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Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019
Open accessAbstract
Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we 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. Our analysis supports the conduct of a third, phase III trial with high‐dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes.
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“Furthermore, studies such as those by Salloway et al. and Biogen’s EMERGE and ENGAGE trials found that treating the plaques alone did not rescue cognitive defects (Knopman et al., 2021; Salloway et al., 2014).”
From Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model (2022) · cites this paper as Knopman et al., 2021
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“however, thus far, treatments to decrease formation of plaques have shown only minimal or no improvement in disease progression or outcomes (Knopman et al., 2021; Selkoe, 2019).”
From Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model (2022) · cites this paper as Knopman et al., 2021
In the citing paper
“The FDA has controversially granted accelerated approval to aducanumab and has opined that the reduction of amyloid is reasonably likely to predict clinical benefit 7,9,[98][99][100][101][102][103][104][105][106][107] .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [7]
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“In spite of this, the FDA granted expedited approval on the grounds of the EMERGE trial’s documented decrease in amyloid levels [132,185,186,187].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [185]
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“Aducanumab demonstrated inconsistent outcomes in its two main clinical trials, the Phase III EMERGE and ENGAGE research investigations.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [185]
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“In the EMERGE experiment, when participants with AD were at risk for cognitive deterioration, there was a decrease in the amount of amyloid-beta plaques.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [185]
In the citing paper
“However, it is considered controversial due to the lack of sufficient evidence to support its efficacy.348,349”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [348]
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Metadata
- Authors
- Knopman, D. S., Jones, D. T., & Greicius, M. D.
- Affiliations
- Mayo Clinic (US)
- Stanford Medicine (US)
- Corresponding author
- Knopman, David S.
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2020-11
- Volume
- 17
- Issue
- 4
- Pages
- 696-701
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W3097527510
- Cited by
- 524
- References
- 13
- Citations by year
- 2026: 53 · 2025: 55 · 2024: 75 · 2023: 107 · 2022: 151 · 2021: 79 · 2020: 4
- FWCI
- 51.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- aducanumab, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Amyloid, Dose-Response Relationship, Drug, Humans, Biomarkers, Treatment Outcome, Treatment Failure, Clinical Trials, Phase III as Topic, Antibodies, Monoclonal, Humanized
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