Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus [RETIRED]: A Report of the AAN Guidelines Subcommittee

Abstract

Objective: To identify the class of evidence for aducanumab use for the treatment of Alzheimer disease and present clinical considerations regarding use.

Methods: The author panel systematically reviewed available clinical trial data detailing aducanumab use in individuals with early symptomatic Alzheimer disease. Level of evidence statements were assigned in accordance with the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed.

Results: Data were identified from 4 clinical trials, 1 rated Class I and 3 rated Class II. The Class I study showed that single doses of aducanumab up to 30 mg/kg were safe and well tolerated. All 3 Class II studies provided evidence that aducanumab (3-10 mg/kg) decreased amyloid deposition on brain PET at 1 year vs placebo. Efficacy data in the Class II studies varied by dose and outcome, but aducanumab either had no effect on mean change on the Clinical Dementia Rating Sum of Boxes scores or resulted in less worsening (vs placebo) that was of uncertain clinical importance. Adverse amyloid-related imaging abnormalities occurred in approximately 40% of individuals treated with aducanumab vs 10% receiving placebo.

Clinical context: Administration of aducanumab will require expanded clinical infrastructure. Evidence-based guidance is needed to address key questions (e.g., safety in populations not enrolled in phase 3 studies, expected benefits on daily function, treatment duration) and critical issues relating to access to aducanumab (e.g., coverage, costs, burden of monthly infusions) that will inform shared decision making between patients and providers.

Figure 1. Severe Amyloid-Related Imaging Abnormalities

Magnetic resonance (3T) neuroimaging performed in a 75-year-old woman with early symptomatic Alzheimer disease who presented with increasing headache, confusion, and left-sided weakness. Symptoms developed 4 months following randomization within a phase 3 study of aducanumab. (A, B) T2 fluid-attenuated inversion recovery sequences depicting right frontal and temporoparietal edema with localized mass effect amyloid-related imaging abnormalities with edema/effusion (ARIA-E). (C, D) Susceptibility-weighted images depicting multiple areas of signal change within areas of edema, corresponding to microhemorrhage (amyloid-related imaging abnormalities with edema/effusion with concurrent microhemorrhage/hemosiderosis [ARIA-H]). Images displayed in radiologic convention. Images courtesy of Dr. T.L.S. Benzinger (Washington University in St. Louis, Missouri).

Figure 2. Detection of Microhemorrhages Varies by Magnet Strength and Imaging Technique

(A, B) Gradient-echo MRI obtained on a 1.5T scanner discloses 3 microhemorrhages. (C, D) Susceptibility-weighted imaging on a 3T scanner discloses multiple additional areas of increased susceptibility consistent with microhemorrhages in the anterior and posterior fossae (arrowheads). Scans completed on the same day in the same patient. Images displayed in radiologic convention. Images courtesy of Dr. T.L.S. Benzinger (Washington University in St. Louis, Missouri).