Date: 2015-07-21
Type of information: Initiation of preclinical development
phase: 3
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago at the 8th IAS Conference on HIV Pathogenesis , Treatment & Prevention (IAS) in Vancouver, Canada .
Company: Gilead (USA - CA)
Product: single tablet regimen containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and tenofovir alafenamide (TAF) 10 mg (E/C/F/TAF)
Action
mechanism: nucleoside reverse transcriptase inhibitor. Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor (NtRTI). It is an investigational novel prodrug of tenofovir, the active agent in Viread® (tenofovir disoproxil fumarate), which is also an NtRTI. Phase 1b dose-ranging studies identified a dose of TAF that is ten times lower than Viread. cytochrome P450 inhibitor. Cobicistat (Tybost®) is a cytochrome P450 3A4 (CYP3A4) inhibitor. It acts as a pharmacokinetic enhancer of atazanavir 300 mg once daily or darunavir 800 mg once daily as part of antiretroviral combination therapy in human immunodeficiency virus-1 (HIV-1) infected adults.
Disease: HIV-1 infection
Therapeutic area: Infectious diseases
Country:
Trial
details: 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 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).
Latest
news: * On July 21, 2015, Gilead Sciences 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 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 percent versus 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. 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 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)). 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. 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.
