Randomized, placebo-controlled, phase 1b study of anti-beta-amyloid antibody aducanumab (biib037) in prodromal ad/mild ad dementia: Interim results by patient subgroup

Background: Aducanumab (BIIB037) is a human mAb against aggregated Aβ peptide being investigated as a disease-modifying AD treatment. Objective: Present interim safety, Aβ reduction, and mini-mental state examination (MMSE) and Clinical Dementia Rating sum of boxes (CDR-sb) changes by disease stage and ApoE4 status. Methods: In this multicenter, double-blind, placebo-controlled, multiple-dose study (PRIME; NCT01677572), patients (age 50-90 years) had positive florbetapir (Amyvid) PET scan and met clinical criteria for prodromal AD or mild AD dementia. Necessary patient/IRB approvals were obtained. Patients received aducanumab or placebo once every 4 weeks for 52 weeks in 7 arms stratified by ApoE4 status. Interim analyses include results to Week 30 (all arms) and Week 54 (placebo, 1, 3, 10 mg/kg; data for 6 mg/kg not yet available). Results: 165 patients were randomized and dosed with placebo, 1, 3, 6, or 10 mg/kg aducanumab (65% ApoE4 carriers; 41% had prodromal AD). Incidence (MRI-based) of the most common AE, amyloid-related imaging abnormalities (ARIA), was dose and ApoE4-status–dependent (ARIA-edema, ApoE4 carriers: 0%, 5%, 5%, 43%, 55%, for placebo, 1, 3, 6, 10 mg/kg aducanumab, respectively; ApoE4 non-carriers: 0%, 0%, 9%, 11%, 17%). Dose- and time-dependent brain Aβ reductions (standard uptake value ratio change) were observed, which were consistent across mild/prodromal and ApoE4 carrier/non-carrier subgroups. Dose-dependent slowing of MMSE and CDR-sb decline was observed at 1 year across disease stages/ApoE4 genotypes. Conclusions: Dose- and ApoE4-dependent ARIA was the main safety finding. Aducanumab reduced Aβ plaques and slowed MMSE/CDR-sb decline across clinical stages and ApoE genotypes.