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

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.