%0 Journal Article %J N Engl J Med %D 2014 %T Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. %A Doody, Rachelle S %A Thomas, Ronald G %A Farlow, Martin %A Iwatsubo, Takeshi %A Vellas, Bruno %A Joffe, Steven %A Kieburtz, Karl %A Raman, Rema %A Sun, Xiaoying %A Aisen, Paul S %A Siemers, Eric %A Liu-Seifert, Hong %A Mohs, Richard %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Antibodies, Monoclonal, Humanized %K Apolipoproteins E %K Biomarkers %K Cognition %K Double-Blind Method %K Female %K Humans %K Intention to Treat Analysis %K Male %K Neuropsychological Tests %K Severity of Illness Index %K tau Proteins %K Treatment Failure %X

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.).

%B N Engl J Med %V 370 %P 311-21 %8 2014 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24450890?dopt=Abstract %R 10.1056/NEJMoa1312889 %0 Journal Article %J Alzheimers Dement %D 2011 %T Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A Sperling, Reisa A %A Aisen, Paul S %A Beckett, Laurel A %A Bennett, David A %A Craft, Suzanne %A Fagan, Anne M %A Iwatsubo, Takeshi %A Jack, Clifford R %A Kaye, Jeffrey %A Montine, Thomas J %A Park, Denise C %A Reiman, Eric M %A Rowe, Christopher C %A Siemers, Eric %A Stern, Yaakov %A Yaffe, Kristine %A Carrillo, Maria C %A Thies, Bill %A Morrison-Bogorad, Marcelle %A Wagster, Molly V %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Cognition Disorders %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K United States %X

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

%B Alzheimers Dement %V 7 %P 280-92 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514248?dopt=Abstract %R 10.1016/j.jalz.2011.03.003