7月23-26日ﾊﾟﾘで開催されているIAS2017(国際ｴｲｽﾞ学会)でﾒﾙｸ社がlate-breaking abstract として薬品化学総合研究ｾﾝﾀｰ ｾﾝﾀｰ長 大類洋特任教授が分子設計･合成したEFdA(MK-8591)のPhase 1bの最新結果を発表しました｡
Single doses as low as 0.5 mg of the novel NRTTI MK-8591 suppress HIV for at least seven days
Randolph P. Matthews
R.P. Matthews1, D. Schurmann2, D.J. Rudd1, V. Levine1, S. Fox-Bosetti1, S. Zhang1, M. Robberechts1, A. Huser2, D.J. Hazuda1, M. Iwamoto1, J.A. Grobler1
1Merck & Co., Inc., Kenilworth, United States, 2Charite Universitatsmedizin Berlin, Research Hospital, Berlin, Germany
Background: MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in early clinical development for the treatment of HIV-1 infection. MK-8591-triphosphate (MK-8591-TP), the active phosphorylated anabolite of MK-8591, exhibits a half-life of ~150-160 hrs in human PBMCs. Here we describe antiviral efficacy and tolerability of single doses of 0.5 mg to 30 mg MK-8591 over 7 to 10 days in HIV-1 infected subjects in an ongoing Phase 1b monotherapy proof-of-concept efficacy study.
Methods: In an open-label study in HIV-1-infected subjects naive to antiretroviral treatment (ART), subjects are being administered a single dose of MK-8591 across a range of doses. Blood samples are being collected for viral load (VL), MK-8591 PK, and MK-8591-TP PK at prespecified time points up to 7 to 10 days post-dose. Following completion of Day 7 or Day 10 procedures, subjects are being offered standard of care ART. Safety, PK, and VL data from the doses of 0.5 mg, 1 mg, 2 mg, 10 mg, and 30 mg (N=6/panel) are available.
Results: Single doses of MK-8591 across the entire tested range were associated with a rapid and robust reduction in VL. At 168 hours postdose, a mean (95% CI) placebo-corrected VL reduction of 1.18 log10 (0.95, 1.46) was observed for 0.5 mg. For the 30 mg dose, mean VL continued to decline through Day 10 with a mean placebo-corrected reduction of 1.57 log10 (1.34, 1.85), with no evidence of recrudescence at any dose. In samples with sufficient VL for testing (14/24), no common mutant strains, including M184V/I, were detected. All doses were generally well tolerated, with a limited number of mild/moderate adverse experiences reported. MK-8591 plasma and MK-8591-TP PBMC PK were similar to previously observed data in healthy subjects.
Conclusions: MK-8591 suppressed HIV replication for at least seven days when administered as a single dose as low as 0.5 mg. The antiviral potency, human pharmacokinetics (PK), and physical properties of MK-8591 have the potential to open new paradigms for extended duration HIV treatment and prophylaxis approaches.