Brain Edema, Imaging Abnormalities Reported for Alzheimer’s Drug

Treatment with donanemab (Kisunla) raised the risk of amyloid-related imaging abnormalities (ARIA) in people with early symptomatic Alzheimer’s disease, a secondary analysis of trial data showed.

In phase II and III trials of nearly 2,000 participants, the frequency of ARIA was 37% in the donanemab group compared with 14.2% in the placebo group, reported John Sims, MD, of Eli Lilly and Company in Indianapolis, and co-authors. In an open-label extension of about 1,000 patients treated with donanemab, the frequency of ARIA was 32%.

ARIA with edema or effusions (ARIA-E) occurred in 24.4% of donanemab-treated patients in the placebo-controlled trials and 19.8% of donanemab-treated patients in the open-label extension. ARIA with microhemorrhages or hemosiderin deposits (ARIA-H) occurred in 31.3% and 27.2%, respectively, the researchers noted in JAMA Neurology.

ARIA was associated with APOE4 status and baseline imaging findings. Most ARIA events were mild or moderate, asymptomatic, and initially presented within the first six donanemab infusions. In 58.3% of donanemab-treated participants with ARIA-E, the first event occurred by the third infusion; symptoms most frequently reported were headache and confusion.

In the placebo-controlled studies, there were 17 deaths in the donanemab groups and 12 deaths among people who received placebo. In the phase III trial, three donanemab-treated participants had serious ARIA and subsequently died. Besides the ARIA-related deaths, there was no pattern or trend in the events leading to deaths in the placebo-controlled trials and the open-label addendum.

Beyond these studies, one patient, an APOE4 heterozygote, died due to ARIA-E after the fifth donanemab dose in the long-term extension of the phase III trial, Sims and co-authors said. One death also occurred following thrombolytic administration for potential acute stroke-like symptoms in a donanemab-treated patient; an MRI the same day showed severe ARIA-E and the patient subsequently died due to intracranial hemorrhage.

“While ARIA-E events were typically transient and asymptomatic, ARIA can be serious, life threatening, or fatal; therefore, safety monitoring is necessary with donanemab as with other amyloid-targeting therapies used in slowing disease progression in early symptomatic Alzheimer’s disease,” Sims and colleagues wrote.

Donanemab is an amyloid-directed antibody approved in 2024 to treat Alzheimer’s disease. Its label carries a boxed warning for ARIA-E and ARIA-H, stating that ARIA is often asymptomatic, that ARIA-E can mimic ischemic stroke, and that serious intracerebral hemorrhages can occur. The warning also indicates that APOE4 homozygotes treated with this class of medication have a higher incidence of ARIA.

To help clinicians understand and communicate risks to patients, the American Academy of Neurology (AAN) Quality Committee published practical guidance in 2023 about patient selection and treatment monitoring with anti-amyloid monoclonal antibody therapies, which also include lecanemab (Leqembi).

The donanemab secondary analysis “largely reinforces some of the key observations in the donanemab clinical trials — that careful patient selection and close monitoring are paramount to the safe administration of the drug,” noted AAN committee member Lyell Jones, MD, of the Mayo Clinic in Rochester, Minnesota. “It also underscores prior observations that complications tend to emerge early in the course of donanemab administration,” Jones told MedPage Today.

“While these complications and the primary outcome in this analysis are called ‘amyloid-related imaging abnormalities,’ it’s important to recall that these are not always isolated imaging findings, and a meaningful proportion of patients have symptomatic complications with this class of drugs,” Jones added. “It should also be noted that most of the investigators in this study are affiliated with or employed by the drug manufacturer.”

The analysis used data from the placebo-controlled portions of the phase II TRAILBLAZER-ALZ and phase III TRAILBLAZER- ALZ 2 randomized trials, which were conducted from December 2017 to December 2020 and from June 2020 to April 2023, respectively. Additional data from a stand-alone open-label addendum conducted from August 2021 through August 2023 were also included. The ongoing TRAILBLAZER-ALZ 2 long-term extension study was not part of the analysis.

The study included 257 people from TRAILBLAZER-ALZ, 1,736 people from TRAILBLAZER-ALZ 2, and 1,053 people from the open-label addendum. All had early symptomatic Alzheimer’s disease and elevated amyloid levels. The placebo-controlled trials had tau inclusion criteria, but the addendum study did not.

Mean age was 74, and 55.6% were women. Participants received donanemab or placebo intravenously every 4 weeks for up to 72 weeks. Outcomes were assessed through 76 weeks.

ARIA-E was associated with six baseline variables. Risk was increased with a higher number of APOE4 alleles, a greater number of microhemorrhages, the presence of cortical superficial siderosis, greater amyloid plaque, and elevated mean arterial pressure. Risk was decreased with use of antihypertensives.

Longer-term information about people who experienced ARIA during the trials are needed, Sims and co-authors acknowledged.

Modified dose titration may reduce ARIA occurrence, they noted. Early data from the phase IIIb TRAILBLAZER-6 study showed an alternate dosing plan lowered the risk of ARIA-E.

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