乌鸦传媒

A man treated with the recently approved Alzheimer's drug aducanumab (Aduhelm) had six amyloid-related imaging abnormality (ARIA) episodes, researchers reported.

Over 44 months in a long-term extension study, the Alzheimer's disease patient had recurrent episodes of asymptomatic mild or moderate ARIA-edema (ARIA-E), with one episode including mild ARIA-hemorrhage (ARIA-H) with mild superficial siderosis, noted Jacob Hall, MD, of the Neurology Center of Southern California in Temecula, and co-authors in a letter published in .

Brain abnormalities like were first observed on MRI in trials of a monoclonal antibody against amyloid-beta over a decade ago and have since been associated with other amyloid-modifying therapies, including aducanumab.

"With the arrival of anti-amyloid antibody therapies comes increasing concern surrounding ARIA and its management," Hall told 乌鸦传媒.

"For patients who may be prescribed aducanumab, it is of great importance to ensure that prescribers are familiar with the safety and management principles surrounding ARIA," Hall continued. "Appropriate use recommendations and representative case examples will be central tools in this educational effort."

Since its controversial approval on June 7, aducanumab has had a slow uptake in the Alzheimer's field, with some people questioning not only the drug's efficacy, but its adverse effects. In phase III clinical trials, ARIA-E or ARIA-H occurred in roughly 40% of participants in high-dose aducanumab groups. Details about the aducanumab phase III trials and adverse events have not yet been published in a peer-reviewed journal, but ARIA-E episodes generally resolved in 4 to 16 weeks, and most patients with ARIA continued in the studies, drug maker Biogen said.

More recently, a Freedom of Information Act request from the financial services firm Baird uncovered data about three cases of aducanumab-related ARIA reported from June to August 2021 in the FDA's Adverse Event Reporting System (FAERS). All three FAERS cases required hospitalization, and one was involving a 77-year-old woman on multiple other medications who experienced ARIA and status epilepticus, according to Endpoints News. While Baird analysts emphasized that FAERS reports do not ascribe causality, they also noted that "these additional events reflect a picture of a drug that is far from benign."

The recommends that, after titration, Alzheimer's patients should receive doses of 10 mg/kg by infusion every 4 weeks. Brain MRI is required before starting treatment; patients also need to have MRIs before their 7th and 12th infusions. If severe ARIA-H is seen on MRI, treatment may be continued with caution only after clinical evaluation and follow-up MRI shows that ARIA-H is stable.

Case Report

The JAMA Neurology letter described a high-functioning man who first presented with slowly progressive short-term memory and word-finding difficulties in 2007 at age 67. He had a history of first-degree atrioventricular block, hypertension, and hearing loss, and was taking antihypertensives, memantine (Namenda), and donepezil (Aricept). His APOE genotype was ε3/ε4.

In 2014, he enrolled in the phase Ib of aducanumab and was randomized to the placebo arm. In 2015, he entered the long-term extension study and was randomized to titration to 6-mg/kg monthly infusions, the maximum allowed dose for APOE ε4 carriers in early protocol versions.

Asymptomatic ARIA first emerged after four 3-mg/kg doses:

• At month 7, he developed asymptomatic moderate ARIA-E, prompting the dose to be suspended until ARIA resolved at month 10; after that, it was continued at 3-mg/kg dosing.
• At month 12, he developed a symptomatic mild ARIA-E; dosing continued uninterrupted with resolution at month 15.
• At month 18, after receiving two 6-mg/kg doses, he had asymptomatic moderate ARIA-E again, prompting dose suspension until resolution at month 21, followed by dose reduction to 3 mg/kg. At this point, a protocol amendment allowed titration to 10 mg/kg, which was achieved by month 24.
• At month 26, he developed asymptomatic mild ARIA-E, prompting dose reduction to 6 mg/kg, with resolution at month 28.
• At month 29, asymptomatic mild ARIA-E recurred, prompting further dose reduction to 3 mg/kg, with resolution at month 32.
• At month 35, he developed asymptomatic mild ARIA-E and mild ARIA-H with mild superficial siderosis, prompting dose suspension. ARIA-E resolved at month 36 and ARIA-H was stable through month 39; the patient then resumed continued 3-mg/kg dosing.

The trial was halted at month 44 of the long-term extension. "Despite the uniquely complicated course, this participant was able to complete 31 infusions with a cumulative aducanumab dose of 124 mg/kg and his amyloid PET scan became visually negative," Hall said.

In the aducanumab trials, ARIA-E occurred in 35% of participants receiving the 10-mg/kg dose. were particularly susceptible: 42% of participants with an APOE ε4 allele experienced ARIA-E compared with 20% of noncarriers.

for aducanumab have proposed uninterrupted dosing through asymptomatic mild ARIA-E and ARIA-H and dose suspension for asymptomatic moderate to severe ARIA, Hall and co-authors noted. "This participant was treated largely in alignment with these recommendations, although with additional conservative measures taken for later episodes due to number of recurrences," they wrote.

"Of the 46 participants who experienced ARIA-E in the phase Ib trial and long-term extension, recurrent episodes occurred in eight," the researchers observed. "We present a participant treated with aducanumab over 44 months with six asymptomatic ARIA episodes, the most in the three aducanumab trials."

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