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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]
In the citing paper
“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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The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes
Kepp, K. P., Sensi, S. L., Johnsen, K. B., Barrio, J. R., Høilund‐Carlsen, P. F., Neve, R. L., Alavi, A. A., Herrup, K., Perry, G. L., Robakis, N. K. R. K., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230099 · Cited by 56
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“Amyloid deposition was reduced in all treatment groups at 10 mg/kg during 26 weeks [77,78], 41.”
BackgroundIs Greenness Associated with Dementia? A Systematic Review and Dose–Response Meta-analysis
Zagnoli, F., Filippini, T., Jimenez, M. P., Wise, L. A., Hatch, E. E., & Vinceti, M. (2022) · Current Environmental Health Reports · doi:10.1007/s40572-022-00365-5 · Cited by 57
Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
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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 [132,185–187].”
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Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer’s disease
Coles, M., Steiner-Lim, G. Z., & Karl, T. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.962922 · Cited by 57
“Further, the recent FDA approval of the monoclonal antibody agent, aducanumab, has been controversial given its failure to demonstrate clinical efficacy despite reducing Aβ (Knopman et al., 2021).”
BackgroundPharmacotherapy of Alzheimer’s disease: an overview of systematic reviews
Majidazar, R., Rezazadeh‐Gavgani, E., Sadigh‐Eteghad, S., & Naseri, A. (2022) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-022-03363-6 · Cited by 54
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The Interaction Between NF-κB and Estrogen in Alzheimer’s Disease
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Tau Aggregation Inhibiting Peptides as Potential Therapeutics for Alzheimer Disease
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Biomaterials-based anti-inflammatory treatment strategies for Alzheimer’s disease
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“…preclinical stage, and the approval of the first Aβ monoclonal antibody Aducanumab by the U.S. FDA is accompanied by much controversy because of its inadequate evidence of efficacy and adverse effects such as Aβ-related imaging abnormalities (e.g., edema and microhemorrhage) (Knopman et al., 2021).”
8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases
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“…some 450 therapies have failed in Phase II or Phase III clinical studies, with slightly more than half of these examples based on the “amyloid hypothesis” and its derivatives, and among the remaining therapies there are cases of failure based on other hypotheses as well (Knopman et al., 2021).”
BackgroundSubstantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies
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Self-citationAmyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials
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Tau positron emission tomography in preclinical Alzheimer’s disease
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Adenosine receptor signalling in Alzheimer’s disease
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Sanchez-Varo, R. M., Sánchez‐Mejías, E., Fernandez-Valenzuela, J. J., Castro, V. D., Mejias‐Ortega, M., Gómez-Arboledas, Á., Jiménez, S., Sanchez-Mico, M. V., Trujillo‐Estrada, L., Moreno‐González, I., et al. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.752594 · Cited by 42
The Implication of Physiological Ketosis on The Cognitive Brain: A Narrative Review
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New Possibilities in the Therapeutic Approach to Alzheimer’s Disease
Doroszkiewicz, J., & Mroczko, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168902 · Cited by 46
“One such controversy was the inconsistent results of Phase 3 trials [51,52].”
BackgroundOptimal MoCA cutoffs for detecting biologically-defined patients with MCI and early dementia
Ilardi, C. R., Menichelli, A., Michelutti, M., Cattaruzza, T., & Manganotti, P. (2022) · Neurological Sciences · doi:10.1007/s10072-022-06422-z · Cited by 40
Association of autoimmune diseases with Alzheimer's disease: A mendelian randomization study
Yeung, C. H. C., Yeung, S. L. A., & Schooling, C. M. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.09.052 · Cited by 37
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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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