Aims

To characterize the aducanumab Phase 3 safety profile.

Methods

EMERGE and ENGAGE were identically-designed, randomized, double-blind, placebo-controlled Phase 3 studies that evaluated the efficacy and safety of aducanumab in patients with early Alzheimer’s disease (AD; mild cognitive impairment due to AD or mild AD dementia). Participants received (via intravenous injection) high-dose aducanumab, low-dose aducanumab, or placebo, monthly, randomized 1:1:1, for 18 months. Amyloid Related Imaging Abnormalities (ARIA) risk minimization included dose titration, routine brain magnetic resonance imaging (MRI) monitoring and dose suspension. An independent data monitoring committee routinely reviewed safety data. To minimize the potential of functional unblinding due to ARIA, clinical efficacy raters were different from the raters who assessed and monitored safety and efficacy raters remained blinded to all safety assessments.

Results

The integrated dataset from EMERGE and ENGAGE consisted of a total of 3,285 participants (n=2,198 aducanumab-treated; n=1087 placebo-treated) who received at least 1 dose during the placebo-controlled period. ARIA-Edema (ARIA-E) were the most common adverse events (35.2%) in the 10 mg/kg group, with a higher incidence in apolipoprotein ε4 (ApoE ε4) carriers compared to noncarriers (43.0% versus 20.3%, respectively). ARIA-E were transient and typically asymptomatic (74.0%). Brain microhemorrhages and localized superficial siderosis were typically asymptomatic and were more common in aducanumab-treated participants who had ARIA-E (40.3% and 38.7%, respectively), compared to participants without ARIA-E (7.6% and 1.6%, respectively). There were no fatal events due to ARIA.

Conclusions

ARIA are predominantly transient and asymptomatic and can be mitigated with dose titration and routine brain MRI monitoring