Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.
OBJECTIVE
To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease.


METHODS
Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial.


METHODS
Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks.


METHODS
Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale.


RESULTS
Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures.


CONCLUSIONS
LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.
Fleisher
Adam S
AS
University of California, San Diego, La Jolla, CA 92037, USA. afleisher@ucsd.edu
Raman
Rema
R
Siemers
Eric R
ER
Becerra
Lida
L
Clark
Christopher M
CM
Dean
Robert A
RA
Farlow
Martin R
MR
Galvin
James E
JE
Peskind
Elaine R
ER
Quinn
Joseph F
JF
Sherzai
Abdullah
A
Sowell
B Brooke
BB
Aisen
Paul S
PS
Thal
Leon J
LJ
D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D000647:Amnesia / Q000139:chemically induced / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood / Q000134:cerebrospinal fluid; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D004311:Double-Blind Method; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D007415:Intestinal Obstruction / Q000139:chemically induced / Q000201:enzymology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D001381:Azepines; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine