Despite the premature halting of the ENGAGE and EMERGE trials due to futility analysis, the EMERGE trial demonstrates an improvement in Alzheimer disease (AD) symptoms with aducanumab compared to placebo.
After stopping for futility, identically designed trials ENGAGE and EMERGE reveal diverging results; reappraisal of EMERGE trial data demonstrates an improvement of AD symptoms with aducanumab administration versus placebo.
Dr. Budd Haeberlein, principal researcher for Biogen in Cambridge, Massachusetts, and colleagues reported their findings in the March 18, 2022, issue of the Journal of Prevention of Alzheimer’s Disease.
Aducanumab is a human monoclonal antibody that targets amyloid beta, a protein that accumulates in the brain and is implicated in the development of progressive and irreversible AD. Aducanumab’s efficacy was assessed through 2 double-blind, phase 3 trials: EMERGE and ENGAGE.
A total of 1812 patients aged 50 to 85 years with mild AD and confirmed amyloid pathology completed the 78-week protocol in either EMERGE or ENGAGE. Patients were randomized 1:1:1 to receive high-dose aducanumab, low-dose aducanumab, or placebo.
In both trials, the primary outcome measure was change in Clinical Dementia Rating Sum of Boxes (CDR SB) from baseline to week 78. Secondary and tertiary outcome measures included auxiliary dementia scales and assessment of daily living aptitude.
The trials commenced in August 2015. A futility analysis based on data completed by December 2018 showed that treatment was unlikely to confer a clinical benefit, and the trials were halted on March 21, 2019. However, Dr. Budd Haeberlein and colleagues reasoned that changes in the treatment protocols partway through the trials rendered earlier data unable to predict later results, thus invalidating the futility analysis assumptions.
Subsequent analysis, including all data completed before the futility declaration, showed mixed results.
In EMERGE, the primary endpoint was met, with patients receiving high-dose of aducanumab demonstrating a difference of −0.39 in CDR-SB score at week 78 versus those receiving placebo (95% CI, −0.69 to −0.09; P = .012). Significant differences were also achieved in all secondary and tertiary endpoints.
In contrast, ENGAGE did not meet its primary endpoint. At week 78, patients receiving high-dose aducanumab demonstrated no significant difference in CDR-SB score compared to placebo (0.03 difference; 95% CI, −0.26 to 0.33).
Rates of adverse events were equal between trials, with amyloid-related imaging abnormalities (ARIA) being most common. Aside from ARIA, the types and frequencies of adverse events were similar to symptoms generally experienced by patients with AD.
“EMERGE is the first phase 3 trial to demonstrate an association between reduction of biomarkers of AD pathology and a statistically significant slowing of clinical decline,” concluded Dr. Budd Haeberlein and colleagues. They added, “Clinical efficacy of aducanumab will be further evaluated in a forthcoming clinical trial.”
The trials were sponsored by Biogen.
The Journal of Prevention of Alzheimer’s Disease. Published March 18, 2022