Aducanumab for Symptomatic Alzheimer Disease

Background and Objective

Alzheimer disease (AD) is a neurodegenerative process initially associated with episodic memory decline and pathologically associated with β-amyloid plaques and neurofibrillary tangles. Aducanumab, a recombinant human IgG1 monoclonal antibody that promotes amyloid clearance, has been FDA-approved for patients with mild cognitive impairment and mild dementia due to AD (NEJM JW Neurol Nov 2021 and N Engl J Med 2021; 385:769). This report from the AAN Guidelines Subcommittee was created to assist in the interpretation of published data for clinical decision-making.

Key Points

Evidence Summary:

• An ascending-dose, phase I study of aducanumab for patients with AD provided class I evidence that single doses of aducanumab up to 30 mg/kg are safe and tolerable (Alzheimers Dement (N Y) 2016; 2:169).

• PRIME, a multiple-dose, phase II study of aducanumab for patients with prodromal or mild AD (J Nucl Med 2019;60:100) showed class II evidence that aducanumab (3–10 mg/kg) decreases the amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR) at 1 year versus placebo; an exploratory analysis showed that doses of 10 mg/kg are associated with less worsening of the Clinical Dementia Rating (CDR) Sum of Boxes score at 1 year versus placebo.

• ENGAGE and EMERGE, two phase III studies of aducanumab for patients with early AD, were terminated after an interim futility analysis.

• ENGAGE showed class II evidence that aducanumab (3–10 mg/kg) decreases amyloid PET SUVR but does not significantly affect a mean change in CDR Sum of Boxes scores at 78 weeks versus placebo.

• EMERGE, with an identical design as ENGAGE, also showed decreases in amyloid PET SUVR values; doses at 10 mg/kg showed less worsening of CDR Sum of Boxes scores at 78 weeks that was of uncertain clinical importance versus placebo.

• In ENGAGE and EMERGE, adverse amyloid-related imaging abnormalities (ARIA) were seen in 40% of patients receiving aducanumab versus 10% of those receiving placebo.

Regulatory Decisions:

• The FDA approved aducanumab based on the reduction of amyloid burden on amyloid PET imaging.

Clinical Considerations:

• Aducanumab, as a weight-based infusion administered every 4 weeks and titrated to 10 mg/kg over 6 months, is the first FDA-approved medication to target underlying neuropathology for AD. But whether the treatment leads to clinically meaningful outcomes requires further study.

• Current FDA recommendations for the use of aducanumab are for those with early symptomatic AD. Although these recommendations do not require objective evidence of amyloid deposition prior to treatment, treatments that target underlying AD pathology should be reserved for patients who have elevated cerebral amyloid with validated amyloid PET and cerebrospinal AD biomarkers.

• Aducanumab should be avoided in patients at high risk for serious adverse effects, such as those who are taking anticoagulants or who have a history of symptomatic hemorrhage.

• Per prescribing recommendations, a brain MRI should be performed at baseline (within 1 year of aducanumab initiation) and before the 7th and 12th monthly infusions; clinical evaluation and brain MRI are also indicated if a patient has signs or symptoms of ARIA.

• Apolipoprotein E4 carriers treated with aducanumab (10 mg/kg) were more likely to have ARIA in the ENGAGE and EMERGE trials, which may inform risk stratification.

• The optimal duration of treatment with aducanumab is unknown, and FDA prescribing instructions do not include treatment duration information. Considerations may include coverage, access, adverse effects, efficacy perception, shared decision making, and biomarker criteria.

• A team-based approach is essential for dementia care. Substantial investment in creating an appropriate infrastructure for the safe administration of aducanumab treatment is needed, including availability of clinicians with expertise in appropriately staging AD, outpatient infusion space, specialized nursing services for patient monitoring, and increased capacity to obtain AD biomarker data.

• Average cost of aducanumab treatment is >$75,000 per year; what costs will be covered by payers is unknown.

• Obtaining patient and caregiver preferences is important when making treatment decisions.

Future Research:

• Future directions include safety and efficacy in patients excluded from the clinical trials (including underrepresented minorities and those with atypical presentations of AD or concurrent pathology), as well as whether reduction of amyloid is associated with clinically meaningful outcomes.