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Phase 2 Safety Trial Targeting Amyloid β Production With a  -Secretase Inhibitor in Alzheimer Disease
Adam S. Fleisher, MD;
Rema Raman, PhD;
Eric R. Siemers, MD;
Lida Becerra, MS;
Christopher M. Clark, MD;
Robert A. Dean, MD;
Martin R. Farlow, MD;
James E. Galvin, MD, MPH;
Elaine R. Peskind, MD;
Joseph F. Quinn, MD;
Abdullah Sherzai, MD;
B. Brooke Sowell, MS;
Paul S. Aisen, MD;
Leon J. Thal, MD
Arch Neurol. 2008;65(8):1031-1038.
Objective To evaluate the safety, tolerability, and amyloid β (Aβ) response to the  -secretase inhibitor LY450139 in Alzheimer disease.
Design Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial.
Setting 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.
Main Outcome Measures Primary outcome measures were adverse events, plasma and cerebrospinal fluid Aβ 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 Aβ40 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 Aβ 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 Aβ concentrations were consistent with inhibition of -secretase.
Trial Registration clinicaltrials.gov Identifier: NCT00244322
Author Affiliations: University of California, San Diego, La Jolla (Drs Fleisher, Raman, Sherzai, and Thal and Mss Becerra and Sowell); Eli Lilly & Co, Indianapolis, Indiana (Drs Siemers and Dean); Departments of Neurology, University of Pennsylvania, Philadelphia (Dr Clark), Indiana University School of Medicine, Indianapolis (Dr Farlow), and Oregon Health Science University, Portland (Dr Quinn); Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri (Dr Galvin); University of Washington, Seattle (Dr Peskind); and Georgetown University, Washington, DC (Dr Aisen). Dr Aisen is now with the University of California, San Diego.
Deceased.
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