Safety and Tolerability of the γ-Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease

Objective: To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the gamma-secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD). Design: Randomized, double-blind, placebo-controlled, 24-week phase 2 study. Setting: Global, multicenter trial. Patients: A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years, 58.9% were APOE epsilon 4 carriers, and baseline measures of disease severity were similar among groups. Intervention: Avagacestat, 25, 50, 100, or 125 mg daily, or placebo administered orally daily. Main Outcome Measures: Safety and tolerability of avagacestat. Results: Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups. Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and 125-mg dose groups. Treatment-emergent serious ad-verse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal and dermatologic. Other adverse events occurring more frequently in patients undergoing treatment included reversible glycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomatic magnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients. Conclusions: Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for gamma-secretase target engagement, but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses. This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD.