Though primary efficacy results have yet to be published,
Courtesy of Memory and Aging Program at Butler Hospital
Dr. Stephen Salloway
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.
Safety findings
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.