Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer’s Disease Dementia

BACKGROUND: LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ)(1–40) and Aβ(1–42) concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD). OBJECTIVE: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia. METHODS: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. RESULTS: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. CONCLUSION: LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.