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 -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD).


METHODS
Randomized, double-blind, placebo-controlled,24-week phase 2 study.


METHODS
Global, multicenter trial.


METHODS
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.


METHODS
Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily.


METHODS
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 and125-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 anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic 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 -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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00810147
Neuroscience Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut 06492, USA. vlad.coric@bms.com
Vladimir
V
Coric
Christopher H
CH
van Dyck
Stephen
S
Salloway
Niels
N
Andreasen
Mark
M
Brody
Ralph W
RW
Richter
Hilkka
H
Soininen
Stephen
S
Thein
Thomas
T
Shiovitz
Gary
G
Pilcher
Susan
S
Colby
Linda
L
Rollin
Randy
R
Dockens
Chahin
C
Pachai
Erik
E
Portelius
Ulf
U
Andreasson
Kaj
K
Blennow
Holly
H
Soares
Charles
C
Albright
Howard H
HH
Feldman
Robert M
RM
Berman
D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000097:blood* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007391:International Cooperation; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009483:Neuropsychological Tests; D017063:Outcome Assessment, Health Care; D010069:Oxadiazoles / Q000097:blood* / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D013449:Sulfonamides / Q000097:blood* / Q000627:therapeutic use*; D013997:Time Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; C554092:BMS 708163; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D013449:Sulfonamides; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases