E/C/F/TAF Regimen Demonstrates Statistical Superiority with Significant Improvements in Bone and Renal Laboratory Parameters Compared to TDF-based Regimens1
VANCOUVER, July 21, 2015 – Gilead Sciences, Inc. (NASDAQ: GILD) today 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.1
In November 2014, Gilead filed a New Drug Application (NDA) with the U.S. 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)2, as well as improved renal and bone laboratory parameters as compared to TDF in earlier clinical trials in combination with other antiretroviral agents.3
“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.1
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 percent; 93 percent for all TDF-based regimens; difference in percentages: 4.1 percent, 95 percent CI: 1.6 percent to 6.7 percent). The rates of virologic failure were similar between the two arms (E/C/F/TAF, 1.0 percent; TDF-based regimen, 1.3 percent). 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 percent; TDF-based regimen, 2.5 percent). The most commonly reported adverse events included upper respiratory tract infection, diarrhea, nasopharyngitis and headache.1
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 TDFbased regimen group (hip: E/C/F/TAF, 1.37 percent; TDF-based regimen, -0.26 percent; spine: E/C/F/TAF, 1.79 percent; TDF-based regimen, -0.28 percent (p < 0.001 for the differences between groups at Week 48)).1
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 percent vs. +10 percent; p<0.001); urine albumin-to-creatinine ratio (UACR) (-18 percent vs. +9 percent; p<0.001); urine retinol binding protein-to-creatinine ratio (-33 percent vs. +18 percent; p<0.001) and urine beta-2 microglobulin-to-creatinine ratio (-52 percent vs. +19 percent; 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.1
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 percent to 26 percent, 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 percent) 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.4
“The data presented at IAS this week demonstrate the potential of E/C/F/TAF to help 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/TAF5 and 48-week data from an international trial examining the safety and efficacy of Stribild among treatment-naïve women6 (Posters WELBPE13 and MOLBPE08, respectively).
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) (R/F/TAF) from Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, 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.
About Study 109
Study 109 is a randomized, open-label, multi-national, active-controlled study to evaluate the noninferiority 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.1
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 percent, 248 patients) compared with the TDF-based regimen group (17.2 percent, 82 patients) were of Hispanic or Latino ethnicity (p < 0.001). Most patients were male (89.3 percent), with a median age of 41 years (range: 21 to 77 years); most were either white (67.2 percent) or black (18.9 percent). Additional information about the study can be found at www.clinicaltrials.gov.1
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility that the FDA and other regulatory authorities may not approve E/C/F/TAF, F/TAF, R/F/TAF, D/C/F/TAF and other F/TAF-based regimens in the currently anticipated timelines or at all, and marketing approvals, if granted, may have significant limitations on their use. As a result, E/C/F/TAF, F/TAF, R/F/TAF, D/C/F/TAF and other F/TAF-based regimens may never be successfully commercialized. In addition, Gilead may be unable to file for regulatory approval for these TAF-based regimens with the FDA and other regulatory authorities in the currently anticipated timelines. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-Q for the quarter ended March 31, 2015, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
The European SmPCs for Viread, Stribild, Atripla and Truvada, are available from the EMA website at www.ema.europa.eu.
Viread, Stribild and Truvada are registered trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.
For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
1. Mills A et al., Switching From a Tenofovir Disoproxil Fumarate (TDF)-Based Regimen to a Tenofovir Alafenamide (TAF)-Based Regimen: Data in Virologically Suppressed Adults Through 48 Weeks of Treatment. IAS 2015; Vancouver
2. Ruane PJ et al., Antiviral Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir Alafenamide as 10-Day Monotherapy in HIV-1–Positive Adults. JAIDS. 2013;63(4):449-455
3. Sax P et al., Renal and bone safety of tenofovir alafenamide vs tenofovir disoproxil fumarate: combined safety results of studies GS-US-292-0104 and GS-US-292-0111 [presentation slides]. Presented at the 22nd Conference on Retroviruses and Opportunistic Infections (CROI), February 23–26, 2015, Seattle, WA, USA. Abstract 143LB
4. Gupta SK et al., Subjects with renal impairment switching from tenofovir disoproxil fumarate to tenofovir alafenamide have improved renal and bone safety through 48 weeks. IAS 2015; Canada: Abstract TUAB0103
5. Gallant J et al., Efficacy and safety of switching to simpler single tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in HIV-1/hepatitis B co-infected adults in North America and Japan (NCT02071082): week 24 results. IAS 2015; Canada: Abstract WELBPE13
6. Squires K et al., Elvitegravir (EVG) / cobicistat (COBI) / emtricitabine (FTC)/ tenofovir disoproxil fumarate (TDF) is superior to ritonavir (RTV) boosted atazanavir (ATV) plus FTC/TDF in treatment naïve women with HIV-1 infection (WAVES Study). IAS 2015; Canada: Abstract MOLBPE08