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

• Published in: Archives of neurology (Chicago) Vol. 69; no. 11; pp. 1430 - 1440
• Main Authors: Coric, Vladimir, van Dyck, Christopher H, Salloway, Stephen, Andreasen, Niels, Brody, Mark, Richter, Ralph W, Soininen, Hilkka, Thein, Stephen, Shiovitz, Thomas, Pilcher, Gary, Colby, Susan, Rollin, Linda, Dockens, Randy, Pachai, Chahin, Portelius, Erik, Andreasson, Ulf, Blennow, Kaj, Soares, Holly, Albright, Charles, Feldman, Howard H, Berman, Robert M
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 01.11.2012
• Subjects: 80 and over; Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Alzheimer Disease - diagnosis; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Amyloid beta-Peptides; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid Precursor Protein Secretases; Amyloid Precursor Protein Secretases - antagonists & inhibitors; antagonists & inhibitors; Biological and medical sciences; blood; Body Weight; Body Weight - drug effects; cerebrospinal fluid; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; diagnosis; Dose-Response Relationship; Dose-Response Relationship, Drug; Double-Blind Method; Drug; drug effects; drug therapy; Enzyme Inhibitors; Enzyme Inhibitors - blood; Enzyme Inhibitors - therapeutic use; Female; Humans; Immunoprecipitation; International Cooperation; Magnetic Resonance Imaging; Male; Mass Spectrometry; Medical sciences; Medicin och hälsovetenskap; metabolism; Middle Aged; Neurology; Neuropsychological Tests; Neurosciences; Neurovetenskaper; Outcome Assessment (Health Care); Oxadiazoles; Oxadiazoles - blood; Oxadiazoles - therapeutic use; Psychiatric Status Rating Scales; psychology; Sulfonamides; Sulfonamides - blood; Sulfonamides - therapeutic use; tau Proteins; tau Proteins - cerebrospinal fluid; therapeutic use; Time Factors; Nervous system diseases; Degenerative disease; Safety; Alzheimer disease; Central nervous system disease; Cerebral disorder
• ISSN: 0003-9942; 1538-3687; 1538-3687
• DOI: 10.1001/archneurol.2012.2194

OBJECTIVE To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the γ-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 ϵ4 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 adverse 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 γ-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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00810147