Aducanumab Therapy to Treat Alzheimer’s Disease: A Narrative Review

Abstract

Background. Aducanumab, a new monoclonal antibody that targets β-amyloid aggregates, has been granted conditional approval by the U.S. FDA for treatment of mild Alzheimer’s disease (AD). The approval of this drug without a confirmed significant clinical impact has resulted in several debates. Objective. In this narrative review, aducanumab approval-related controversy, the drug’s pharmacokinetics and pharmacodynamic characteristics, evidence from the efficacy and safety trials of aducanumab, implications of the drug approval, and the future directions in the management of patients with AD are summarized. Methods. Using relevant keywords, Google Scholar, Web of Science, and MEDLINE databases and manufacturer’s website were searched. Results. Infusion of aducanumab at a higher dose resulted in a modest slowing of cognitive decline among patients with mild cognitive impairment or early-onset AD dementia. The drug however can cause amyloid-related imaging abnormalities. Due to modest impact on cognition, the use of this drug by patients with AD will most likely be limited. The manufacturer is required to run an extended phase IIIb trial to verify the benefit of this drug. Access to therapy requires a careful selection of patients and periodic monitoring to ensure the optimal use of the drug. Conclusion. Despite the limitations, aducanumab is the first disease-modifying therapy approved for the treatment of AD. Aducanumab addresses a part of the pathogenesis of AD; therefore, drugs that can act on multiple targets are needed. In addition, the search for preventive strategies, validated plasma-based assays, and newer drugs for AD, which are effective, safe, convenient, and affordable, is vital.

The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer’s Disease

“…Notably, the drug aducanumab (trade name: Aduhelm TM ) was initially approved by the FDA based on the drug’s ability to breakdown Aβ aggregates, a common surrogate endpoint for AD. However, the FDA approval for aducanumab was later reversed due to multiple factors, including inefficacy to improve cognitive function, high costs, and occurrence of several adverse events [ 59 ]. The list of other failed drugs in clinical trials has been comprehensively summarized in another review [ 60 ].…”

“…An overview of the drug development landscape for AD is summarized in Table 1 [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ], indicating the effort at multiple fronts for the development of AD treatments.…”

The Fate of Tau Aggregates Between Clearance and Transmission

“…Bepranemab, an anti-tau IgG4 antibody developed by Hoffmann-La Roche, is currently undergoing phase 2 clinical trials in AD patients (NCT04867616) ( Albert et al, 2019 ). JNJ-63733657, an anti-tau IgG1 antibody developed by Janssen, is undergoing phase 2 trials in AD patients (NCT04619420) ( Beshir et al, 2022 ). In the extracellular space, antibody-tau complexes are expected to be cleared as extracellular waste by microglia, astrocytes or the glymphatic system.…”

Serotonin 5-HT6 Receptor Ligands and Butyrylcholinesterase Inhibitors Displaying Antioxidant Activity—Design, Synthesis and Biological Evaluation of Multifunctional Agents against Alzheimer’s Disease

“…Aducanumab was approved under the accelerated approval pathway, based on effects on a surrogate endpoint, which in this case was a reduction of amyloid beta plaques in the brains of patients with AD. Its efficacy in terms of clinical benefits is yet to be determined [ 62 , 63 ]. Hence, there is still an unmet need to search for effective therapy for AD, primarily with disease-modifying effects but preferably with a symptoms-relieving component for patients with the already developed disease.…”