RESULTS FROM A FIRST-IN-HUMAN STUDY WITH THE BACE INHIBITOR CNP520

CNP520 inhibits the β-site APP cleaving enzyme 1 (BACE-1), leading to reduced formation of amyloid-β (Aβ). It is under clinical development as potentially disease-modifying treatment in asymptomatic subjects at risk of developing Alzheimer’s disease because of their ApoE genotype. This randomized, double-blind, placebo-controlled, first-in-human (FiH) study has been conducted to assess the safety/tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single- and multiple ascending doses of CNP520. Single ascending doses were orally administered to healthy adults (n=38/14 CNP520/placebo) and elderly subjects ≥60 years (n=50/17), respectively. Multiple ascending doses were administered over two (n=45/18) and four weeks (n=10/2) to elderly only. In addition, ten healthy adults received a single dose of CNP520 under fasted and fed conditions in a cross-over fashion. Safety and tolerability were assessed based on adverse event (AE), laboratory, vital sign, ECG and other safety data. Pharmacodynamic effects were determined in elderly subjects primarily by quantification of Aβ 1-40 concentrations in cerebrospinal fluid (CSF). After single dosing, serial CSF sampling over 36h was performed. After multiple dosing, sampling was done by means of single lumbar punctures at baseline and 24h after last dose (2-week exposure) or at 2 and 4 weeks (4-week exposure). CNP520 concentrations were quantified both in plasma and CSF. CNP520 was safe and well tolerated following single and multiple doses. There was a similar incidence of AEs with CNP520 and placebo. Dose-dependent reduction of Aβ 1-40 concentrations in CSF by >90% after multiple dosing was determined. The extent of Aβ lowering was stable over four weeks of once-daily dosing. Pharmacokinetic properties included lack of relevant food effect and a terminal elimination half-life that allows once-daily dosing. The safety/tolerability, PK and PD data obtained in this FiH study support further development of CNP520 in healthy subjects at risk of Alzheimer’s disease.