The FINANCIAL — Gilead Sciences, Inc. on February 23 announced 48-week results from a Phase 3 study (Study 1089) evaluating the safety and efficacy of switching virologically suppressed HIV-1 infected adult patients from regimens containing emtricitabine and tenofovir disoproxil fumarate (F/TDF) (Truvada) to regimens containing the investigational fixed-dose combination of emtricitabine and tenofovir alafenamide (200/10 mg and 200/25 mg) (F/TAF).
At Week 48, the F/TAF-based regimens were found to be statistically non-inferior to the F/TDF-based regimens, based on percentages of patients with HIV-1 RNA levels less than 50 copies/mL. The study also demonstrated statistically significant improvements in renal and bone laboratory parameters among patients receiving F/TAF-based regimens. The data were presented in an oral session (Session O-2) at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, according to Gilead.
“This study reinforces the benefits we’ve consistently seen in other trials evaluating TAF-based regimens, including high rates of viral suppression and improvements in renal and bone lab safety parameters,” said Joel Gallant, MD, MPH, lead author of the Phase 3 study, Medical Director of Specialty Services at Southwest CARE Center in Santa Fe, N.M. “This is also the first study to demonstrate the potential versatility of F/TAF as a fixed-dose combination HIV treatment backbone that can be paired with a range of third agents to help meet the diverse needs of people living with HIV.”
TAF is a novel targeted prodrug of tenofovir that has demonstrated high antiviral efficacy similar to and at a dose less than one-tenth that of Gilead’s Viread (tenofovir disoproxil fumarate, TDF). TAF has also demonstrated improvement in surrogate laboratory markers of renal and bone safety as compared to TDF in clinical trials in combination with other antiretroviral agents. Data show that because TAF enters cells, including HIV-infected cells, more efficiently than TDF, it can be given at a much lower dose and there is 90 percent less tenofovir in the bloodstream.
In the study, 663 patients were randomized 1:1 in a blinded fashion either to switch to an F/TAF- or continue an F/TDF-based regimen (F/TAF, 333 patients; F/TDF, 330 patients) containing a third antiretroviral agent that was part of the participant’s pre-existing treatment regimen. Dosing of F/TAF was dependent on the third agent: 200/10 mg with ritonavir-boosted protease inhibitors (darunvair, atazanavir and lopinavir) and 200/25 mg with unboosted third agents (raltegravir, dolutegravir, nevirapine, efavirenz, rilpivirine and maraviroc).
Through Week 48, similar high rates of virologic suppression (HIV-1 RNA <50 c/mL) were maintained in both treatment groups (F/TAF-based regimens, 94.3 percent; F/TDF-based regimens, 93.0 percent; difference in percentages: 1.3 percent, 95 percent CI: -2.5 percent to +5.1 percent). Drug-related serious adverse events were rare in both groups (F/TAF-based regimens, 0.0 percent; F/TDF-based regimens, 0.3 percent); drug discontinuation due to adverse events also was low across both groups (F/TAF-based regimens, 2.1 percent; F/TDF-based regimens, 0.9 percent). The most commonly reported adverse events in both arms included upper respiratory tract infection, diarrhea, nasopharyngitis, headache and bronchitis.
Statistically significant differences were observed in mean changes from baseline to Week 48 in bone mineral density (BMD) between patients receiving F/TAF-based regimens compared to patients receiving F/TDF-based regimens (hip: F/TAF-based regimens, +1.14 percent; F/TDF-based regimens, -0.15 percent; spine: F/TAF-based regimens, +1.53 percent; F/TDF-based regimens, -0.21 percent, p<0.001 for both). Additionally, more patients receiving F/TAF-based regimens experienced a greater than three percent improvement in BMD from baseline to Week 48, compared with those receiving F/TDF-based regimens (hip: F/TAF, 17 percent; F/TDF, 9 percent, p=0.003; spine: F/TAF, 30 percent; F/TDF, 14 percent, p< 0.001).
Statistically significant differences also were observed in multiple tests of renal function between patients receiving F/TAF-based regimens compared to patients receiving F/TDF-based regimens, which included median changes from baseline to Week 48 in estimated GFR (+8.4 mL/min vs. +2.8 mL/min, p<0.001) and median percent changes in: urine protein-to-creatinine ratio (UPCR) (-14.6 percent vs. +7.7 percent; p<0.001); urine albumin-to-creatinine ratio (UACR) (-7.7 percent vs. +12.3 percent; p<0.001); urine retinol binding protein-to-creatinine ratio (-16.3 percent vs. +18.2 percent; p<0.001) and urine beta-2 microglobulin-to-creatinine ratio (-39.6 percent vs. +22.0 percent; p<0.001). There were no cases of proximal renal tubulopathy in either arm.
“The data presented at CROI this week further support the efficacy, safety and tolerability advantages of TAF for a range of patients who face a lifetime of treatment,” said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. “If approved, we look forward to offering F/TAF as part of the full portfolio of TAF-based products, which have the potential to represent the next generation of safe, simple and highly effective regimens.”
In April 2015, Gilead filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for two fixed-dose combinations of F/TAF (200/10 mg and 200/25 mg), and the FDA has set a target review date under the Prescription Drug User Fee Act (PDUFA) of April 7, 2016. A Marketing Authorization Application (MAA) in the European Union (EU) for F/TAF was fully validated on May 28, 2015.
F/TAF is an investigational product and has not been determined to be safe or efficacious.
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