Though primary efficacy results have yet to be published, new safety findings from two large, randomized trials of aducanumab offer details on which patients are more likely to experience complications associated with the controversial Alzheimer's drug.
Amyloid-related imaging abnormalities, or ARIA, have been seen linked to a variety of experimental amyloid-lowering treatments for Alzheimer's disease. The abnormalities include brain bleeding (ARIA-H) and brain edema (ARIA-E), detected on magnetic resonance imaging.
In a study published Nov. 22 in JAMA Neurology, Stephen Salloway, MD, director of neurology and the memory and aging program at Butler Hospital and the Martin M. Zucker Professor of Psychiatry and Human Behavior and Professor of Neurology at the Warren Alpert Medical School of Brown University in Providence, R.I., and his colleagues, reported that 41% of 1,029 patients in the high-dose (10 mg/kg) treatment groups of aducanumab (Aduhelm, Biogen) developed ARIA.
Thirty-five percent of the high-dose patients (n = 362) developed ARIA-E, and 94 had symptoms, with headache the most commonly reported, followed by confusion. ARIA-E occurred only sporadically in the placebo groups, while ARIA-H was more common. Microbleeds were seen in 19% of the high-dose patients compared with 6.6% in the placebo group, while superficial siderosis occurred in about 15%, versus 2.2% on placebo. Most of the ARIA-E events occurred during the first eight doses of the infusion treatment. People with one or more copies of the APOE4 genetic variant saw higher risk of ARIA-E associated with treatment compared with noncarriers (hazard ratio [HR] 2.5; 95% confidence interval [CI], 1.90-3.20). Evidence of brain micro-hemorrhages at baseline was associated with higher risk of ARIA-E (HR 1.7; 95% CI, 1.31-2.27) compared with patients without MRI evidence of brain bleeds in the year before treatment began.
Older age independently increased risk of ARIA-H, with a risk that was seen increasing 6% with each additional year of age.
The identically designed EMERGE and ENGAGE trials of aducanumab enrolled nearly 3,300 patients worldwide (mean age 70.4, 52% female). Participants were screened to include only those with amyloid-positive mild cognitive impairment (81% of the cohort) or mild Alzheimer's dementia. Both trials were halted early after a futility analysis concluded that treatment was unlikely to result in benefit.
A post hoc analysis later determined that patients in one trial, EMERGE, showed slight clinical benefit on follow-up in the high-dose group only. The Food and Drug Administration approved the drug in July 2021 on the basis of that finding, overriding the consensus of its independent advisory committee, which was not persuaded. Since then the drug has become synonymous with controversy, not aided by its high list price of more than $50,000 per year, with many insurers and large health care systems refusing to deliver it. The recent reported death of a woman participating in an open-label extension trial of aducanumab, who was admitted to the hospital with brain swelling, has added to safety concerns.
Brain Bleeds and Age Affect Risk
In an interview with MDedge Neurology, neurologist Madhav Thambisetty, MD, PhD, a senior investigator with the National Institute on Aging in Baltimore, and a member of the FDA advisory committee that recommended against approval for aducanumab, said that while physicians are aware that APOE4 carriers face higher risks of treatment-related complications, the new safety findings offer additional guidance on patient selection.
"The older you are the greater your risk of ARIA, and the more micro-hemorrhages you have at baseline the greater your risk. Those are important findings that were not previously well publicized before," Thambisetty said.
In the EMERGE and ENGAGE trials, Thambisetty pointed out, patients with four or more micro-hemorrhages at baseline were excluded. The new findings reveal that even a small number of bleeds at baseline can contribute to ARIA risk.
"Patients in real-world clinical practice are going to be very different from the tightly controlled, well-screened participants who were enrolled in these trials. Microbleeds are very common in Alzheimer's patients, occurring in 18-32%. Now that these findings are available, it's important for a practicing physician to obtain a baseline MRI scan and really pay attention to microbleeds, because that will affect treatment decisions."
Thambisetty cautioned that the new results made no mention of another important safety outcome: loss of brain volume associated with treatment.
Changes in brain volume have been seen associated with other amyloid-lowering treatments, though the reasons for this are poorly understood. Participants in EMERGE and ENGAGE "received numerous MRI scans," Thambisetty said. "This was one of the strengths of the trials. Thanks to an open-label extension we now have more than 2 years of MRI data from meticulously monitored patients, and there has been no mention of brain volume changes despite this being a prespecified outcome. This, for me, is one of the glaring omissions of this paper, and the fact that it's not even mentioned is really worrisome."
The sponsor of the aducanumab trials, Biogen, has yet to publish efficacy findings in a peer-reviewed journal, instead presenting them piecemeal at conferences.
"The current paper was a secondary analysis," Thambisetty said. "The authors say the primary analysis will be published elsewhere. I think it's important to reflect upon the fact that these clinical trials enrolled more than 3,000 participants at more than 300 trial centers in 20 countries. We now have an approved drug that's commercially available. And yet we don't have a single peer-reviewed publication discussing the efficacy data. None of this is in the interest of our patients, or in advancing the science."
The EMERGE and ENGAGE trials were funded by Biogen. Eight of the current paper's 14 authors are Biogen employees. Salloway, the lead author, disclosed financial support from Biogen and other manufacturers, as did two of his coauthors. Thambisetty disclosed no financial conflicts of interest.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
Lead Image: National Institute of Neurological Disorders and Stroke/NIH
Image 1: Memory and Aging Program at Butler Hospital
Image 2: National Institute on Aging
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Cite this: Microbleeds, Age Contribute to ARIA Risk With Aducanumab - Medscape - Nov 30, 2021.