Considerations for the real‐world management of ARIA from the aducanumab phase 3 studies EMERGE and ENGAGE

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Abstract Background Amyloid‐related imaging abnormalities (ARIA), a spectrum of imaging findings detected on brain magnetic resonance imaging (MRI), are associated with the investigational use of amyloid‐targeting monoclonal antibodies, including aducanumab, in patients with Alzheimer’s disease (AD). EMERGE (NCT02484547) and ENGAGE (NCT02477800) were Phase 3 studies that evaluated the efficacy and safety of aducanumab in patients with early AD. Methods ARIA risk minimization included dose titration, routine brain MRI monitoring, ad hoc MRI testing as clinically indicated, and among patients who developed ARIA, possible dose suspension or permanent discontinuation. The criteria for dose suspension or discontinuation were based on the radiographic severity of ARIA and presentation of clinical symptoms. On detection of an ARIA episode, follow‐up MRIs were conducted approximately every 4 weeks to document radiographic resolution of ARIA‐edema (ARIA‐E) or stabilization of ARIA‐hemorrhage (ARIA‐H), which refers to brain microhemorrhages and localized superficial siderosis. Results The integrated data set from EMERGE and ENGAGE consisted of 3285 participants (aducanumab treated, n=2198; placebo treated, n=1087). In the 10‐mg/kg group (n=1029 with ≥1 postbaseline MRI), ARIA‐E was the most common adverse event (35.2%), with a higher incidence in apolipoprotein ε4 carriers compared with noncarriers (43.0% versus 20.3%, respectively). Radiographic severity of ARIA‐E was characterized as mild (30.1%), moderate (57.7%), or severe (12.2%). ARIA‐E typically occurred within the first 32 weeks of treatment with aducanumab and were mostly asymptomatic (74.0%). Among participants who reported symptoms in the setting of ARIA, the majority of symptoms during ARIA were characterized as mild (67.7%) or moderate (28.3); the most common symptoms were headache (46.6%), confusion (14.6%), dizziness (10.7%), and nausea (7.8%). ARIA‐E were transient but recurred in 10.6% of participants in the 10‐mg/kg group. ARIA‐H microhemorrhage and superficial siderosis were typically asymptomatic and more common in participants who had ARIA‐E (40.3% and 38.7%, respectively), compared with participants without ARIA‐E (7.6% and 1.6%, respectively). In participants with ARIA‐E and ARIA‐H, these events frequently overlapped temporally. There were no fatal events due to ARIA. Conclusions ARIA are mostly asymptomatic; evidence supports the use of routine brain MRI to monitor for events in clinical practice.

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