Randomized, Double-Blind, Placebo-Controlled Studies to Evaluate Treatment with Aducanumab (BIIB037) in Patients with Early Alzheimer’s Disease: Phase 3 Study Design (S1.003)

OBJECTIVE: To describe the design of two Phase 3 studies evaluating efficacy and safety of aducanumab (BIIB037) in patients with Early Alzheimer’s disease (AD). BACKGROUND: Aducanumab is a human monoclonal antibody against aggregated amyloid beta (Aβ) being investigated as a disease-modifying treatment for AD. Interim results from an ongoing Phase 1b study in prodromal/mild AD demonstrated target engagement, pharmacodynamic effect of Aβ reduction, and a clinical effect on exploratory outcomes; the main safety/tolerability findings were amyloid-related imaging abnormalities (ARIA). DESIGN/METHODS: Two randomized, placebo-controlled, Phase 3 studies (ENGAGE; EMERGE), identical in design, are enrolling patients (N≍1350, ≍150 sites per study) aged 50-85 years, with Early AD, Clinical Dementia Rating (CDR) Global Score 0.5, Repeatable Battery for Assessment of Neuropsychological Status score ≤85, Mini-Mental State Examination (MMSE) score 24-30, and presence of brain amyloid (measured by PET). For the 18-month placebo-controlled period, patients will be randomized 1:1:1 to monthly IV low- (3 or 6 mg/kg) or high-dose (6 or 10 mg/kg) aducanumab (based on ApoE4 carrier status; dose titration to limit ARIA), or placebo. The primary endpoint is change from baseline in CDR-Sum of Boxes score (Week 78). Secondary endpoints are change from baseline in MMSE, AD Assessment Scale-Cognitive Subscale, and AD Cooperative Study-Activities of Daily Living Inventory (MCI version) scores (Week 78). Tertiary endpoints include safety, pharmacokinetics, and clinical, radiologic, and patient/informant-reported outcomes. Following the placebo-controlled period, individuals may enter the 24-month dose-blind extension in which those randomized to placebo in placebo-controlled period will be re-randomized 1:1 (based on ApoE e4 carrier status) to low- or high-dose aducanumab, to evaluate long-term safety, tolerability and efficacy of aducanumab. RESULTS: N/A. CONCLUSION: ENGAGE and EMERGE are Phase 3 clinical trials designed to confirm the clinical efficacy and safety profile of aducanumab in individuals with Early AD. Study support: funded by Biogen Disclosure: Dr. Viglietta holds stock and/or stock options in Biogen Idec. Dr. O9Gorman holds stock and/or stock options in Biogen Idec. Dr. Williams holds stock and/or stock options in Biogen Idec. Dr. Tian has received personal compensation for activities with Biogen as an employee. Dr. Tian holds stock and/or stock options in Biogen which sponsored research in which Dr. Tian was involved as an investigator. Dr. Sandrock holds stock and/or stock options in Biogen as an employee of the company. Dr. Doody has received research support from Accera, Genentech, Merck Serono, and Takeda. Dr. Salloway has receiveed research support for the conduct of clinical trials sponsored by Lilly, Merck, Roche, Functional Neuromodulation, Biogen, Genentech, and Avid. Dr. Barkhof has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, Genzyme, Janssen Research, Merck Serono, Novartis, Roche, Sanofi, Synthon BV, and Teva as a consultant. Dr. Vellas has received personal compensation for activities with Biogen Idec, GlaxoSmithKline, Lilly, Lundbeck, Medivation, MSD, Nestle, Nutricia, Pfizer, Roche, Sanofi, Servier, and TauRx Therapeutics. Dr. Sano has received personal compensation for activities with Biogen, Eli Lilly, F Hoffman-La Roche Ltd, Forum Pharmaceutical, Genentech, Neurocog Trials, Otsuka, Takeda, Targaset, and VTV Therapeutics. Dr. Aisen receives research support from Eli Lilly, the Alzheimers Association & the NIH and NIA. Dr. Sevigny holds stock and/or stock in Biogen Idec.