharmacoenhancing agent; emtricitabine and tenofovir disoproxil fumarate. The regimen was approved by the US Food and Drug Administration (FDA) on August 27, 2012 for use by treatment-naïve HIV-positive adults based on 48-week results from Studies 102 and 103. A marketing application for Stribild is currently under review in the European Union.

Study 102 found that at 96 weeks of treatment, 84 per cent of Stribild patients (n=293/348) and 82 per cent of Atripla patients (n=287/352) achieved HIV RNA (viral load) < 50 copies/mL, based on the FDA snapshot algorithm (95 per cent CI for the difference: -2.9 to +8.3 per cent for Stribild vs. Atripla; predefined criterion for non-inferiority was a lower bound of a two sided 95 per cent CI of -12 per cent).

Similarly, results from Study 103 show that 83 per cent of Stribild patients (n=294/353) and 82 per cent of patients receiving the atazanavir-based regimen (n=292/355) achieved HIV RNA < 50 copies/mL, based on the FDA snapshot algorithm (95 per cent CI for the difference: -4.5 to +6.7 per cent for Stribild vs. the atazanavir-based regimen; predefined criterion for non-inferiority was a lower bound of a two sided 95 per cent CI of -12 per cent).

In both Studies 102 and 103, rates of discontinuation due to adverse events were similar across all treatment groups (five per cent for Stribild in each study, seven per cent for Atripla and six per cent for the atazanavir-based regimen). The most common adverse events occurring in at least 10 per cent of Stribild patients in Study 102 were diarrhea, nausea, upper respiratory infection, headache, abnormal dreams, fatigue, depression and insomnia; in Study 103, they were diarrhea, nausea, upper respiratory infection, headache, nasopharyngitis, depression, back pain and fatigue. In Study 102, there were consistently higher reports at each study visit through 96 weeks of abnormal dreams and dizziness in the Atripla arm, with 14 per cent and four per cent of patients experiencing abnormal dreams and dizziness, respectively, on the Atripla arm vs. eight per cent and one per cent, respectively on the Stribild arm at 96 weeks. Similarly, in Study 103, reports of diarrhea were consistently higher through 96 weeks of treatment on the atazanavir-based arm compared to Stribild, with four per cent of Stribild patients vs. nine per cent of patients on an atazanavir-based regimen experiencing this problem at 96 weeks.

The frequency of Grade 3-4 adverse events and laboratory abnormalities was also comparable between study regimens. However, in Study 102, patients taking Stribild experienced lower rates of neuropsychiatric side effects (Grades 1-4) through 96 weeks compared to Atripla patients, including abnormal dreams (15 per cent for Stribild vs. 28 per cent for Atripla), dizziness (eight per cent vs. 25 per cent) and insomnia (11 per cent vs. 16 per cent). Patients taking Stribild also experienced lower increases in total cholesterol and LDL (low-density lipoprotein or “bad” cholesterol) compared to Atripla, and in Study 103, experienced significantly smaller increases in triglycerides compared to those taking the atazanavir-based regimen. Additionally, through week 96, reports of Grade 3-4 hyperbilirubinemia were lower in the Stribild arm compared to the atazanavir-based arm (0.6 per cent vs. 65 per cent).

In September 2012, Stribild was added to US Department of Health and Human Services (DHHS) guidelines as an “alternative” treatment regimen for patients new to HIV therapy. Atripla and ritonavir-boosted atazanavir plus Truvada are both listed as “preferred” first-line regimens in the guidelines. Stribild has a Boxed Warning of lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B; see below for important safety information.

Gilead recently initiated WAVES, a phase III b study evaluating Stribild compared to ritonavir-boosted atazanavir plus Truvada among more than 500 HIV-positive treatment-naïve women. Additional studies examining the efficacy and safety of switching treatment-experienced virologically suppressed patients to Stribild are also underway.

Study 102 is a randomized (1:1), double-blind phase III clinical trial comparing the efficacy, safety and tolerability of Stribild (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 < 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 Stribild 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 per cent of patients had HIV RNA > 100,000 copies/mL, and 13 per cent of patients had CD4 counts = 200 cells/mm3.

At 96 weeks, mean increases in CD4 cell counts were 295 cells/mm3 for Stribild patients and 273 cells/mm3 for Atripla patients (p=0.19). Virologic failure rates were six per cent for Stribild compared to eight per cent for Atripla.

Five per cent of Stribild patients and seven per cent of Atripla patients discontinued treatment due to adverse events. The most common adverse events leading to treatment discontinuation among patients taking Stribild were renal events, depression and fatigue. Between 48 and 96 weeks of treatment, two Stribild patients discontinued due to serum creatinine increase without features of proximal renal tubulopathy, and both patients improved after treatment discontinuation.

Median changes from baseline in total cholesterol, HDL (high-density lipoprotein or “good” cholesterol) and LDL at 96 weeks were, respectively, +9, +6 and +9 mg/dL for Stribild and +18, +8 and +16 mg/dL for Atripla (total cholesterol, p<0.001; HDL, p=0.008; LDL, p=0.011). The median change in triglycerides was +4 mg/dL for Stribild and +8 mg/dL for Atripla (p=0.41).

Study 103 is a randomized (1:1), double-blind phase III clinical trial comparing the efficacy, safety and tolerability of Stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (n=353) versus atazanavir 300 mg boosted by ritonavir 100 mg plus Truvada (emtricitabine and tenofovir disoproxil fumarate) (n=355) among HIV-infected treatment-naïve adults with baseline HIV RNA levels > 5,000 copies/mL. The primary endpoint of the study is the proportion of patients achieving HIV RNA levels < 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 Stribild arm had a median HIV RNA of 4.88 log10 copies/mL and mean CD4 cell count of 364 cells/mm3. Patients in the atazanavir-based arm had a median HIV RNA of 4.86 log10 copies/mL and mean CD4 cell count of 375 cells/mm3. Across both arms, 41 per cent of patients had HIV RNA > 100,000 copies/mL and 13 per cent had CD4 counts = to 200 cells/mm3.

At 96 weeks, patients in both arms experienced similar increases in CD4 cell counts (mean increase of 256 cells/mm3 for Stribild and 261 cells/ mm3 for the atazanavir-based regimen). The virologic failure rate was 7 per cent for both treatment regimens. Five per cent of Stribild patients and 6 per cent of patients on the atazanavir-based regimen discontinued treatment due to adverse events. The most common adverse events leading to treatment discontinuation among patients taking Stribild were renal events, diarrhea, pyrexia, nausea, vomiting and fatigue. Between 48 and 96 weeks of treatment, one Stribild patient and one patient in the atazanavir-based regimen discontinued due to serum creatinine increase without features of proximal renal tubulopathy, and both patients improved after treatment discontinuation.

Ocular icterus (associated with elevated bilirubin levels) was less common among Stribild patients (less than 1 per cent) compared to patients taking the atazanavir-based regimen (14 per cent).

Median changes from baseline in total cholesterol, HDL and LDL at 96 weeks, were, respectively, +14, +6 and +14 mg/dL for Stribild, and +8, +5 and +11 mg/dL for the atazanavir-based regimen (total cholesterol, p=0.046; HDL, p=0.24; LDL, p=0.32). The median change in triglycerides was +5 mg/dL for Stribild and +16 mg/dL for the atazanavir-based regimen (p=0.012).

Studies 102 and 103 are ongoing in a blinded fashion. After week 192, patients 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 Stribild. Additional information about the study can be found at www.clinicaltrials.gov.

Stribild contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir 150 mg; cobicistat 150 mg; emtricitabine 200 mg; and tenofovir disoproxil fumarate 300 mg. Stribild is indicated in the United States as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve. A Marketing Authorisation Application (MAA) for the regimen was validated for review by the European Medicines Agency (EMA) on December 20, 2011. Stribild does not cure HIV-1 infection.

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds. 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. Gilead submitted a New Drug Application (NDA) to FDA for elvitegravir as a standalone agent on June 27, 2012, and the agency has set a target action date under the Prescription Drug User Fee Act (PDUFA) of April 27, 2013. An MAA for elvitegravir in the EU was validated for review by EMA on June 18, 2012.

Cobicistat is Gilead’s proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. Unlike ritonavir, cobicistat acts only as a pharmacoenhancing or “boosting” agent and has no antiviral activity. Gilead submitted an NDA to FDA for cobicistat as a standalone agent on June 28, 2012, and a PDUFA date of April 28, 2013 has been set. An MAA for cobicistat in the EU was validated for review by EMA on May 22, 2012.

Elvitegravir and cobicistat as standalone agents are investigational products and their safety and efficacy have not yet been established.