BOSTON—Compared with fixed dosing, dose titra- tion 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.
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 Enayet-allah, 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
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. NR
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces
Aβ plaques in Alzheimer’s disease. Nature. 2016;537(7618):
Dose Titration May Reduce Risk
of ARIA Associated With Aducanumab
The treatment appears to decrease the burden of amyloid plaques and slow
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.