Gilead announces Phase 3 results for investigational once-daily single tablet HIV regimen containing tenofovir alafenamide (TAF)

Gilead Sciences, Inc. (NASDAQ: GILD) today 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 22^nd Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

TAF is a novel nucleotide reverse transcriptase inhibitor (NRTI) that has demonstrated high antiviral efficacy at a dose 10 times lower than Gilead’s Viread^® (tenofovir disoproxil fumarate, TDF), as well as improved renal and bone laboratory parameters in clinical trials.

“Long-term renal and bone health have been ongoing concerns, especially as people with HIV live longer and remain on antiretroviral treatment for greater periods of time,” said Paul Sax, MD, a Clinical Director at Brigham and Women’s Hospital, Professor of Medicine at Harvard Medical School and the lead researcher of the E/C/F/TAF safety analysis. “These results show that a TAF-based single tablet regimen has the potential to help address the needs of appropriate HIV patients facing life-long antiretroviral therapy.”

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.

“TAF delivers high levels of tenofovir directly to HIV-infected cells,” said David Wohl, MD, Associate Professor of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill and lead author of the E/C/F/TAF efficacy analysis. “This means that patients benefit from high efficacy at a remarkably low dose.”

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.

“Given its high efficacy and favorable renal and bone safety profile, Gilead believes E/C/F/TAF represents an important evolution in the treatment of HIV,” said Norbert W. Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. “We look forward to the opportunity to offer patients this and other next-generation, TAF-based therapies that have the potential to improve HIV treatment.”

Based on initial data from Studies 104 and 111 announced in September 2014, Gilead filed a New Drug Application for E/C/F/TAF with the U.S. Food and Drug Administration 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 this week 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). Two other studies on emergent resistance in treatment-naïve adult and adolescent patients taking E/C/F/TAF (Abstracts 6/Margot and 952/Porter) were presented February 21–22 at the International HIV Drug Resistance Workshop, an affiliated pre-conference workshop.

E/C/F/TAF is an investigational product and has not been determined to be safe or efficacious.