BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease

Decourt, Boris; Macias, Mi Mi P.; Sabbagh, Marwan N.; Adem, Abdu

doi:10.1016/b978-0-12-803959-5.50010-6

Cited by 1 publication

(1 citation statement)

References 154 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent discoveries suggest that BACE1 protein levels and activity are increased in sporadic AD brain samples and CSF [5-10]. Thus BACE1 modulation represents a promising therapeutic target for AD and tremendous efforts have been placed in the past 15 years to develop BACE1 inhibitors that can cross the blood brain barrier [11]. …”

Section: Introductionmentioning

confidence: 99%

Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s Disease: Results from a Double-Blind, Placebo-Controlled Trial

Decourt

Drumm-Gurnee

Wilson

et al. 2017

CAR

Self Cite

View full text Add to dashboard Cite

Introduction To date there is no cure for Alzheimer's disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects. Methods This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. Results A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. Conclusion This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition.

show abstract

Section: Introductionmentioning

confidence: 99%