P3‐366: The comparison of effects of repetitive transcranial magnetic stimulation by session of stimulation on visuospatial neglect in stroke patients

LY2886721 (5-35mg) 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 Ab1-40, Ab1-42 and Ab1-X and CSF sAPPb 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. Results: 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 Ab 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, CSFAbs gradually increased after placebo treatment. LY2886721 dose-dependently lowered all CSFAb isoforms. 24-hr TACFB for CSFAb 1-40, Ab 1-42, and Ab 1-X in the 35 mg LY2886721 group was -27.9, -31.1 and -52.9%, respectively. LY2886721 dose-dependently decreased CSF sAPPb and increased CSF sAPPa. In the MAD study, LY2886721 dose-dependently lowered plasma and CSF Abs. Placebo, 5, 15 and 35 mg LY2886721 TAFCB for plasma Ab 1-40 was +3.46, -51.8, -63.6 and -76.9 %, respectively and change in CSF Ab 1-40 was -0.46, -17.7, -29.1 and -57.6 %, respectively. LY2886721 dose-dependently decreased CSF sAPPb and increased CSF sAPPa. Conclusions: LY2886721 appeared safe and well-tolerated at single and multiple doses producing dose-dependent central disposition, BACE target engagement and lowering of multiple Ab isoforms. LY2886721 could enter phase 2 in 2012.