Specifically, the drug’s label calls for three MRI brain scans before, and during, the titration period. The problem is the trial data used for the drug’s approval by the U.S. Food and Drug Administration included five MRIs to screen for ARIA.
“We recommend proceeding as per the clinical trials,” said Meghan Riddle, MD, associate director, Memory and Aging program, Butler Hospital, and assistant professor of psychiatry and human behavior, Brown University, Providence, R.I.
Dr. Riddle shared her team’s clinical experience with aducanumab, as well as information on four ARIA cases from their clinic, during a presentation at the American Association for Geriatric Psychiatry (AAGP) 2022 Annual Meeting.
Significant safety risk?
As previously reported by this news organization, the FDA granted accelerated approval of aducanumab for AD last year.
ARIA is the most common risk associated with aducanumab and has two types: ARIA-E (with edema) and ARIA-H (with hemosiderin). These can co-occur, particularly in areas of high amyloid burden, Dr. Riddle noted during her presentation.
ARIA is often detected incidentally via MRI. Patients are usually asymptomatic, but when they do have symptoms, headache, dizziness, and vision changes are the most common complaints. However, these are generally mild, said Dr. Riddle.
Nevertheless, in some cases, there can be severe sequelae, including severe edema or bleeding and seizures, she added.
A major risk factor for ARIA is apolipoprotein 4 (APOE ε4) status. Carriers are twice as likely to develop ARIA as non-carriers.
“If you’re heterozygote for APOE ε4, you have about a 40% chance of developing ARIA, and if you’re homozygote, you have about a 66% chance of developing ARIA,” Dr. Riddle said.
Given the high rate of ARIA in APOE ε4 carriers, the team from Butler Hospital recommends APOE testing prior to treatment with aducanumab.
The risk for developing ARIA is highest within the year of dose titration, Dr. Riddle noted. The current FDA label recommends obtaining a recent brain MRI, within 1 year, and then scans before the 7th and 12th infusions. However, the protocol during the clinical trials of aducanumab included MRI at baseline and prior to the 5th, 7th, 9th, and 12th infusions.
Dr. Riddle’s group has opted to continue the research protocol with new patients. “There’s concern that the decreased MRI monitoring based on the current FDA label may pose a significant safety risk, particularly among those who we know are already at a higher risk of developing ARIA,” she said.
Dr. Riddle also shared how her team selects aducanumab candidates. They need to have mild cognitive impairment (MCI), a mini-mental state examination (MMSE) score of 24 to 30, and a recent MRI to review for eligibility and APOE testing.
The most common reason for treatment exclusion is advanced disease and comorbidity, such as stroke.
Once approved for treatment, patients receive monthly infusions titrated over 6 months – 1 mg/kg for 2 months, 3 mg/kg for 2 months, 6 mg/kg for 2 months, then 10 mg/kg.
Patients are monitored to ensure safety and tolerability and regular review of MRI findings. In addition, patients and their families receive ongoing education about the drug.
Dr. Riddle and her team permanently discontinue the aducanumab if patients develop microhemorrhage, more than one area of superficial siderosis, more than 10 microhemorrhages, more than two episodes of ARIA, or severe symptoms of ARIA.