J. M. Custodio, X. Wei, H. Wang, M. Hepner, J. Z. Zack, C. Callebaut, S. McCallister, M. Miller, B. P. Kearney, S. Ramanathan; Gilead Sciences, Foster City, CA
BACKGROUND: Alafenamide (TAF), a new antiretroviral agent with a favorable pharmacokinetic (PK) and safety profile vs. TFV disoproxil fumarate (TDF), has been coformulated with DRV, COBI, and FTC into D/C/F/TAF, the first protease inhibitor (PI) STR, for treatment of HIV infection. TAF, administered alone or as D/C/F/TAF, was evaluated across two studies to determine the optimal TAF dose for inclusion in the STR.
METHODS: In Study 1, 38 HIV-infected subjects received 10 day monotherapy of either open label TDF 300 mg or TAF 8, 25, or 40 mg in a blinded, placebo controlled manner. In Study 2, 10 healthy subjects received D/C/F/TAF (800/150/200/10 mg) for 21 days. Antiviral activity was assessed in Study 1. Safety and PK were assessed in both studies.
RESULTS: All treatments were generally well tolerated. No subject experienced a treatment-emergent adverse event (AE) that led to discontinuation and the majority of AEs were Grade 1. Following TAF 8, 25, or 40 mg or TDF in Study 1, TAF demonstrated efficacy at doses ≥ 8 mg, as evidenced by a mean±SD change from baseline in HIV-1 RNA on Day 11 of -0.99 ± 0.46, -1.50 ± 0.41, -1.74 ± 0.19, and -0.81± 0.58 log10 copies/mL, respectively. In Study 2, following D/C/F/TAF, TAF exposures (AUC and Cmax) were higher (~31-59%) following single-dose (Day 1), vs. multiple-dose (Day 21), indicative of a mixed inhibitory/inductive effect on TAF absorption. Following D/C/F/TAF, TAF exposures were associated with efficacy demonstrated in Study 1, while TFV exposures were ~90% lower vs. historical data following TDF-containing boosted-PI regimens.
CONCLUSION: Administration of D/C/F/TAF containing TAF 10 mg resulted in efficacious TAF exposures, and substantially lower systemic TFV exposures, vs. TDF alone or as TDF-containing boosted-PI regimens. Clinical development of D/C/F/TAF is ongoing.