Date: 2017-02-14
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the Conference on Retroviruses and Opportunistic Infections (CROI)
Company: Gilead (USA - CA)
Product: Genvoya® (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir alafenamide 10 mg or E/C/F/TAF)
Action
mechanism: nucleoside reverse transcriptase inhibitor. Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor (NtRTI). It is an investigational novel prodrug of tenofovir, the active agent in Viread® (tenofovir disoproxil fumarate), which is also an NtRTI. Phase 1b dose-ranging studies identified a dose of TAF that is ten times lower than Viread. cytochrome P450 inhibitor. Cobicistat (Tybost®) is a cytochrome P450 3A4 (CYP3A4) inhibitor. It acts as a 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.
Disease: HIV-1 infection
Therapeutic area: Infectious diseases
Country:
Trial
details: Studies 104 and 111, originally planned for 96 weeks and extended to 144 weeks, were randomized, double-blind, controlled Phase 3 trials conducted among 1,733 treatment-naïve adults living with HIV. The primary endpoint of the study was at Week 48, in which Genvoya® was non-inferior to Stribild®. Genvoya® was also non-inferior at the secondary endpoint of efficacy at Week 96. At study enrollment, 15 percent of subjects were women, 25 percent identified themselves as Black or of African descent and 23 percent had viral loads ?100,000 copies/mL. Patients were randomized 1:1 to receive a single tablet regimen of Genvoya® or Stribild®; randomization included stratification for CD4 count (< 50 cells/µL, 50 to 199 cells/µL, or ? 200 cells/µL) and region (United States or ex-United States) at screening..
Latest
news: * On February 14, 2017, Gilead Sciences announced 144-week data from two Phase 3 studies (Studies 104 and 111) evaluating the safety and efficacy of Genvoya® (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir alafenamide 10 mg) for the treatment of HIV-1 infection in treatment-naïve adults. Through Week 144, Genvoya® demonstrated significantly higher rates of virologic suppression compared to Gilead’s Stribild® (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg), based on the percentage of patients with HIV-1 RNA levels less than 50 copies/mL. Patients receiving Genvoya® also demonstrated favorable renal and bone laboratory parameters compared to those treated with Stribild®. The data were presented in a poster session (Poster 0393) at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. In the combined analysis of Studies 104 and 111, a total of 1,733 treatment-naïve adults with HIV were randomized to receive either Genvoya® or Stribild®. At Week 144, 84.2 percent (n=729/866) of patients taking Genvoya and 80 percent (n=694/867; 95 percent CI: 0.6 percent to 7.8 percent, p=.021) of patients taking Stribild achieved HIV-1 RNA levels less than 50 copies/mL. Additionally, at Week 144, 81.1 percent (n=702/866) of patients taking Genvoya and 75.8 percent (n=657/867; 95 percent CI: 1.5 to 9.2 percent, p=.006) of patients taking Stribild® achieved HIV-1 RNA levels less than 20 copies/mL, a secondary endpoint. At Week 144, virologic failure was similar between groups (Genvoya®, 4.6 percent; Stribild®, 3.9 percent); the difference in overall results was driven by fewer discontinuations on Genvoya due to adverse events or other reasons not related to efficacy (Genvoya®, 11.2 percent; Stribild®, 16.0 percent). There were statistically significant fewer adverse events leading to discontinuation in the Genvoya® arm compared to the Stribild® arm (Genvoya®, 1.3 percent; Stribild®, 3.3 percent, p=0.01). The most common drug-related adverse events in both groups were nausea, diarrhea and headache. A separate analysis investigated the effect of the two regimens on laboratory parameters of kidney, bone and plasma lipid levels. To examine kidney function, specific protein markers of glomerular and tubular function were examined, all of which favored Genvoya®. This included a statistically significant difference in the median change in estimated glomerular filtration rate (eGFR) from baseline to Week 144 (Genvoya®, -1.6 mL/min; Stribild, -7.7 mL/min, p<0.001). There were no cases of renal tubulopathy in the Genvoya® arm and four cases in the Stribild® arm. No participants on Genvoya® had renal-related discontinuations compared to 12 participants in the Stribild arm (p?0.001). The analysis also found that decreases in bone mineral density (BMD) were significantly less in the Genvoya® group versus the Stribild® group for both lumbar spine and total hip (spine: Genvoya®, -0.92 percent; Stribild®, -2.95 percent, p<0.001; hip: Genvoya®, -0.75 percent; Stribild, -3.36 percent, p<0.001). The long-term clinical significance of changes in eGFR and BMD is not known. Finally, patients on Genvoya had statistically higher increases in total, LDL and HDL cholesterol from baseline to Week 144 compared to patients on Stribild. There was no significant difference in the total cholesterol-to-HDL ratio at Week 144, nor any difference in the rate of initiation of lipid-modifying agents. * On October 22, 2015, Gilead Sciences announced 96-week results from two Phase 3 studies (Studies 104 and 111) evaluating Genvoya® (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir alafenamide 10 mg or E/C/F/TAF), for the treatment of HIV-1 infection in treatment-naïve adults. Genvoya® was found to be statistically non-inferior to Stribild® (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg or E/C/F/TDF), based on percentages of patients with HIV-1 RNA levels less than 50 copies/mL. Patients receiving Genvoya® also had improved renal and bone laboratory parameters compared to those treated with Stribild. The data were presented at the 15th European AIDS Conference (EACS) in Barcelona.
In the combined analysis of Studies 104 and 111, a total of 1,733 treatment-naïve adults with HIV were randomized to receive either Genvoya® or Stribild®. At 96 weeks, 86.6 percent (n=750/866) of patients taking Genvoya® and 85.2 percent (n=739/867; CI -1.8 percent to +4.8 percent, p=0.36) of patients taking Stribild® achieved HIV-1 RNA levels less than 50 copies/mL. The analysis found that the rate of virologic success between the two regimens was similar across patient subgroups (age, gender, race, baseline HIV-1 RNA level and baseline CD4 count). Discontinuations due to adverse events were low in both treatment arms (1.2 percent (n=10) for Genvoya® vs. 2.3 percent (n=20) for Stribild). The most common side effects were headache, diarrhea and nausea.
The combined analysis investigated the effect of the two regimens on kidney, bone and lipid laboratory parameters over the 96-week period. To examine kidney function, multiple laboratory tests of renal and tubular function were conducted, all of which statistically favored Genvoya®. This included a statistically significant difference in the median change in estimated glomerular filtration rate (eGFR) from baseline to week 96, favoring Genvoya® (-2.0 mL/min for Genvoya vs. -7.5 mL/min for Stribild®, p<0.001). Patients taking Genvoya® had smaller declines in bone mineral density (BMD) compared to patients taking Stribild®, as assessed by DXA (spine: -0.96 vs. -2.79, p<0.001; hip: -0.67 vs. -3.28, p<0.001). Patients on Genvoya® had statistically higher increases in total, LDL and HDL cholesterol from baseline than patients on Stribild®, while there was no significant difference between the arms in the total cholesterol to HDL ratio. Finally, there were no reports of proximal renal tubulopathy (including Fanconi Syndrome) in the Genvoya® arm while there were two cases in the Stribild arm.
Additional investigational Phase 3 study results for Genvoya® that will be presented at EACS include a 48-week analysis of Study 109 in adult patients switching from boosted atazanavir (ATV) plus F/TDF to Genvoya® (session: PS10), sub-analyses of Studies 104 and 111 examining Genvoya vs. Stribild among treatment-naïve adult women at 48 weeks (poster: PE7/13) and drug resistance through 48 weeks in treatment-naive subjects receiving Genvoya (poster: PE9/5).
