P1‐044: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of LY3202626, a Novel Bace1 Inhibitor, in Healthy Subjects and Patients with Alzheimer’s Disease
Brian A. Willis, Stephen Loucian Lowe, Leslie L. Daugherty, Robert A. Dean, Brett A. English, Larry Ereshefsky, Hakop Gevorkyan, Douglas E. James, Stanford S. Jhee, Qun Lin, Albert Lo, Dustin J. Mergott, Scott A. Monk, Masako H. Nakano, Jennifer A. Zimmer, Michael C. Irizarry · Alzheimer s & Dementia · 2016
LY3202626 is a small molecule non-selective BACE1 inhibitor. In dogs, LY3202626 is highly potent, producing dose-dependent reductions in CSF and plasma Aβ concentrations. The initial human study (I7X-EW-LLCA, clinicaltrials.gov identifier NCT02323334) described herein was a single and multiple ascending dose trial, in 4 parts, to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of LY3202626 in healthy subjects (HS) and patients with Alzheimer’s disease (AD). In Part A, HS received placebo or LY3202626 (0.1 to 45 mg) as single doses. Part B evaluated CSF PK/PD in HS by serial sampling after single dose placebo or LY3202626 (1.6 to 26 mg) administration. In Part C, HS received daily doses of placebo or LY3002626 (1 to 26 mg) for 14 days. In Part D, patients with AD received daily doses of 6 mg for 14 days. In Parts C and D, CSF was obtained by lumbar puncture at baseline and 24 hrs after last dose. Plasma and CSF LY3202626 concentrations were measured by LC/MS/MS. Plasma and CSF Aβ1-40 and Aβ1-42 were measured by immunoassay. PK/PD was assessed after single doses and at steady state. Adverse events, vital signs, ECG, clinical laboratories, neurological and eye exams were assessed throughout the study and for up to 42 days after the last dose to characterize safety and tolerability. LY3202626 was well tolerated by HS (n=92) and AD patients (n=2) at all doses. In HS, maximum plasma LY3202626 concentrations (Cmax) were observed approximately 3 hrs post-dose. The terminal half-life was around 21 hrs, and PK was generally dose proportional. LY3202626 appeared to freely penetrate the blood brain barrier, with CSF Cmax approximately 6 hrs post-dose. Plasma steady-state was achieved within 8 to 10 days. Following single doses, LY3202626 produced dose-dependent reductions in plasma and CSF Aβ1-40 and Aβ1-42. At steady-state, Aβ1-40 in CSF was reduced by approximately 50%, 75%, and >90% at daily doses of 1, 6, or 26 mg, respectively. LY3202626 is a well-tolerated, potent, low dose, freely CNS penetrant BACE inhibitor. These data support further clinical development of LY3202626.