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N Engl J Med. 2014 Jan 23;370(4):311-21. doi: 10.1056/NEJMoa1312889.

Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.

Author information

  • 1From the Alzheimer's Disease and Memory Disorders Center, Department of Neurology, Baylor College of Medicine, Houston (R.S.D.); Alzheimer's Disease Cooperative Study, Department of Family and Preventive Medicine (R.G.T., R.R., X.S.), and the Department of Neurosciences (R.G.T., R.R., P.S.A., R.M.), University of California at San Diego, San Diego; Indiana Alzheimer Disease Center, Indiana University (M.F.), and Eli Lilly (E.S., H.L.-S., R.M.) - both in Indianapolis; the Department of Neuropathology, School of Medicine, and the Department of Neuropathology and Neuroscience, School of Pharmacological Science, University of Tokyo, Tokyo (T.I.); Gerontopole, Unité Mixte de Recherche 1027, Centre Hospitalier Universitaire Toulouse, Toulouse, France (B.V.); the Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia (S.J.); and the Center for Human Experimental Therapeutics, University of Rochester Medical Center, Rochester, NY (K.K.).

Abstract

BACKGROUND:

Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain.

METHODS:

In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease.

RESULTS:

Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49).

CONCLUSIONS:

Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).

PMID:
24450890
[PubMed - indexed for MEDLINE]
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