Alzheimer Disease Trial Terminated Early Due to Futility and Adverse Events
Brandy R. Matthews, MD
Another disappointing result in the battle to reduce amyloid burden in AD
Alzheimer disease (AD) is a progressive neurodegenerative illness affecting cognition and behavior, associated with characteristic neuropathological changes including tau tangles and amyloid-beta plaques. Semagacestat is an investigational drug that functionally inhibits the action of gamma secretase on the amyloid precursor protein, an important step in the amyloid cascade of plaque deposition in the brain, which presumably is associated with the development of clinical symptoms. Phase 1 and 2 semagacestat data suggested a dose-dependent decrease in plasma amyloid-beta levels but no reduction in amyloid-beta levels in cerebrospinal fluid (CSF) in humans.
Investigators conducted this multinational, phase 3, double-blind, randomized, manufacturer-sponsored trial to compare the effects of two doses of semagacestat with placebo. The co-primary endpoints were change in cognition (using Alzheimer's Disease Assessment Scale for cognition) and change in function (using Alzheimer's Disease Cooperative Study–Activities of Daily Living) over 76 weeks. A group of researchers, independent of the manufacturer, analyzed the data, prepared the report, and submitted the manuscript for publication.
Of more than 2000 patients screened, 1537 patients with mild-to-moderate AD were randomized. The trial was terminated early based on evidence of clinical worsening and safety concerns in the active treatment groups and results of a futility analysis. At that time, 463 subjects had completed the trial. All three groups demonstrated worsening of cognition and function. Patients in the semagacestat-treated groups were more likely to discontinue treatments and have adverse events (e.g., nonmelanoma skin cancers, infections, or laboratory abnormalities). Changes on structural or functional neuroimaging did not clearly differ across groups. Semagacestat recipients had no evidence of reduction in CSF amyloid-beta levels.
Citation(s):
Doody RS et al. A Phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013 Jul 25; 369:341.
