Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. Methods: The effect of LY3202626 versus vehicle on amyloid-beta (A beta) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. A beta levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey's post hoc test and clinical data used summary statistics. Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615 +/- 0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275 +/- 0.176nM for lowering A beta(1-40) and 0.228 +/- 0.244nM for A beta(1- 42) in PDAPP neuronal cultures. In dogs, CSF A beta(1-x) concentrations were significantly reduced by similar to 80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF A beta(1-42) was reduced by 73.1 +/- 7.96 % following administration of 6mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.