Gilead Sciences, Inc., a biopharmaceutical company that discovers, develops and commercialises innovative therapeutics, announced detailed 48-week data from an open-label phase 3 study (Study 109) evaluating its investigational once-daily single tablet regimen (STR) of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir alafenamide 10 mg (E/C/F/TAF) among 1,436 virologically suppressed adult patients switching from tenofovir disoproxil fumarate (TDF)-containing regimens.
The study met its primary endpoint by demonstrating non-inferiority of E/C/F/TAF to the TDF-based regimens at week 48. The study also demonstrated statistical superiority among patients with HIV-1 RNA levels less than 50 copies/mL at week 48 and statistically significant improvements in bone and renal laboratory parameters. These data were presented in an oral session (session TUAB0102) at the 8th IAS Conference on HIV Pathogenesis, Treatment & Prevention (IAS) in Vancouver, Canada.
In November 2014, Gilead filed a New Drug Application (NDA) with the US Food and Drug Administration (FDA) for E/C/F/TAF, the first investigational once-daily TAF-based STR. TAF is an investigational novel nucleotide reverse transcriptase inhibitor (NRTI) that has demonstrated high antiviral efficacy at a dose less than one-tenth that of Gilead's Viread (TDF), as well as improved renal and bone laboratory parameters as compared to TDF in earlier clinical trials in combination with other antiretroviral agents.
"The results of this study demonstrate that E/C/F/TAF has the potential to offer clear advantages for patients with HIV over existing TDF-based therapies," said Tony Mills, MD, lead author of the phase 3 study, medical director, Southern California Men's Medical Group, and assistant professor of clinical medicine, University of California, Los Angeles. "This is the first large study to demonstrate that switching from a TDF-based regimen to E/C/F/TAF can help improve patients' bone and kidney measures."
In the open-label study, virologically suppressed adults with normal renal function taking one of four different TDF-based regimens for at least 96 weeks were randomized 2:1 to receive E/C/F/TAF or to maintain their TDF-based regimen. The four TDF-based treatments evaluated in the study included the following single tablet and multi-pill regimens: elvitegravir/cobicistat/emtricitabine/TDF (Stribild®); efavirenz/emtricitabine/TDF (Atripla); atazanavir/ritonavir + emtricitabine/TDF (Truvada) or atazanavir/cobicistat + Truvada.
Among the 1,436 patients who were randomized in the study (E/C/F/TAF, 959 patients; TDF-based regimen, 477 patients), virologic success rates at week 48 were higher in patients taking E/C/F/TAF (97 per cent versus 93 per cent for all TDF-based regimens; difference in percentages: 4.1 per cent, 95 per cent CI: 1.6 per cent to 6.7 per cent). The rates of virologic failure were similar between the two arms (E/C/F/TAF, 1.0 per cent; TDF-based regimen, 1.3 per cent). General safety was similar between the two arms through 48 weeks of treatment, with similar percentages of patients in each group having any adverse events. Adverse events leading to treatment discontinuation were more common among patients treated with a TDF-based regimen (E/C/F/TAF, 0.9 per cent; TDF-based regimen, 2.5 per cent). The most commonly reported adverse events included upper respiratory tract infection, diarrhea, nasopharyngitis and headache.
Statistically significant improvements from baseline to week 48 in mean bone mineral density (BMD) at the hip and spine were observed in patients in the E/C/F/TAF group as compared to patients in the TDF-based regimen group (hip: E/C/F/TAF, 1.37 per cent; TDF-based regimen, -0.26 per cent; spine: E/C/F/TAF, 1.79 per cent; TDF-based regimen, -0.28 per cent (p<0.001 for the differences between groups at week 48).
Significant improvements in multiple tests of renal function also were observed among patients treated with E/C/F/TAF compared with TDF-based regimens. At week 48, patients who switched to E/C/F/TAF had a median percentage change from baseline in urine protein-to-creatinine ratio (UPCR) (-21 per cent vs. +10 per cent; p<0.001); urine albumin-to-creatinine ratio (UACR) (-18 per cent vs. +9 per cent; p<0.001); urine retinol binding protein-to-creatinine ratio (-33 per cent vs. +18 per cent; p<0.001) and urine beta-2 microglobulin-to-creatinine ratio (-52 percent vs. +19 per cent; p<0.001). There were no cases of Fanconi Syndrome in the E/C/F/TAF arm and one case in the TDF-based regimen arm.
In the same IAS oral session, researchers reported new 48-week data from a separate trial that also found improvements in multiple laboratory parameters of renal and bone safety among HIV-infected, virologically suppressed adult patients who switched treatment regimens to E/C/F/TAF from both TDF- and non-TDF containing regimens (session TUAB0103). This open-label study (Study 112) included 242 patients with mild-to-moderate renal impairment (eGFRCG 30-69 mL/min), showing that from baseline to Week 48 the prevalence of proteinuria (UPCR > 200 mg/g) and albuminuria (UACR > 30 mg/g) decreased from 41 percent to 16 percent and from 49 per cent to 26 per cent, respectively, among these patients who switched to E/C/F/TAF. Significant increases in mean percent change in hip (+1.47 percent) and spine (+2.29 per cent) BMD were also observed (p<0.001 for both). Patients taking non-TDF based regimens pre-switch had no significant changes from baseline measures of renal function or BMD.
"The data presented at IAS this week demonstrate the potential of E/C/F/TAF to help address the long-term care of a range of patients," said Norbert Bischofberger, PhD, executive vice president, research and development and chief scientific officer, Gilead Sciences.
"Gilead has a long history of innovation in the field of HIV, and E/C/F/TAF and the rest of the TAF-based portfolio is poised to represent the next generation of safe, simple and highly effective regimens."
Gilead is presenting data from two other important trials at IAS, including a phase 3, 24-week study in HIV patients co-infected with hepatitis B who switched from a multi-pill regimen to a single tablet regimen of E/C/F/TAF and 48-week data from an international trial examining the safety and efficacy of Stribild among treatment-naïve women.
In addition to E/C/F/TAF, Gilead has filed NDAs with the FDA for two other TAF-based HIV medicines: two doses of an investigational fixed-dose combination of F/TAF (200/10 mg and 200/25 mg) for use in combination with other HIV antiretroviral agents; and an investigational, once-daily STR that combines Gilead's emtricitabine (200 mg) and TAF (25 mg) with rilpivirine (25 mg) from Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, (R/F/TAF), for the treatment of adult and pediatric patients 12 years of age and older.
Under the Prescription Drug User Fee Act, the FDA has set a target action date of November 5, 2015, for E/C/F/TAF and April 7, 2016, for F/TAF. Marketing Authorization Applications (MAA) in the European Union were fully validated on December 23, 2014, and May 28, 2015, for E/C/F/TAF and F/TAF respectively. Gilead will submit a MAA for R/F/TAF in the third quarter of 2015.
A fourth investigational TAF-based HIV treatment is under development, containing Gilead's TAF, emtricitabine and cobicistat, with Janssen's darunavir (D/C/F/TAF).
E/C/F/TAF and other TAF-based regimens are investigational products and have not been determined to be safe or efficacious.
Study 109 is a randomized, open-label, multi-national, active-controlled study to evaluate the non-inferiority of switching to a TAF-containing combination STR relative to maintaining TDF-containing combination regimens in virologically-suppressed HIV-1 positive adult subjects (HIV-1 RNA <50 copies/mL at Week 48) following the switch. The study was also designed to test for statistical superiority between the two study arms once non-inferiority was achieved.
A total of 1,436 virologically suppressed patients with normal renal function were randomized in the study. Demographic and general baseline characteristics were similar between the two treatment groups with the exception of ethnicity; a higher proportion of patients in the E/C/F/TAF group (25.9 per cent, 248 patients) compared with the TDF-based regimen group (17.2 per cent, 82 patients) were of Hispanic or Latino ethnicity (p<0.001). Most patients were male (89.3 per cent), with a median age of 41 years (range: 21 to 77 years); most were either white (67.2 per cent) or black (18.9 per cent).