The Food and Drug Administration has granted accelerated approval to Aduhelm (aducanumab-avwa) for the treatment of Alzheimer disease.
Aduhelm is a human monoclonal antibody that is derived from a de-identified library of B cells collected from healthy elderly subjects with no signs of cognitive impairment or cognitively impaired elderly subjects with unusually slow cognitive decline. The treatment, which is administered as a monthly intravenous infusion (every 4 weeks and at least 21 days apart), binds to aggregated β-amyloid and promotes removal of amyloid from the brain.
The approval was based on data from the phase 3 EMERGE study (ClinicalTrials.gov Identifier: NCT02484547), which enrolled 1638 adults aged 50 to 85 years with early Alzheimer disease. Results showed that aducanumab high dose met the primary endpoint achieving a statistically significant reduction of 22% in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores at week 78 vs placebo (P =.01).
While the phase 3 ENGAGE study (ClinicalTrials.gov Identifier: NCT02477800) did not meet its primary endpoint (change from baseline in CDR-SB score at 78 weeks), a subset of the data appeared to support the outcome in the EMERGE study. Data from the phase 1b PRIME study (ClinicalTrials.gov Identifier: NCT01677572), which showed that the effect of aducanumab on amyloid plaque was dose and time dependent, also supported approval.
“We know that the Peripheral and Central Nervous System Drugs Advisory Committee, which convened in November 2020 to review the clinical trial data and discuss the evidence supporting the Aduhelm application, did not agree that it was reasonable to consider the clinical benefit of the one successful trial as the primary evidence supporting approval,” said Dr Patrizia Cavazzoni, Director, FDA Center for Drug Evaluation and Research. “After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for accelerated approval.”
The FDA’s accelerated approval pathway is based on a surrogate endpoint, which in the case of Aduhelm was the reduction of amyloid beta plaque. This type of approval is contingent upon verification of clinical benefit in a confirmatory trial.
With regard to safety, the most common adverse reactions reported during clinical trials included amyloid related imaging abnormalities (ARIA)-edema, headache, amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) microhemorrhage, ARIA-H superficial siderosis, and fall.
Aduhelm is supplied in single-dose vials in 170mg/1.7mL and 300mg/3mL strengths. Titration is required for treatment initiation.
- FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. [press release]. Silver Spring, MD: US Food and Drug Administration; June 7, 2021.
- Aduhelm [package insert]. Cambridge, MA and Tokyo, Japan; Biogen and Eisai: June, 7 2021.