Continuing Education Activity

Aducanumab is a medication used in the management and treatment of Alzheimer disease. It is an amyloid beta-directed monoclonal antibody. This activity describes the indications, action, and contraindications for aducanumab as a possible agent in the management of Alzheimer disease. Aducanumab indications in Alzheimer disease are specific to subjects with mild cognitive impairment or mild dementia stage of the progressive neurodegenerative ailment. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of patients with Alzheimer disease.

Objectives:

• Discuss the mechanism of action of aducanumab.
• Describe the indicated use for aducanumab.
• Explain the possible side effects of aducanumab.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when dosing and monitoring aducanumab treatment for Alzheimer disease.

Indications

Aducanumab is a newly approved agent identified as an amyloid beta-directed monoclonal antibody. It is indicated in the management of Alzheimer disease (AD).[1] Aducanumab indications in Alzheimer disease are specific to subjects with mild cognitive impairment or mild dementia stage of the progressive neurodegenerative ailment.[2] The indication for initiating aducanumab was updated from the previous one, in which it was indicated for all patients with Alzheimer disease.[3]  

Aducanumab therapy was tested in clinical trials in the subset of subjects with mild cognitive impairment or mild dementia stage of AD. The safety or effectiveness of inducting the amyloid-beta (Aβ)-directed antibody earlier in the disease course has not been analyzed or reported. Aducanumab received FDA's accelerated approval in 2021 based on subjects with mild cognitive impairment or mild dementia associated with AD demonstrating a reduction in Aβ plaques.[4] Aducanumab's continued use and full approval will require further verification of its clinical benefits in post-approval studies. Its approval was controversial and led to three FDA advisory board members resigning.[5]

Alzheimer disease is a progressive, chronic, neurodegenerative disease and the most common etiology of dementia.[6] In dementia patients aged 65 and above, Alzheimer disease accounts for two-thirds of the dementia cases and is the sixth preeminent cause of mortality in the US.[7] Alzheimer disease's characteristic hallmarks are extracellular neuritic plaques generated by the deposition of beta-amyloid protein and intracellular buildup of tau proteins, resulting in intracytoplasmic neurofibrillary tangles(NFT).[8][9][10] 

Disease onset is quite insidious, causing a gradual decline of behavioral and cognitive abilities manifesting as an initial short-term memory impairment accompanied by impaired language, attention, comprehension, and executive functioning.[6] Current symptomatic management of Alzheimer disease entails treatment with cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists, as there is no cure or curative treatment to date.[6][11]

Knopman S. et al. analyzed the data from two clinical trials with aducanumab. The investigators conclude that the efficacy of aducanumab cannot be proven when the two clinical trials yield different results.[12]

FDA Approved Use

The drug is approved for use in Alzheimer disease in patients with mild cognitive impairment or mild dementia stage of the disease.

Mechanism of Action

Aducanumab is an immunotherapeutic classified as a human immunoglobulin gamma 1 (IgG1) monoclonal antibody. It exerts its mechanism of action by crossing the blood-brain barrier and selectively targeting and binding aggregated soluble oligomers and insoluble fibril conformations of Aβ plaques in the brain.[13][14] 

Biochemical and structural analyses showed that the aducanumab binds to a linear epitope formed by Aβ amino acids 3 to 7.[15] As compared to previously studied antibodies, aducanumab binds to the N-terminus of Aβ in an extended conformation. Based on weak monovalent affinity, fast binding kinetics, and strong avidity for epitope-rich aggregates, aducanumab has been shown to discriminate between Aβ monomers and oligomeric or fibrillar aggregates.[15] 

The greater selectivity of aducanumab for aggregated Aβ forms results in reducing the brain Aβ plaques.[13][16] In a small subset of patients using tau PET, a reduction in phosphorylated tau was also observed in the cerebrospinal fluid and medial temporal NFTs.[17]

Administration

Aducanumab is available as a clear to opalescent and colorless to yellow solution currently available in single-dose vials for intravenous (IV) infusion administration. Based on the subject's body weight per kilogram (kg), aducanumab should be diluted with 100 mL of 0.9% sodium chloride injection before administration as an infusion. It is also recommended the diluted agent solution be settled at room temperature before starting therapy and should be administered without delays. Unused diluted portions after administration of aducanumab should be discarded.

Available Single Dosages Vials

• 170 mg/1.7 mL (100 mg/mL) 
• 300 mg/3 mL (100 mg/mL) 

The dosing should be titrated, reaching 10 mg/kg by the seventh infusion. The IV infusion should be administered every four weeks with a minimum of 21 days between infusions. The infusion should be given over a 1-hour time frame. 

Dosing Schedule

The regimen for aducanumab is titrated upward over time.[18] It is as follows:

• First infusion (1 mg/kg)
• Second infusion (1 mg/kg)
• Third infusion (3 mg/kg)
• Fourth infusion (3 mg/kg)
• Fifth infusion (6 mg/kg)
• Sixth infusion (6 mg/kg)
• Seventh infusion onwards (10 mg/kg)

Missed dose analyses have yet to be studied. Subjects who have missed a dosage of aducanumab are recommended to continue the next dose immediately at the dosage given at the previous infusion. For subjects who have missed three or more infusions and are expected to continue management with aducanumab, infusion dosage should be re-initiated at a dose one step lower than the one administered previously. Continued treatment following the dosing titration schedule is recommended.[3]

Fig 1: Flow chart demonstration of aducanumab administration[3]

Adverse Effects

Reported adverse effects in clinical trial studies:

• ARIA-edema (ARIA-E) (35%)*[19] 
• ARIA-hemosiderin deposition (ARIA-H) microhemorrhage (19%)*
• ARIA-H superficial siderosis (15%)*
• Headache (21%) 
• Fall (15%) 
• Diarrhea (9%)
• Confusion/delirium/altered mental status/disorientation (8%)
• Hypersensitivity (angioedema, urticaria) (<1%)
• Immunogenicity (<1%)[20]

*Amyloid-related imaging abnormalities (ARIA)

Aducanumab can cause a small elevation in serum aminotransferase; however, there are no reports of liver injury.[1]

Contraindications

No contraindications have yet been reported.

No drug-drug interactions are currently reported as of this writing. Conventional therapy for Alzheimer disease was used during pivotal trials, and aducanumab may be used concomitantly with the other medications utilized to manage AD.[3]

Monitoring

A diagnosis of AD with MCI or mild dementia should be confirmed before considering Aducanumab. A thorough history and physical and neurological examination of the patient should be conducted with a timeline of the onset of cognitive decline.[3] Underlying co-occurring disorders that may result in cognitive deterioration should be assessed thoroughly by laboratory workup: complete blood count (CBC), complete metabolic panel (CMP), thyroid-stimulating hormone (TSH), lipid panel, liver function tests (LFT), vitamin B12 levels. Brain imaging to rule out potential neurological conditions such as normal pressure, hydrocephalus (NPH), vascular dementia, malignancy, or subdural hematoma should also be established before initiating aducanumab.[3]

Routine monitoring for ARIA by brain magnetic resonance imaging (MRI) is recommended before initiating and during aducanumab therapy. Brain MRI should be taken within a 12-month period before starting aducanumab. Another MRI should be considered before the seventh infusion and the twelfth infusion of 10 mg/kg of aducanumab. Dosing adjustments in renal and hepatic dysfunction are not advised as aducanumab is not expected to be metabolized in the liver or renally cleared. Immunogenicity of aducanumab was observed during clinical studies. Anti-aducanumab antibodies developed in 0.6% of subjects receiving aducanumab.

To date, no sufficient data on aducanumab use during pregnancy and lactation in humans has been reported in the scientific literature or manufacturer's label. Aducanumab was tested during animal reproductive studies, and no adverse effects were detected.[21]

Toxicity

Warning and Precautions

It is vital to obtain a brain MRI before starting aducanumab, as ARIA may develop with treatment. ARIA-E can be visualized as brain edema or sulcal effusions, and ARIA-H can be observed as microhemorrhage and superficial siderosis on brain imaging. Clinical manifestations of ARIA were present during clinical studies in 24% of subjects who demonstrated radiographic ARIA. Symptoms include headache, confusion, delirium, altered mental status, disorientation, dizziness, vision abnormality, and nausea—the most common being headache (13%).

ARIA predominantly occurred during the initial titration of therapy of the first eight doses. Patients showing indications of ARIA should be thoroughly evaluated and receive a possible brain MRI to determine the severity before reconsidering treatment. Brain imaging should also be obtained before the first and sixth 10 mg/kg dosage (seventh infusion and twelfth infusion) to monitor the development of asymptomatic ARIA. Greater clinical attention is advised if imaging is suggestive of ARIA. For subjects demonstrating severe radiographic ARIA-H, a clinical evaluation alongside brain imaging confirming stabilization and no increases of microhemorrhages and superficial siderosis should be considered before continuing aducanumab. For patients exhibiting radiographic ARIA-E or mild to moderate ARIA-H on imaging, aducanumab may be continued with greater attention.[20]

Hypersensitivity

During the administration of aducanumab infusion, hypersensitivity reactions (angioedema, urticaria) may occur. In the event of such an occurrence, timely discontinuation of aducanumab and appropriate management should be initiated.

Enhancing Healthcare Team Outcomes

Aducanumab was fast-track FDA-approved in 2021 and is indicated for its use in Alzheimer disease (AD) patients with mild cognitive impairment or mild dementia stage of the disease. The care of patients with AD requires management and supervision from an interprofessional healthcare team. This healthcare team should include a primary care physician (PCP) and mid-level practitioner, a neurologist, nursing staff, and a pharmacist. Routine care and follow-up for patients with AD by the interprofessional healthcare team can lead to efficient clinical evaluations, leading to precise management plans, and more reliable patient outcomes.

Before initiating aducanumab, the prescribing clinician should obtain brain imaging by MRI within a 12-months period. The healthcare professional administering aducanumab should carefully follow the titration schedule during the first seven infusions. During infusion administration of aducanumab, the provider should be prepared and equipped in a setting with appropriate management in the event of hypersensitivity-like reactions. Another MRI should be obtained during the seventh infusion (first 10 mg/kg dosage) and the twelfth infusion (sixth 10 mg/kg dosage). Patients should be fully advised about the adverse effects of therapy.

The neurologist should fully advise patients of the potential adverse effects of ARIA and its asymptomatic or clinical manifestations. The interprofessional healthcare team should routinely follow up with patients receiving aducanumab and thoroughly inquire about any new-onset symptoms indicative of ARIA. Symptoms include headache, confusion, delirium, altered mental status, disorientation, dizziness, vision abnormality, and nausea. A follow-up MRI may be necessary to determine the severity of ARIA and the determination to continue or halt therapy.

Pregnant patients considering aducanumab should be advised that there are no data from reproductive studies in humans. Adacunumab in animal reproductive studies demonstrated no adverse effects, but the findings may have no relevance in humans. The interprofessional healthcare team should thoroughly educate and discuss aducanumab, its adverse effects, and therapy aims with patients and their caretakers. Perpetual intercommunication within the healthcare team in managing AD patients receiving aducanumab can potentially improve patient outcomes.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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Disclosure: Inderbir Padda declares no relevant financial relationships with ineligible companies.

Disclosure: Mayur Parmar declares no relevant financial relationships with ineligible companies.