Alzheimer's and Aducanumab: Unjust Profits and False Hopes

Fleck, Leonard M.

doi:10.1002/hast.1264

Cited by 22 publications

(12 citation statements)

References 3 publications

(2 reference statements)

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“…For the last three decades, over 900 billion USD has been invested in drug development and clinical trials with no proven effective benefit for treating patients with AD [ 56 ]. Multiple studies have recently demonstrated a strong relationship between the pathogenesis of AD and some vascular-associated diseases, including atherosclerosis and hypertension [ 57 , 58 ]. Moreover, Aguilar et al, 2021, have shown that vascular smooth muscle cells contribute to the neuroinflammation and tau hyperphosphorylation in the early and late stages of the disease [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer’s Disease

et al. 2022

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Background: Despite research on the molecular bases of Alzheimer’s disease (AD), effective therapies against its progression are still needed. Recent studies have shown direct links between AD progression and neurovascular dysfunction, highlighting it as a potential target for new therapeutics development. In this work, we screened and evaluated the inhibitory effect of natural compounds from native Peruvian plants against tau protein, amyloid beta, and angiotensin II type 1 receptor (AT1R) pathologic AD markers. Methods: We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation (MD), and MM/GBSA estimation, to identify metabolites from Peruvian plants with inhibitory properties, and compared them to nicotinamide, telmisartan, and grapeseed extract drugs in clinical trials. Results: Our results demonstrated the increased bioactivity of three plants’ metabolites against tau protein, amyloid beta, and AT1R. The MD simulations indicated the stability of the AT1R:floribundic acid, amyloid beta:rutin, and tau:brassicasterol systems. A polypharmaceutical potential was observed for rutin due to its high affinity to AT1R, amyloid beta, and tau. The metabolite floribundic acid showed bioactivity against the AT1R and tau, and the metabolite brassicasterol showed bioactivity against the amyloid beta and tau. Conclusions: This study has identified molecules from native Peruvian plants that have the potential to bind three pathologic markers of AD.

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Section: Discussionmentioning

confidence: 99%

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer’s Disease

et al. 2022

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“…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 ). In phase III, among patients treated with high-dose aducanumab, ∼35% of patients occurred ARIA-related cerebral edema (ARIA-E), and ∼18–22.7% of patients had ARIA-related microhemorrhages (ARIA-H) or other side effects, such as headache, dizziness, and nausea.…”

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

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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.

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“…The FDA should have required a third phase 3 trial with a high-dose of aducanumab before approval. 37 , 59 Secondly, there is no evidence that Aβ reduction correlates with clinical benefits, so the majority of experts consider that Aβ plaques are not a valid surrogate endpoint. 10 , 60 Moreover, recent studies showed that tau accumulation correlates better with cognitive impairment than Aβ.…”

Section: Controversymentioning

confidence: 99%

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

Vaz¹,

Silva²,

Monteiro³

et al. 2022

CIA

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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.

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Alzheimer's and Aducanumab: Unjust Profits and False Hopes

Cited by 22 publications

References 3 publications

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer’s Disease

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against 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

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