Brain inflammation known as amyloid-related imaging abnormalities (ARIA) occurred in about 40% of people with early Alzheimer's disease in the two phase III studies of aducanumab (Aduhelm), a secondary analysis of trial data showed.
In an integrated dataset of and findings, 41.3% of 1,029 people on the 10-mg/kg dose of aducanumab experienced ARIA, reported Karen Smirnakis, MD, of drugmaker Biogen in Cambridge, Massachusetts, and co-authors in .
ARIA-edema (ARIA-E) occurred in 35.2% of participants on the 10-mg/kg dose, including 43% of APOE4 carriers. ARIA-microhemorrhage and ARIA-superficial siderosis occurred in 19.1% and 14.7% of participants, respectively. Most people with ARIA were asymptomatic.
Safety findings for aducanumab, which was approved in June to treat Alzheimer's disease, had not been reported in a peer-reviewed journal before. To date, the drug's efficacy findings have not been published.
"It was gratifying to see the details on the incidence of ARIA in the two aducanumab trials appear in a peer-reviewed publication," noted David Knopman, MD, of the Mayo Clinic in Rochester, Minnesota, who was not involved with the analysis.
"These results have been previously presented in public, and there are no surprises about the high rate of ARIA overall and its increased predilection for persons who carry the APOE4 allele," Knopman told 鶹ý. "Also, the low but not trivial risk of serious consequences of ARIA was well known."
"The relevance or concern about the ARIA data have clinical meaning only in relation to the efficacy of aducanumab, something that was deemed inconclusive by the FDA," Knopman added. "We are still awaiting a presentation of the efficacy data from the two phase III aducanumab trials in a peer-reviewed publication. It's rather unsatisfying to review safety data without also having efficacy data."
Aducanumab was approved based on two parallel phase III studies of people with mild cognitive impairment or very early dementia due to Alzheimer's disease. Both trials were stopped for futility. Subsequent analysis showed reduced clinical decline in one study, but not the other.
The recommends that, after titration, Alzheimer's patients should receive maintenance doses of 10 mg/kg by infusion every 4 weeks. Prescribing information includes a warning for ARIA. Brain MRI is required before starting treatment, and patients need to have MRIs before their seventh and 12th infusions. If severe ARIA-hemorrhage (ARIA-H, which includes microhemorrhages, larger hemorrhages, and superficial siderosis) is seen on MRI, treatment may be continued with caution only after clinical evaluation and follow-up MRI shows that ARIA-H is stable.
ARIA Findings
The analysis looked at 1,029 phase III study participants who had received the 10-mg/kg dose and who had at least one post-baseline scan. MRIs were interpreted by radiologists with expertise in ARIA who classified findings as mild, moderate, or severe. Based on the study protocol, participants with radiographically mild and asymptomatic ARIA could continue dosing without interruption.
ARIA-E was the most common adverse event in the pooled data, affecting 362 people (35.2%). In 72.7% of ARIA-E episodes, initial events occurred within the first eight aducanumab doses. Most first ARIA-E events occurred before the scheduled 12th dose (by week 44).
ARIA-E was severe in 12.2% of cases, moderate in 57.7%, and mild in 30.1%. Recurrent ARIA-E episodes occurred in 10.6% of participants.
ARIA-microhemorrhage affected 197 people (19.1%), and localized superficial siderosis affected 151 (14.7%). Brain hemorrhages measuring more than 1 cm in diameter were rare and occurred in three people (0.3%), similar to placebo. ARIA-H occurred more frequently in people who also had ARIA-E: microhemorrhages occurred in 40.3% and superficial siderosis occurred in 38.7%.
Of people with ARIA-microhemorrhage, 11.7% had severe episodes. Of those with ARIA-superficial siderosis, 21.9% had severe episodes.
Overall, 75.8% of people with any ARIA were asymptomatic. Of 103 people with symptomatic ARIA, most had headache (46.6%), followed by confusion (14.6%), dizziness (10.7%), and nausea (7.8%). Less frequent ARIA symptoms included fatigue, visual impairment, blurred vision, and gait disturbance, each occurring in 4.9% of symptomatic participants.
Severe symptoms during ARIA included seizure, which occurred in four people (3.9% of people with symptomatic ARIA). Seizures also occurred in nine people in the placebo group. No deaths due to ARIA were reported.
Within 16 weeks, 82.8% of ARIA-E episodes resolved on MRI. Most ARIA-microhemorrhage (68.5%) and ARIA-superficial siderosis (92.5%) events stabilized within 8 weeks.
Trial Protocol
In EMERGE and ENGAGE, 1,076 people received placebo; other participants also received lower doses of aducanumab. Doses were administered every 4 weeks by infusion. Mean age of participants was 70.4, and 52% were female. Most people (81%) had mild cognitive impairment due to Alzheimer's disease. People taking non-aspirin antiplatelet agents or anticoagulation treatments were excluded from the study.
ARIA occurred most frequently in people on the 10-mg/kg dose, but was also seen in the 6-mg/kg (26.5%) and 3-mg/kg (36.2%) groups.
"Important to the interpretation of ARIA-H incidence in this study is the fact that patients with pre-existing microhemorrhages (more than four) or areas of superficial siderosis were excluded from the phase III trials, which may have contributed to the overall observed incidence of ARIA-H," Smirnakis and co-authors noted.
Limitations to the analysis included the early termination of the trials: 35% of EMERGE and 30% of ENGAGE participants withdrew at that point, leading to fewer people completing a full course of dosing. Most people in the phase III aducanumab trials were white, and results may not apply to other populations, the researchers acknowledged.
Besides this analysis, recent reports include a man who experienced six episodes of ARIA-E while being treated with aducanumab. In addition, the FDA and Biogen are investigating the admitted to the hospital with seizure and diagnosed with cerebral edema thought to be ARIA-E.
Disclosures
The EMERGE and ENGAGE trials were funded by Biogen.
Smirnakis is a shareholder of Biogen. Some co-authors also are Biogen shareholders; others reported relationships with Biogen, Eisai, Avid, Lilly, Novartis, Genentech, Roche, Bayer, IXICO, Combinostics, Janssen, Merck, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust, and Queen Square Analytics.
Knopman serves on a data safety monitoring board for the DIAN study. He also serves on a data safety monitoring board for a tau therapeutic for Biogen but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, and Alzeca Biosciences but received no personal compensation. He receives funding from the NIH. He also is a former member of the FDA Peripheral and Central Nervous System Drugs Advisory Committee.
Primary Source
JAMA Neurology
Salloway S, et al "Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease" JAMA Neurol 2021; DOI: 10.1001/jamaneurol.2021.4161.