#AAIC21 – Most Aduhelm-linked Imaging Abnormalities Seen as Asymptomatic
Most amyloid-related imaging abnormalities (ARIA) occurring in Alzheimer’s patients receiving Aduhelm (aducanumab) are temporary, moderate in severity, and asymptomatic (without symptoms), according to an analysis of data from the Phase 3 ENGAGE and EMERGE trials.
Most ARIA-edema (ARIA-E), or fluid accumulation in the brain, occurred within the first eight doses (six months) of Aduhelm treatment, supporting current recommendations of MRI scans before dose seven and dose 12.
These findings, along with additional efficacy and biomarker data from Aduhelm trials, were presented by Biogen at the Alzheimer’s Association International Conference (AAIC) 2021, held July 26–30 in Denver, Colorado, and virtually. Aduhelm was developed by Biogen, in collaboration with Eisai.
“Our presentations to the dementia research community at AAIC of this robust set of clinical trial data will allow us to engage directly with scientists and neurologists on in-depth analyses of our findings,” Alfred Sandrock, Jr., MD, PhD, Biogen’s head of research and development, said in a press release.
Lynn Kramer, MD, chief clinical officer of Eisai’s neurology business group, said: “The clinical trial results Biogen shared about our joint asset, ADUHELM, at AAIC are important as we believe the data will help inform the scientific community as we continue to explore the strong scientific rationale behind the amyloid beta pathway as one of the earliest changes that occur in Alzheimer’s disease.”
Aduhelm is a human-made antibody that works by specifically targeting the toxic clumps of beta-amyloid protein, thought to be the underlying cause of Alzheimer’s, while leaving functional amyloid beta proteins unharmed.
Given directly into the bloodstream, its regimen includes an initial titration period, followed by a maintenance dose of 10 mg/kg every four weeks.
It was granted accelerated approval by the U.S. Food and Drug Administration in June as the first disease-modifying therapy for Alzheimer’s.
Accelerated, or conditional, approval is granted to a medication whose immediate availability fulfils an unmet medical need, provided that early evidence of its benefits outweigh potential risks. Aduhelm’s continued use and full approval require further verification of its clinical benefits in Phase 4 confirmatory studies.
Similar applications are currently being reviewed by regulatory agencies in the European Union and in Japan.
ARIA, often associated with amyloid-targeting therapies, were the most common adverse effects of Aduhelm in the placebo-controlled Phase 3 ENGAGE (NCT02477800) and EMERGE (NCT02484547) trials. These trials, combined, evaluated the therapy’s safety and effectiveness in nearly 3,300 adults with early Alzheimer’s, supporting its U.S. approval.
As such, Aduhelm’s label includes recommendations to monitor these events through MRIs prior to the 7th and 12th doses of the therapy.
Now, in the poster “Considerations for the real-world management of ARIA from the aducanumab Phase 3 studies EMERGE and ENGAGE,” researchers presented results of an analysis of pooled ARIA-related data from patients treated with the high, approved dose of Aduhelm (10 mg/kg) in both trials.
This included a total of 1,105 patients given the approved dose and 1,087 participants in the placebo group.
Results showed that 454 patients (41%) in the Aduhelm group experienced an ARIA — most commonly ARIA-E (35%) — compared with 111 patients (10%) given a placebo. Most Aduhelm-treated patients with ARIA (76%) were asymptomatic, and most of these events were mild to moderate in severity, as assessed with MRI.
This highlighted that the MRI-based severity of ARIA alone cannot predict symptomatic status in patients given Aduhelm.
Nearly one-quarter (24%) of participants with ARIA reported symptoms, typically mild or moderate in severity, including headache (13%), confusion (5%), dizziness (4%), visual problems (2%), and nausea (2%).
A total of 40% of participants who continued Aduhelm treatment in the presence of MRI-based mild ARIA and no symptoms showed event worsening on MRI, and 6% became symptomatic.
In the Aduhelm group, ARIA-E was more common among patients carrying the APOE4 gene variant than in those who did not (42% vs. 20%), but there was no difference in severity or symptomatic status. The APOE4 gene variant is a known genetic risk factor for ARIA and for late-onset Alzheimer’s.
Most of these ARIA-E events were mild (30%) or moderate (58%) in severity. Nearly all (98%) resolved during the studies, including 68% by three months and 91% by about 4.5 months. About 10% of Aduhelm-treated patients had recurrent ARIA-E.
The majority of first ARIA-E events occurred within the first eight doses of treatment, especially during titration. About half developed prior to dose seven (nearly six months), and 90% prior to dose 12 (about 10 months).
Most ARIA-E events that became moderate or severe on MRI did so within four weeks (55%) or eight weeks (26%) of initial detection.
For ARIA-H — microhemorrhages and unusual iron deposits known as superficial siderosis — MRI-based severe events were typically asymptomatic and most (83%–92%) overlapped with ARIA-E. Rates of ARIA-H events were similar between groups.
There were no deaths related to ARIA.
These findings highlight that Aduhelm-related ARIA are mostly asymptomatic, and support “the use of routine brain MRI to monitor for events in clinical practice,” the researchers wrote.
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