Pooled data from the phase 3 clinical development of aducanumab (Aduhelm; Biogen) suggest that ARIA remains a mostly asymptomatic problem, with MRI providing an effective way to monitor events.
Pooled data from the phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) clinical trials of aducanumab (Aduhelm; Biogen) suggest that incidences of amyloid-related imaging abnormalities (ARIA) are mostly asymptomatic and that the current literature support routine brain MRI as an effective way to monitor for events in clinical practice.
In total, 454 of the 1105 patients treated with high-dose aducanumab in the 2 trials experienced ARIA. Of those, 76% of patients (n = 344) were asymptomatic while 24% (n = 110) reported symptoms—the majority of which were mild (65%; n = 72) or moderate (16%) in nature. In total, 5 patients (4%) experienced severe symptoms. In comparison, the placebo groups (n = 1087) reported 111 individuals with ARIA, of which 95% (n = 106) were asymptomatic and 5% (n = 5) were symptomatic (mild or moderate, n = 4 [80%]).
ARIA management has been an ongoing area of discussion regarding aducanumab, which was approved by the FDA for the treatment of Alzheimer disease in June 2021. These data were presented by Patrick Burkett, MD, PhD, medical director, Global Safety, Biogen, at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-29.
Although ARIA-edema (ARIA-E) was the most common form of the adverse event (AE) reported, with 35% of patients (n = 387) in the treatment groups and 3% (n = 29) of the placebo groups experiencing it, stabilization of ARIA-hemorrhage (ARIA-H) was required for 28% (n = 312) of the treatment and 9% (n = 94) of the placebo groups. Of the total 406 individual cases of ARIA-H, microhemorrhage occurred in 68% (n = 212) of the treatment-group instances and 75% (n = 71) of the placebo-group instances, while superficial siderosis occurred in 51% (n = 162) and 25% (n = 24) of cases, respectively.
“ARIA-E events were typically seen early in treatment, with 50% occurring prior the seventh dose and 90% occurring before the twelfth dose,” Burkett said in his poster presentation. The seventh and twelfth doses were administered at weeks 24 and 44, respectively. All told, 42% (n = 315) of the 749 patients with an APOE4 gene experienced ARIA-E compared to 20% (n = 72) of those without the gene (n = 356).
The most frequently reported symptom of ARIA was headache (13% of participants with ARIA), while other frequent symptoms included confusion (5%), dizziness (4%), visual disturbance (2%), and nausea (2%).
“ARIA events were assessed both radiographically and clinically, and the combination of these clinical and radiographic criteria impacted the management of those events,” Burkett explained. “Most ARIA events, 98%, resolved radiographically during the course of the clinical studies, typically between 12 and 28 weeks after initial detection. The radiographic severity of ARIA was poorly predictive of the symptomatic status of the events. Radiographic events of ARIA-H were typically seen on the same MRI or follow-up for MRI done to monitor ARIA-E events.”
He and colleagues noted in their poster that the study protocol following ARIA-E was to suspend dosing when patients were symptomatic at all, or if they were asymptomatic, to continue dosing unless ARIA-E reached a moderate or severe nature. For ARIA-H, the plan was similar, though when reaching a severe nature, dosing would be discontinued. Serious cases of both ARIA-E and ARIA-H—symptomatic or otherwise—were to result in automatic discontinuation.
Of those who experienced ARIA-E and received at least 1 more dose of aducanumab (n = 172), 58% (n = 100) of cases remained mild and asymptomatic, while 42% (n = 72) experienced change. Of those, notably, new-onset symptoms were reported in roughly 6% (n = 11) of cases, while 40% (n = 69) developed into either moderate (99%) or severe (1%) ARIA cases on MRI.
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