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

Abstract

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-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ 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±0.176 nM for lowering Aβ 1–40 and 0.228±0.244 nM for Aβ 1–42 in PDAPP neuronal cultures. In dogs, CSF Aβ 1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ 1–42 was reduced by 73.1±7.96 % following administration of 6 mg 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.

Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach

“…An explanation could be that inhibition of BACE1 interferes with the processing of the many protein substrates of BACE1, and some of these substrates are related to synaptic plasticity and synaptic homeostasis (i.e., SEZ6 and NRG1). All this clinical trial data suggest on-target toxicity is likely a contributing factor, which implies the only potential future of BACE1 inhibitors lies in a careful titration of highly selective compounds in early populations where the amyloid burden is still minimal as prophylactic therapy, or as affordable oral maintenance therapy following amyloid-clearing therapies with the goal of to achieve a low level of BACE1 inhibition (i.e., Aβ lowering 15–30%) [ 62 ]. Support for this hypothesis can be found indirectly in the protective A673T APP mutation that leads to only 25% reduced Aβ production and still avoids carriers getting AD [ 63 ].…”

Determining Structural Changes for Ligand Recognition between Human and Rat Phosphorylated BACE1 in Silico and Its Phosphorylation by GSK3β at Thr252 by in Vitro Studies

“…14 In addition, some BACE1 inhibitors such as LY3202626 showed liver toxicity. 15,16 Therefore, considering that phosphorylated BACE1 (P-BACE1) is related with high Aβ 1−42 levels could be an interesting strategy to design BACE1 inhibitors with less adverse effects depending on their phosphorylation state.…”

“…The BACE1 inhibitors that inhibit cathepsin D produce retinal toxicity . In addition, some BACE1 inhibitors such as LY3202626 showed liver toxicity. , …”