Titration dosing of aducanumab: Results of a 12-month interim analysis from a randomized, double-blind, placebo-controlled Phase 1b study (PRIME) in patients with prodromal or mild Alzheimer’s Disease (S7.003)

Objective: To report interim results from a Phase 1b study (PRIME) for fixed-dose and titrated aducanumab. Background: Aducanumab (BIIB037) is a human anti-amyloid beta (Aβ) monoclonal antibody being investigated for early Alzheimer’s Disease (AD). Dose- and ApoE ɛ4-dependent ARIA-E was the main safety/tolerability finding in an interim analysis of PRIME. Titration was tested in the attempt to reduce incidence of ARIA versus fixed dosing. Design/Methods: In this randomized, double-blind, placebo-controlled study (NCT01677572), patients (50–90 years; prodromal/mild AD; positive florbetapir PET scans) were randomized 3:1 to fixed aducanumab doses or placebo every 4 weeks for 52 weeks, stratified by ApoE ɛ4 status. After completion of fixed-dose cohort enrollment, a cohort of ApoE ɛ4 carriers was added who received titrated aducanumab (1 mg/kg [2 doses]; 3 mg/kg [4 doses]; 6 mg/kg [5 doses]; 10 mg/kg thereafter; Week 52 average expected dose: 5.3 mg/kg) or placebo. We report interim safety/tolerability (primary endpoint) and exploratory efficacy endpoints (Aβ reduction by PET at 1 year; Clinical Dementia Rating-Sum of Boxes [CDR–SB] and Mini-Mental State Examination [MMSE]). Results: In total, 196 patients were dosed in PRIME (titration cohort: n=31). Compared with placebo, at 12 months there were significant decreases in brain Aβ with titrated aducanumab (adjusted mean [standard error] change from baseline in PET standard uptake value ratio: −0.171 [0.029] vs 0.014 [0.018], respectively; P Conclusions: Titrated and fixed doses of aducanumab reduced amyloid plaques versus placebo. Clinical effects of titration dosing were generally consistent with fixed dosing. Titration appeared to reduce ARIA-E incidence versus fixed dosing in this small patient cohort. Study Supported by: Study and editorial assistance funded by Biogen. Disclosure: Dr. Viglietta has received personal compensation for activities with Biogen as an employee. Dr. Viglietta holds stock and/or stock options in Biogen. Dr. O9Gorman has received personal compensation for activities with Biogen Idec as an employee. Dr. O9Gorman has received stock while serving as an employee of Biogen Idec. Dr. Williams has received personal compensation for activities with Biogen as an employee. Dr. Williams holds stock and/or stock options in Biogen. Dr. Chen has received personal compensation for activities with Biogen as an employee. Dr. Chen holds stock and/or stock option with Biogen. Dr. Enayetallah has received personal compensation for activities with Biogen Idec as an employee. Dr. Chiao has received personal compensation for activities with Biogen Idec Inc. as an employee. Dr. Chiao holds stock and/or stock options in Biogen. Dr. Hock has received (royalty or license fee or contractual rights) payments from Neurimmune AG. Dr. Nitsch has received personal compensation for activities with Neurimmune as an employee. Dr. Nitsch holds stock and/or stock options with Neurimmune. Dr. Budd Haeberlein has received personal compensation for activities with Biogen and Quartet Medicine as an employee or member of the scientific advisory board. Dr. Sandrock has received personal compensation for activities with Biogen as an employee and Flex Pharma and Neurocrine Pharmaceuticals as a advisor.