Aducanumab

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 06.15.2021
Released 06.15.2021
Expires For CME 06.15.2024

Aducanumab

Author: K K Jain MD†

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Aducanumab

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Introduction

Overview

Aducanumab, a monoclonal antibody, is the first approved treatment for the underlying biology of Alzheimer disease. It was approved by the U.S. Food and Drug Administration on June 7, 2021. Clinical trials showed that the drug, administered intravenously, crossed the blood-brain barrier and cleared amyloid deposits in the brain, which was used as the endpoint rather than clinical improvement. In a subset of Alzheimer disease patients who received the highest dose, clinical improvement occurred after long-term use. Approval was based on the assessment that the benefits outweigh the risks. Continued approval for this indication may be contingent on verification of the clinical benefit in a confirmatory trial.

Historical note and terminology

Drugs currently used for the management of Alzheimer disease provide symptomatic relief and do not address the pathomechanism of the disease. Since 2003, there have been no new drug approvals for this disease, but there is considerable research activity for the discovery of new drugs.

Aducanumab, a human monoclonal antibody, was discovered at Neurimmune (a Swiss biotechnology company) in collaboration with the University of Zurich using reverse translational medicine technology. It was then licensed to Biogen in the United States in 2007, which developed it for the removal of amyloid from brains of patients with Alzheimer disease. A phase 1b study with brain scans to measure amyloid plaques was done from 1915 to 2016, based on 1 year of monthly intravenous infusions of aducanumab. Phase 2 trials were not required by the U.S. Food and Drug Administration (FDA) and were not conducted. A phase 3 trial followed the conclusion of phase 1 studies and was discontinued in March 2019.

The FDA approval process was restarted in October 2019 on the basis that analysis of a larger dataset of patients showed that the drug reduced clinical decline in a subset of patients with early Alzheimer disease when given at higher doses. On November 6, 2020, the Peripheral and Central Nervous System Drugs Advisory Committee of the FDA recommended against the approval of aducanumab because it was based on a single positive study (01). In a rare decision overriding the recommendation of its advisory committee, the FDA approved aducanumab to treat patients with Alzheimer disease on June 7, 2021, using the accelerated approval pathway. Under the accelerated approval pathway, the FDA approves a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drugs clinical benefit. Drug companies are required to conduct post-approval studies to verify the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial does not verify the drugs anticipated clinical benefit, the FDA has regulatory procedures in place that could lead to the removal of the drug from the market.

Despite the controversy over the FDAs approval of aducanumab, there are opinions supporting FDA approval. According to some experts on Alzheimer disease, the perspective of the panel (FDA Advisory) was too narrow, ignoring important scientific and clinically meaningful considerations. Based on the review of the totality of the data, and our extensive experience with Alzheimer disease trials, research, and clinical care of patients and families, we conclude that aducanumab achieves the standard of meaningful efficacy with adequate safety in early Alzheimer disease (04).

Aducanumab is an expensive drug. The wholesale cost of treatment with aducanumab is about $4312 per infusion, making the annual cost around $56,000 for a high dose. For commercially insured patients, the out-of-pocket costs could be reduced to nothing under certain assistance programs. Patients covered by Medicare through a Medicare Advantage plan have a maximum annual out-of-pocket cap.

Pharmacology

Aducanumab is a human, immunoglobulin gamma 1 monoclonal antibody directed to amyloid beta, which accumulates as amyloid beta plaques in the brains of patients with Alzheimer disease.

Pharmacodynamics. There is a structural rationale for the low affinity of aducanumab for non-pathogenic monomers and its greater selectivity for aggregated amyloid beta forms than other targeting antibodies (02). In a transgenic mouse model of Alzheimer disease, aducanumab was shown to enter the brain, bind parenchymal amyloid beta, and reduce soluble and insoluble Aβ in a dose-dependent manner. After observing a significant reduction in the numbers of senile plaques in hippocampi of aducanumab-treated mouse models of Alzheimer disease, proteomic studies identified novel proteomic patterns of senile plaques and surrounding tissue involved in the pathogenesis of Alzheimer disease, indicating that chronic treatment with aducanumab could inhibit amyloid beta toxicity as well as increase phagocytosis and cell viability (03).

In a phase 1 trial on patients with prodromal or mild Alzheimer disease, 1 year of monthly intravenous infusions of aducanumab reduced brain amyloid beta in a dose- and time-dependent manner, and this was accompanied by a slowing of clinical decline as measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores (07). Amyloid beta plaques were measured by florbetapir positron emission tomography (PET) imaging and showed that standard uptake value ratio reduction (which is unitless) occurs primarily in the cortical regions in patients treated with aducanumab (08). Aducanumab also reduced biomarkers of tau pathophysiology, ie, CSF p-tau and tau PET, in clinical studies.

Pharmacokinetics. Based on studies conducted by the manufacturer, important points of pharmacokinetics include the following:

	• Steady-state concentrations of aducanumab are reached by 16 weeks of repeated dosing with 4-week regimens, and the systemic accumulation is 1.7-fold.
	• The peak concentration (Cmax), trough concentration (Cmin), and area under the curve (AUC) at steady state increases proportional to the dose of aducanumab.
	• The mean value for volume of distribution at steady state is 9.63 L.
	• Aducanumab is degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG, and clearance is approximately 0.0159 L/hr.
	• The terminal half-life is 24.8 days.

Routes of administration. Intravenous infusion.

Pharmacogenetics. Amyloid‐related imaging abnormalities (ARIA), a common, dose‐dependent effect of amyloid‐targeting antibodies, are strongly associated with the apolipoprotein E (APOE) ε4 allele. Risk stratification with APOE ε4 genotyping may help guide treatment decisions.

Clinical trials

The U.S. Government website of clinical trials lists 8 clinical trials of aducanumab for Alzheimer disease. Four of these trials were terminated, 3 were completed, and 1 is ongoing.

A phase 1b randomized, double-blind, placebo-controlled single ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of intravenous aducanumab in patients with mild-to-moderate Alzheimer disease demonstrated an acceptable safety and tolerability profile and linear pharmacokinetics at doses of 30 mg/kg or less (05).

Two phase 3 randomized, double-blind, placebo-controlled, parallel-group studies were done to evaluate the efficacy and safety of aducanumab in subjects with early Alzheimer disease: ENGAGE (NCT02477800) and EMERGE (NCT02484547). The primary objective was to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes score as compared with placebo in participants with early Alzheimer disease. Secondary objectives were to assess the effect of monthly doses of intravenous aducanumab as compared with placebo on clinical progression as measured by Mini-Mental State Examination, Alzheimer Disease Assessment Scale-Cognitive Subscale (13 items), and Alzheimer Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version). These studies were terminated in 2019, when an analysis showed that the trials were unlikely to meet their primary endpoint. However, 1 clinical trial tended to show positive results in a follow-up analysis of a subset of patients.

A critical analysis of the 2 phase 3 trials noted that post hoc analyses had led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer disease and claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials (06). The authors of this comment identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. This analysis supports the conduct of a third phase 3 trial with high-dose aducanumab.

The primary objective of an ongoing phase 3 open study is to evaluate the long-term safety and tolerability of aducanumab after a wash-out period imposed by the discontinuation of feeder studies in participants who had previously received aducanumab or who had previously received placebo (NCT04241068).

Adverse effects

Hypersensitivity reactions. Angioedema and urticaria have occurred. If a hypersensitivity reaction occurs, promptly discontinue the infusion of aducanumab and initiate appropriate treatment.

Amyloid-related imaging abnormalities (ARIA). A recent brain MRI is required prior to initiating treatment with aducanumab. MRI is repeated prior to the seventh and twelfth infusions. Amyloid-related imaging abnormalities (ARIA) are the most common adverse reaction and occurred in at least 10% of the patients in clinical trials. ARIA represent effusion through the blood-brain barrier (ARIA-E), which occurred in approximately 35% of those receiving high-dose aducanumab in clinical trials or for hemorrhages (ARIA-H). Most (80%) ARIA events are without symptoms, but headaches may develop. If severe ARIA with cerebral edema are observed, treatment may be continued with caution only after a clinical evaluation and a follow-up MRI demonstrates radiographic stabilization.

In a patient with apolipoprotein E (APOE) ε4 allele in a clinical trial, ARIA were accompanied by cerebral edema, malignant hypertension, and epileptiform activity, which were treated with nicardipine and levetiracetam (09). Subsequent clinical and imaging worsening required a course of methylprednisolone. Symptoms and ARIA resolved over 6 months, whereas headaches persisted. Optimal management strategies are expected to develop with the management of a larger number of these adverse effects. The patient or caregiver should be informed of ARIA.

Immunogenicity. Like all therapeutic proteins, aducanumab has potential for immunogenicity. During treatment in placebo-controlled and long-term extension periods of clinical trials, up to 0.6% of patients receiving aducanumab once monthly developed anti-aducanumab-avwa antibodies. Because of the limited number of patients who tested positive for anti-aducanumab-avwa antibodies, no conclusions were made concerning a potential effect of these antibodies on drug efficacy.

References

01: Alexander GC, Emerson S, Kesselheim AS. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 2021;325(17):1717-8. PMID 33783469
02: Arndt JW, Qian F, Smith BA, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep 2018;8(1):6412. PMID 29686315
03: Bastrup J, Hansen KH, Poulsen TBG, et al. Anti-Aβ antibody aducanumab regulates the proteome of senile plaques and closely surrounding tissue in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 2021;79(1):249-65. PMID 33252074
04: Cummings J, Aisen P, Lemere C, Atri A, Sabbagh M, Salloway S. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther 2021;13(1):98.** PMID 33971962
05: Ferrero J, Williams L, Stella H, et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer's disease. Alzheimers Dement (N Y) 2016;2(3):169-76. PMID 29067304
06: Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement 2021;17(4):696-701.** PMID 33135381
07: Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 2016;537(7618):50-6.** PMID 27582220
08: Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease: Nature 2017;546(7659):564. PMID 28640269
09: VandeVrede L, Gibbs DM, Koestler M, et al. Symptomatic amyloid-related imaging abnormalities in an APOE ε4/ε4 patient treated with aducanumab. Alzheimers Dement (Amst) 2020;12(1):e12101. ** PMID 33072846

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Aducanumab

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Aducanumab

Aducanumab

Introduction

Overview

Historical note and terminology

Pharmacology

Clinical trials

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Aducanumab

Introduction

Overview

Historical note and terminology

Pharmacology

Clinical trials

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Acupuncture

Illicit drug use: neurologic complications

Placebo and nocebo effects in neurologic disorders

Drug-induced neurologic disorders

Drug-induced disturbances of smell and taste

Neurologic complications of vaccination

Drug-induced aseptic meningitis

Drug-induced parkinsonism

This is an article preview.
Start a Free Account
to access the full version.