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P3‐363: BACE inhibitor LY2886721 safety and central and peripheral PK and PD in healthy subjects (HSs)

2012; Wiley; Volume: 8; Issue: 4S_Part_16 Linguagem: Inglês

10.1016/j.jalz.2012.05.1588

1552-5279

Ferenc Martényi, Robert A. Dean, Stephen L. Lowe, Masako Nakano, Scott A. Monk, Brian A. Willis, Celedon Gonzales, Dustin J. Mergott, Daugherty Leslie, Patrick C. May, Audia James, Hakop Gevorkyan, Stanford S. Jhee, Larry Ereshefsky, Martin Citron,

HER2/EGFR in Cancer Research

LY2886721, a BACE inhibitor, dose-dependently lowers Aβs in animals. Herein LY2886721 safety, PK and PD were investigated in randomized, double blind phase I single and multiple ascending dose (SAD, MAD) studies. In SAD part A, placebo or LY2886721 (1-35 mg) were administered PO. In SAD part B, effects of placebo or LY2886721 (10-35 mg) on Aβs, sAPPβ and sAPPα were determined in serially-sampled CSF. In MAD, single daily doses of placebo and LY2886721 (5-35 mg) were administered PO for 14 days. CSF was obtained by LP at baseline and 24 hrs after last dose. Plasma and CSF LY2886721 concentrations were measured by LC/MS/MS. Plasma and CSF Aβ1-40, Aβ1-42 and Aβ1-X and CSF sAPPβ and sAPPa were measured by immunoassay. PK/PD was assessed after single and steady state dosing. Adverse event, vital sign, ECG, lab and eye exams were assessed throughout the study and for 6 weeks after last dose to characterize safety and tolerability. LY2886721 appeared safe and well-tolerated in 29 and 39 HSs completing SAD and MAD studies, respectively. C max was achieved 2-4 hrs after dosing. Mean t 1/2 was approximately 12 hrs. In SAD part A, 24-hour time-averaged change from baseline (TACFB) in plasma Aβ 1-40 for placebo and 1, 7, 15, 25 and 35 mg LY2886721 groups was -0.14, -25.0, -38.3, -56.1, -62.0 and -63.7%, respectively. In part B, CSF Aβs gradually increased after placebo treatment. LY2886721 dose-dependently lowered all CSF Aβ isoforms. 24-hr TACFB for CSF Aβ 1-40, Aβ 1-42, and Aβ 1-X in the 35 mg LY2886721 group was -27.9, -31.1 and -52.9%, respectively. LY2886721 dose-dependently decreased CSF sAPPβ and increased CSF sAPPα. In the MAD study, LY2886721 dose-dependently lowered plasma and CSF Aβs. Placebo, 5, 15 and 35 mg LY2886721 TAFCB for plasma Aβ 1-40 was +3.46, -51.8, -63.6 and -76.9 %, respectively and change in CSF Aβ 1-40 was -0.46, -17.7, -29.1 and -57.6 %, respectively. LY2886721 dose-dependently decreased CSF sAPPβ and increased CSF sAPPα. LY2886721 appeared safe and well-tolerated at single and multiple doses producing dose-dependent central disposition, BACE target engagement and lowering of multiple Aβ isoforms. LY2886721 could enter phase 2 in 2012.