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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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“The most prominent are antiam-yloid antibody treatments Aducanumab (9), Lecanemab (10), and more recently Donanemab (11), which can effectively clear amyloid plaques but questions remain about their clinical benefit (12).”
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“The FDA has approved Aducanumab with much controversy, since the approval was based on a surrogate endpoint without known clinical benefits (NCT02477800 and NCT02484547) [218,219].”
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“(3) We are of the opinion that a further phase 3 high-dose trial is needed to assess whether aducanumab is truly a clinically efficacious agent.(4)”
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“Ad hoc analysis has been controversial, with at least one study supporting clinical benefit [27] and another did not [28].”
MethodMorales, C. D., Cotton‐Samuel, D., Lao, P. J., Chang, J. F., Pyne, J. D., Alshikho, M. J., Lippert, R. V., Bista, K. C., Hale, C., Edwards, N. C., et al. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01395-x · Cited by 10
“Indeed, among myriad failed trials, three phase 3 trials that included patients with very mild or presympto-matic disease suggest some degree of clinical efficacy in primary [9, 10] or post hoc [11] analyses, which led to FDA approval of lecanemab and aducanumab.”
BackgroundPharmacokinetic evaluation of donanemab for the treatment of Alzheimer’s
Song, T., Wang, Y., Silverglate, B., & Grossberg, G. T. (2024) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2024.2357637 · Cited by 13
“However, conflicting evidence for the clinical efficacy of adu-canumab [15–17] and risk of adverse events [18] has limited its use.”
BackgroundZhang, N., Nao, J., & Dong, X. (2024) · Current Neuropharmacology · doi:10.2174/1570159x23666241211095018 · Cited by 13
“Clinical trials showed that the monoclonal drug cleared Aβ from the brain, but there was insufficient evidence that it slowed or stopped the progression of AD [12].”
Alzheimer's disease knowledge graph enhances knowledge discovery and disease prediction
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Practical Considerations in the Administration of Aducanumab for the Neurologist
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“The burden of Aβ pathology is reduced with the use of this medication, but no correlation between biomarker change and cognitive benefits has been demonstrated.(19) The populations included in these trials were not ethnically diverse, and many populations, including Blacks, Hispanics, and indigenous people, were not w…”
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Dementia—so much done, so much to do, so much to gain by doing so
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“Essentially, it is an open-label extension of EMERGE and ENGAGE keeping patients on treatment and collecting more data.”
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A Machine Learning Approach to Predict Cognitive Decline in Alzheimer Disease Clinical Trials
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Ferroptosis and Alzheimer’s disease: a new insight into neurodegeneration
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“58,59 While these results are encouraging given the limited therapeutic options for early symptomatic stages of the disease, the observed effect sizes should be interpreted with caution, particularly regarding their clinical relevance.”
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“However, there is still an intense debate about the efficiency of these newly developed disease-modifying drugs [11,12].”
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Cerebellar Crus II Regulates Recognition and Spatial Memory in Mice
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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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