BOSTON—Compared with fixed dosing, dose titration appears to reduce the risk of amyloid-related imaging abnormalities (ARIA) associated with aducanumab, according to research presented at the 69th Annual Meeting of the American Academy of Neurology. The drug also may reduce the burden of amyloid plaques and slow cognitive decline.
Ahmed Enayetallah, MD, PhD
Aducanumab is a human anti-amyloid beta monoclonal antibody under investigation for early Alzheimer’s disease. In an interim analysis of the PRIME study, dose- and APOE ε4-dependent ARIA of the edema type was the main safety and tolerability finding. Ahmed Enayetallah, MD, PhD, of Biogen, and colleagues investigated whether dose titration would reduce the incidence of ARIA, compared with fixed dosing.
In a double-blind, placebo-controlled study, the researchers randomized participants with prodromal or mild Alzheimer’s disease 3:1 to fixed doses of aducanumab or placebo every four weeks for 52 weeks, stratified by APOE ε4 status. After the enrollment of this cohort, the investigators added a cohort of APOE ε4 carriers who received titrated aducanumab or placebo. Patients assigned to aducanumab received two 1-mg/kg doses, four 3-mg/kg doses, five 6-mg/kg doses, and 10-mg/kg doses thereafter.
The trial’s primary end points were safety and tolerability. Exploratory efficacy end points included amyloid beta reduction by PET at one year, Clinical Dementia Rating–Sum of Boxes (CDR–SB), and Mini-Mental State Examination (MMSE).
A total of 196 patients were dosed in the study, and the titration cohort included 31 participants. The treatment groups were well balanced. Compared with placebo, titrated aducanumab was associated with significant decreases in brain amyloid beta at 12 months. The adjusted mean change from baseline in PET standard uptake value ratio was –0.171 versus 0.014, respectively. The difference was observable at week 26 and was maintained to week 54.
Titrated aducanumab also was associated with a slowing of clinical decline on CDR–SB and MMSE. Results in the titration cohort were generally consistent with those reported in fixed-dose cohorts. The incidence of ARIA was lower with titrated dosing versus higher fixed dosing of aducanumab in APOE ε4 carriers. The researchers did not find any new safety signals in the titration cohort during the placebo-controlled period.
Biogen funded the study.
Suggested Reading
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537(7618):50-56.