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:

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).

Indications

Aducanumab is indicated for use in Alzheimer disease.

Contraindications

None.

Goals and duration of treatment

The goal of aducanumab therapy is to reduce amyloid beta plaques in the brains of patients with early Alzheimer disease, which is associated with cognitive improvement. This has been demonstrated in extension studies of clinical trials beyond 4 years.

Dosing

Titration is required at initiation of treatment. The recommended maintenance dosage of aducanumab is 10 mg/kg administered as an intravenous infusion over approximately 1 hour every 4 weeks.

Special considerations

The age of patients in clinical trials of aducanumab has ranged from 50 to 85 years. There were no notable differences in the incidence of adverse reactions between these age groups and no additional safety concerns in patients 65 years of age and older compared to younger patients. Because aducanumab is not expected to undergo renal elimination or metabolism by hepatic enzymes, no studies have been conducted to evaluate the pharmacokinetics of the drug in patients with renal or hepatic impairment.

Interactions

None reported.

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.