お知らせ

大類洋特任教授の研究成果に関する最新結果をメルク社が発表

2017-07-29

7月23-26日パリで開催されているIAS2017(国際エイズ学会)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。

CROI2016では10mg一度の経口投与で10日間抗HIV活性が持続するという試験結果であったが、今回は0.5mg一度の投与で少なくとも7日間活性が持続するという結果であった。

EFdAの活性と物理化学的物性はHIV感染の化学療法と防御にパラダイムシフトを起こすであろうという発表でした。
 

Title
Single doses as low as 0.5 mg of the novel NRTTI MK-8591 suppress HIV for at least seven days
Presenter
Randolph P. Matthews
Authors
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
Institutions
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.