Aducanumab: evidence from clinical trial data and controversies

Tampi, Rajesh R.; Forester, Brent P.; Agronin, Marc E.

doi:10.7573/dic.2021-7-3

Cited by 129 publications

(96 citation statements)

References 15 publications

(9 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Constant efforts were poured to develop therapeutic agents worldwide. Aducanumab, which was recently approved conditionally by the FDA, is the antibody-based treatment by targeting Aβ oligomers [ 34 ]. Patients with mutations in representative genes, such as APP , PSEN1 , and PSEN2 , would have been affected in their Aβ production or aggregation, supporting the preferential treatment by Aβ-targeting therapeutics, including aducanumab.…”

Section: Discussionmentioning

confidence: 99%

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Shim

Kang

Bae

et al. 2022

IJMS

View full text Add to dashboard Cite

Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.

show abstract

Section: Discussionmentioning

confidence: 99%

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Shim

Kang

Bae

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…From June 2021, aducanumab was approved to treat mild AD until today, which has been caused considerable medical and scientific controversy ( Tampi et al, 2021 ). Although aducanumab does reduce Aβ, there is a lack of reliable evidence that it has significant benefits to patients with AD ( Fleck, 2021 ).…”

Section: Immunotherapies With Mabs In Patients With Ad and Its Animal...mentioning

confidence: 99%

Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab

Shi

Chu

Zhu

et al. 2022

Front. Aging Neurosci.

151

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most prevalent form of age-related dementia in the world, and its main pathological features consist of amyloid-β (Aβ) plaque deposits and neurofibrillary tangles formed by hyperphosphorylated tau protein. So far, only a few AD treatments approved have been applied in the clinic, but the effects of these drugs are limited only for partial symptomatic relief to patients with AD and are unable to alter AD progression. Later, all efforts for AD treatments with targeting the pathogenic factors were unsuccessful over the past decades, which suggested that the pathogenesis of AD is complex. Recently, disease-modifying therapies (DMTs) that can change the underlying pathophysiology of AD, with anti-Aβ monoclonal antibodies (mabs) (e.g., aducanumab, bapineuzumab, gantenerumab, solanezumab, and lecanemab) have been developed successively and conducted in clinical trials based on the theory that a systemic failure of cell-mediated Aβ clearance contributes to AD occurrence and progression. In the review, we summarized recent studies on the therapeutic effects and clinical trial results of these mabs in patients with AD. Specifically, we focused on the discussion of the impact of aducanumab and lecanemab on AD pathology and clinical profiles. The review provides a possible evidence for applying immunotherapy with anti-Aβ mabs in AD and analyzes lessons learned from these clinical trials in order to further study the therapeutic and adverse effects of these anti-Aβ mabs on AD.

show abstract

“…They considered that the results of the studies were conflicting, and the data presented did not show sufficient evidence of clinical efficacy. 19 , 39 Contrary to the independent committee decision, the FDA granted accelerated approval to aducanumab on June 7, 2021, leading to the resignation of three members of the PCNS committee. 20 , 40 The accelerated approval pathway allows patients to have early access to drugs that target a serious disease and which provide a meaningful improvement over current treatments.…”

Section: Clinical Development and Regulatory History Overviewmentioning

confidence: 99%

“…Importantly, monitoring the ARIA with MRI scans will increase the cost of treatment and the complexity of infrastructures needed. 39 …”

Section: Controversymentioning

confidence: 99%

Role of Aducanumab in the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Vaz¹,

Silva²,

Monteiro³

et al. 2022

CIA

View full text Add to dashboard Cite

Aducanumab is a monoclonal antibody selective for amyloid β (Aβ) aggregates. In June 2021, aducanumab became the first drug underlying the pathophysiology of Alzheimer’s disease (AD) approved by the US Food and Drug Administration (FDA), under the accelerated approval pathway. The decision was based on the ability of aducanumab to remove Aβ plaques, without any evidence that the Aβ clearance is correlated with less cognitive or functional decline. This decision has generated a considerable debate in the scientific community, especially because the results from the two Phase 3 trials, EMERGE and ENGAGE, were divergent and, even after the post hoc analysis, the data were insufficient to prove aducanumab efficacy. Moreover, some researchers think that this approval will be an obstacle to the progress and also demonstrated concerns about aducanumab cost and its safety profile. The European Medicines Agency’s rejection of aducanumab in December 2021 just brought more controversy over FDA’s decision. Now, Biogen is designing the FDA’s required confirmatory study, named ENVISION, which should be complete in 2026. Despite the controversy, the aducanumab showed to affect downstream tau pathology, which could open doors for a combination therapy approach for AD (anti-tau and anti-amyloid drug). This review summarizes the clinical development of aducanumab until regulatory agencies’ decisions, the available trials data and the controversy over aducanumab approval for AD.

show abstract

Aducanumab: evidence from clinical trial data and controversies

Cited by 129 publications

References 15 publications

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab

Role of Aducanumab in the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Contact Info

Product

Resources

About