Abstract Details

Title Pharmacokinetic (PK) and Pharmacodynamic (PD) Effects of BACE Inhibitor LY2886721 in Healthy Volunteers (HVs) at Steady State

Topic Aging and Dementia

Presentation(s) P01 - (-)

Poster/Presentation
Number 017

Objective

Background LY2886721, a potent BACE inhibitor, dose-dependently lowers A?s in animals and humans.

Design/Methods PK and PD were assessed with daily oral LY2886721 or placebo administration for 14 days in HVs in two trials: A Multiple Ascending Dosing (MAD) with 5, 15 and 35 mg and a second Single Dose followed by MAD with 70 mg LY2886721. CSF was obtained by LP at baseline and 24 hours after last 14 day dose. Plasma (single dose, multiple dose) and CSF (multiple dose) LY2886721 concentrations were measured by LC/MS/MS. Plasma and CSF A?1-40, A?1-42 , A?1-X and CSF sAPP? and sAPPa were measured by immunoassay. Adverse events, vital signs, electrocardiograms, labs and eye exams were assessed.

Results LY2886721 appeared safe and well tolerated in 47 HVs completing the studies. The t1/2 of LY2886721 is approximately 12 hours. LY2886721 produced dose-dependent lowering of plasma A?1-40 compared to baseline The 24-hour time-averaged change from baseline (TACFB) in plasma A?1-40 after 14-day dosing with placebo, 5, 15, 35 and 70mg LY2886721 A?1-40 was -3.18, -51.8, -63.6,-76.9 and -82.9 %, respectively. The 35 and 70 mg doses were associated with >80% plasma A?1-40 reduction at nadir and levels did not return to baseline at 168 hours after any investigated dose. The change in CSF A?1-40 was -2.1-12.5, -30.8, -57.8, and -74.4 % respectively. LY2886721 administration for 14 days at 70 mg also significantly decreased CSF A?1-42 (-71.1%), sAPP? (-77.2 %), and increased CSF sAPP? (+58.9%).

Conclusions Good safety and tolerability profile and robust central PD effects of LY2886721 have been established in HVs. Further investigation of LY2886721 is ongoing in Phase 2 clinical trials of patients with mild AD and MCI due to AD.

Authors/Disclosures
Ferenc Martenyi, MD, PhD (Prothena Biosciences) PRESENTER	No disclosure on file
Brian A. Willis, PhD (Eli Lilly and Co.)	Dr. Willis has received personal compensation for serving as an employee of Eisai, Inc. Dr. Willis has stock in Eli Lilly and Co.
Robert A. Dean	Robert A. Dean has received personal compensation for serving as an employee of Acumen Pharmaceutics. Robert A. Dean has received personal compensation for serving as an employee of Gates Ventures. Robert A. Dean has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Robert A Dean Consulting, LLC. Robert A. Dean has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acumen.
	No disclosure on file
Steven F. Komjathy, MD (Acorda Therapeutics)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Patrick May	No disclosure on file

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