Date: 2015-02-26
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 22nd Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle
Company: Gilead Sciences (USA - CA)
Product: tenofovir alafenamide (TAF)
Action
mechanism: nucleotide reverse transcriptase inhibitor.Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor. It is an investigational novel prodrug of tenofovir, the active agent in Viread® (tenofovir disoproxil fumarate). It has demonstrated high antiviral efficacy at a dose 10 times lower than Viread®, as well as improved renal and bone laboratory parameters in clinical trials.
Disease: HIV-1 infection
Therapeutic area: Infectious diseases
Country:
Trial
details: Study 104 and Study 111 are randomized, double-blind, 96-week clinical trials among 1,744 treatment-naïve HIV-1 infected adults with viral load greater than or equal to 1,000 copies/mL. In Study 104, 867 patients were randomized (1:1) and received E/C/F/TAF (n=435) or Stribild® (n=432). In Study 111, 866 patients were randomized (1:1) and received E/C/F/TAF (n=431) or Stribild® (n=435). The primary efficacy endpoint of the studies is the proportion of patients with viral load < 50 copies/mL at 48 weeks of treatment as determined by the FDA-defined snapshot analysis. Key secondary endpoints include change from baseline in bone mineral density at the hip and spine at weeks 48, and change from baseline in serum creatinine at weeks 48. Other secondary endpoints include the proportion of patients with viral load < 20 copies/mL at 48 and 96 weeks of therapy as defined by the FDA snapshot analysis, the proportion of patients with viral load < 50 copies/mL at week 96 as defined by the FDA snapshot and change from baseline in CD4+ cell count at weeks 48 and 96. The studies are ongoing in a blinded fashion. After week 96, patients will continue to take their blinded study drug until treatment assignments have been unblinded, at which point all will be given the option to participate in an open-label rollover extension and receive E/C/F/TAF.
Latest
news: * On February 26, 2015, Gilead Sciences announced detailed 48-week results from two Phase 3 studies (Studies 104 and 111) evaluating its investigational once-daily single tablet regimen containing tenofovir alafenamide (TAF) for the treatment of HIV-1 infection in treatment-naïve adults. A regimen of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and TAF 10 mg (E/C/F/TAF) was found to be statistically non-inferior to Gilead's Stribild® (containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg), based on percentages of patients with HIV-1 RNA levels less than 50 copies/mL. A second analysis found that patients receiving the TAF regimen also had significantly better renal and bone laboratory parameters than those treated with Stribild. The data were presented in two late-breaker presentations (Sessions O-10 and O-11) at the 22nd Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle . In the combined analyses of Studies 104 and 111, a total of 1,733 treatment-naïve adults with HIV were randomized to receive E/C/F/TAF or Stribild. At 48 weeks, 92.4 percent (n=800/866) of patients taking E/C/F/TAF and 90.4 percent (n=784/867; CI -0.7 percent to +4.7 percent, p=0.13) of patients taking Stribild® achieved HIV RNA levels less than 50 copies/mL (Abstract 113LB/Wohl). These analyses 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 (0.9 percent (n=8) for E/C/F/TAF vs. 1.5 percent (n=13) for Stribild®), with the most common side effects being diarrhea, nausea, headache and upper respiratory tract infection. A separate, in-depth analysis investigated the effect of the two regimens on laboratory parameters of kidney, bone and plasma lipid levels (Abstract 143LB/Sax). To examine kidney function, multiple tests of glomerular and tubular function were conducted, all of which statistically favored the E/C/F/TAF regimen. This included a statistically significant difference in the median change in estimated glomerular filtration rate (eGFR) from baseline to week 48, favoring the TAF-based regimen (-6.6 mL/min for E/C/F/TAF vs. -11.2 mL/min for Stribild, p<0.001). The analysis also found that bone mineral density (BMD) was reduced significantly more among patients taking Stribild compared to patients taking E/C/F/TAF (spine: -2.86 vs. -1.30, p<0.001; hip: -2.95 vs. -0.66, p<0.001). Finally, patients on E/C/F/TAF had higher plasma lipid values than patients on Stribild, which appeared to be consistent with the changes seen with other non-TDF based regimens. Based on initial data from Studies 104 and 111 announced in September 2014 (see below) , Gilead filed a New Drug Application for E/C/F/TAF with the FDA on November 5, 2014. Under the Prescription Drug User Fee Act, the agency has set a target action date of November 5, 2015. If approved, E/C/F/TAF would be Gilead's first single tablet regimen to contain TAF. A Marketing Authorization Application (MAA) in the European Union for E/C/F/TAF was fully validated on December 23, 2014. Review of the MAA by the European Medicines Agency is being conducted under the centralized licensing procedure, which, when finalized, provides one marketing authorization in all 28 member states of the European Union . In addition to Studies 104 and 111, several other E/C/F/TAF study results were presented at CROI. Notably, these include an open-label 48-week study (Study 112) supporting the efficacy and safety of E/C/F/TAF for use among HIV-infected patients with mild-to-moderate renal impairment (CrCL = 30mL/min) (Abstract 795/Pozniak). The study included 242 virologically suppressed patients whose treatment regimens were switched from both TDF- and non-TDF-containing regimens to E/C/F/TAF. The study found that 92 percent of study participants remained virologically suppressed at week 48. There was no significant change in eGFR compared to baseline, and significant improvements were observed in other markers of renal function, including proximal renal tubular laboratory parameters and decreased proteinuria (UPCR >200 mg/g) and albuminuria (UACR= 30mg/g). Improvements in BMD (hip and spine) were also observed from baseline to week 48 (median percent change of 0.9 percent and 1.9 percent, respectively). Finally, lipid values among patients taking non-TDF-containing regimens prior to the study decreased, while fasting lipids increased among those who were taking TDF-containing regimens prior to study enrollment. Twenty-four-week data from another Phase 3 study (Study 106) of E/C/F/TAF in treatment-naïve adolescents also were presented (Abstract 953/Bennett). * On September 24, 2014, Gilead Sciences announced that two Phase 3 clinical trials (Studies 104 and 111) evaluating an investigational once-daily single tablet regimen containing tenofovir alafenamide (TAF) for the treatment of HIV-1 infection in treatment-naïve adults met their primary objectives. The studies demonstrated that the single tablet regimen comprising elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and TAF 10 mg (E/C/F/TAF), was non-inferior to Gilead\'s Stribild® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) based on the proportion of patients with HIV RNA levels (viral load) of less than 50 copies/mL at 48 weeks of therapy. In addition, E/C/F/TAF demonstrated more favorable renal and bone safety compared to Stribild. In Study 104, 93.1 percent (n=405/435) of patients taking E/C/F/TAF compared to 92.4 percent (n=399/432), of patients taking Stribild®, with 95 percent CI from -2.6% to 4.5%, achieved HIV RNA of less than 50 copies/mL at week 48. In Study 111, 91.6 percent (n=395/431) of E/C/F/TAF patients compared to 88.5 percent (n=385/435) of Stribild® patients, with 95 percent CI from -1.0% to 7.1%, achieved HIV RNA of less than 50 copies/mL at week 48. Both regimens were generally well tolerated. Discontinuation rates due to adverse events, safety and resistance profiles were comparable between E/C/F/TAF and Stribild® in both studies. Laboratory abnormalities were generally similar for both regimens, with the exception of renal and bone safety indicators, which favored the TAF-based regimen. There was a statistically significant difference in the median change in estimated glomerular filtration rate (eGFR) from baseline to week 48, favoring the TAF-based regimen (-6.8 mL/min for E/C/F/TAF vs. -10.4 mL/min for Stribild® in Study 104 (p<0.001); -5.7 mL/min for E/C/F/TAF vs. -11.9 mL/min for Stribild® in Study 111 (p<0.001)). Additionally, patients taking the TAF-based regimen experienced a significantly smaller median percentage decrease from baseline in lumbar spine bone mineral density compared to Stribild patients (-1.19 vs. -2.67 in Study 104 (p<0.001); -1.11 vs. -2.81 in Study 111 (p<0.001)) and in hip bone mineral density (-0.77 vs. -3.24 in Study 104 (p<0.001); -0.74 vs. -2.78 in Study 111 (p<0.001)). In Study 104, median changes from baseline in total fasting cholesterol, HDL (high-density lipoprotein or \"good\" cholesterol) and LDL (low-density lipoprotein or \"bad\" cholesterol) were, respectively, 30, 7 and 15 mg/dL for E/C/F/TAF and 12, 3 and 2 mg/dL for Stribild (total cholesterol, p<0.001; HDL, p<0.001; LDL, p<0.001). In Study 111, median changes from baseline in total cholesterol, HDL and LDL were respectively, 27, 7 and 11 mg/dL for E/C/F/TAF and 14, 4 and 2 mg/dL for Stribild (total cholesterol, p<0.001; HDL, p<0.001; LDL, p<0.001). Gilead plans to submit data from Studies 104 and 111 for presentation to a scientific conference in early 2015. Several additional ongoing Phase 3 studies are evaluating E/C/F/TAF among multiple HIV patient populations, including patients who switch to E/C/F/TAF from either a single tablet or multi-pill Truvada-containing regimens, patients with a history of antiviral drug resistance, patients with mild to moderate renal impairment and treatment-naïve HIV-positive adolescents. An additional Phase 3b study, WAVES, is evaluating E/C/F/TAF among HIV-positive women who switched from a multi-pill regimen. Based on the results of Studies 104 and 111 and data from these additional ongoing studies, Gilead plans to submit regulatory applications for E/C/F/TAF in the United States and European Union in the fourth quarter of 2014.
