40% of EMERGE, ENGAGE participants had amyloid-related imaging abnormalities

Phase 3 studies of Aduhelm showed amyloid-related imaging abnormalities among approximately 40% of participants, according to study results published in JAMA Neurology.

“Amyloid-related imaging abnormalities (ARIA) comprise a spectrum of imaging findings detected on brain magnetic resonance imaging (MRI) and are associated with the investigational use of monoclonal antibodies targeting amyloid-beta (A-beta), including [Aduhelm (aducanumab, Biogen/Eisai)] in patients with Alzheimer disease,” Stephen Salloway, MD, of Warren Alpert Medical School at Brown University in Rhode Island, and colleagues wrote. “

“ARIA can manifest as brain edema or sulcal effusion (ARIA-E) or as hemosiderin deposits resulting from hemorrhage in the brain parenchyma or on the pial surface (ARIA-H),” they continued. “In past clinical trial settings, ARIA-E resolved radiographically over the course of weeks or months, whereas ARIA-H can remain visible on subsequent imaging.”

According to the researchers, ARIA represented the most common adverse event in PRIME, the phase 1b study of Aduhelm, which was followed by the global phase 3 trials EMERGE and ENGAGE that examined the drug’s safety and efficacy in patients with early AD. These latter two trials offered a large safety data set for outlining ARIA and giving insights for real-world practice, Salloway and colleagues noted.

In the current secondary analysis of data from EMERGE and ENGAGE, the researchers aimed to elucidate the radiographic and clinical characteristics of ARIA among the studies’ 3,285 participants with AD (mean age, 70.4 years; 52% women) who received at least one dose of placebo (n = 1,087) or Aduhelm (n = 2,198) during the placebo-controlled period. Main outcomes and measures included brain MRI used to monitor patients for ARIA. Related symptoms were considered adverse events.

A total of 2,661 participants (81%) had mild cognitive impairment because of AD, and 1,777 (54%) used symptomatic medications for AD. Before study completion, 764 EMERGE and 709 ENGAGE participants withdrew, which was related to early study termination by the sponsor.

According to Salloway and colleagues, all results represent analyses from the 10 mg/kg group, unless otherwise specified. A total of 425 of 1,029 patients (41.3%) had ARIA during the placebo-controlled period, with 14 patients (1.4%) exhibiting serious cases. ARIA-E represented the most common adverse event (35.2%), with 263 initial events (72.7%) within the first eight Aduhelm doses. A total of 94 participants (26%) with an event had symptoms. Headache (46.6%), confusion (14.6%) dizziness (10.7%) and nausea (7.8%) represented common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H.

Participants treated with Aduhelm who carried apolipoprotein E epsilon4 alleles had the higher incidence of ARIA-E. Among those with ARIRA-E, 98.2% of events resolved radiographically and 82.8% resolved within 16 weeks. A total of 29 participants (2.7%) in the placebo group had ARIA-E. The researchers observed ARIA-microhemorrhage and ARIA-superficial siderosis among 197 participants (19.1%) and 151 participants (14.7%), respectively.

“In patients with identified ARIA, prescribers should carefully assess the radiographic and clinical findings when deciding whether to continue dosing,” Salloway and colleagues wrote. “Safety data collected while treating patients with [Aduhelm] in real-world settings as well as clinical settings through the phase 3b EMBARK redosing trial and forthcoming FDA-mandated confirmatory clinical studies will continue to inform best practices and characterization of ARIA in the clinic.”