Aducanumab’s Label Updated to Include Risks on Brain Bleeding

The newly updated label warns patients on aducanumab about the potential risks of brain bleeding, which can be significant and life-threatening.

The FDA has updated its safety-related labeling for aducanumab (Aduhelm; Biogen), an antiamyoid therapy approved for early Alzheimer disease (AD), to better characterize the risk of potential bleeding in the brain while on the therapy.1

Approved by the FDA Center for Drug Evaluation and Research (CDER), the update cited events of intracerebral hemorrhage greater than 1 cm in diameter in patients on aducanumab, and stated that the use of antithrombotic or thrombolytic medications while on the therapy may increase the risk of bleeding in the brain.

Aducanumab gained FDA approval in June 2021 based on 2 phase 3 trials—EMERGE (NCT02484547) and ENGAGE (NCT02477800)—1 of which met its primary end point and 1 that did not. In addition to its efficacy in question, the most common adverse event (AE) observed in these studies were ARIA-edema, occurring at rates of 25.7% and 25.4% in the EMERGE and ENGAGE low-dose groups, respectively, and rates of 34.0% and 35.5% in the EMERGE and ENGAGE high-dose groups, respectively. Comparatively, the placebo group experienced respective ARIA-E rates of 2.2% and 3% in EMERGE and ENGAGE.2,3

Although ARIA can occur in any patient treated with aducanumab, the label informs patients that there is an increased risk in patients who are apolipoprotein (APOE) e4 homozygotes, and that there are tests available to determine APOE e4 genotype. Additionally, the updated patient counseling information encouraged patients to participate in the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET), a voluntary provider-enrolled patient registry that collects information on treatments for AD, including aducanumab.1

In the medication guide section of the updated labeling changes, the FDA pointed out that most people with ARIA-type swelling in the brain do not get symptoms; however, some may experience symptoms such as headache, nausea, confusion, difficulty walking, dizziness, vision changes, and seizures. "Instruct patients to notify their healthcare provider if these symptoms occur," the label stated. MRI scans are typically performed before and during treatment with aducanumab to check for ARIA.

This was the second time changes were made to the safety labeling of aducanumab, the first coming in April 2022. The first revisions formally recognized that seizures are a potential adverse effect.4

Because it was approved under the accelerated approval pathway, Biogen is required to conducted phase 4 studies to confirm aducanumab’s efficacy. In June 2022, the company began its phase 4 ENVISION trial (NCT05310071), enrolling 1500 people with early AD who will be assessed for an 18-month treatment period. A long-term extension will last up to 4 years, with results expected by 2026.5

1. Drug Safety-related Labeling Changes: Aduhelm. FDA. Updated February 8, 2023. Accessed February 15, 2023.
2. Biogen plans regulatory filing for aducanumab in Alzheimer’s Disease based on new analysis of larger dataset from phase 3 studies. News release. Biogen and Eisai. October 22, 2019. Accessed February 15, 2023.
3. Budd Haeberlein S, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Presented at: 12th Annual CTAD Meeting; December 4-7, 2019; San Diego, CA.
4. Drug Safety-related Labeling Changes: Aduhelm. FDA.
5. Biogen Submits Final Protocol for ADUHELM® (aducanumab-avwa) Phase 4 ENVISION Trial to FDA. News release. Biogen. March 30, 2022. Accessed February 15, 2023.
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