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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The FDA granted accelerated approval to aducanumab and stated that reduction of amyloid is reasonably likely to predict clinical benefit.
“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]
The FDA granted expedited approval of aducanumab on the grounds of the EMERGE trial's documented decrease in amyloid levels.
“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]
Aducanumab demonstrated inconsistent outcomes in its two main Phase III clinical trials, EMERGE and ENGAGE.
“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]
In the EMERGE trial, participants with AD at risk for cognitive deterioration showed a decrease in amyloid-beta plaques.
“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]
Aducanumab is considered controversial due to lack of sufficient evidence to support its efficacy.
“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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“Our results may speak to the ongoing and highly publicized controversies surrounding AD clinical trials, where therapeutics designed to expressly prevent plaque formation, while often efficacious in lessening plaque load, are routinely and notoriously ineffective at meeting their primary endpoint, namely preventing of…”
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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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“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
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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).”
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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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“One such controversy was the inconsistent results of Phase 3 trials [51,52].”
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Association of autoimmune diseases with Alzheimer's disease: A mendelian randomization study
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- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › 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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