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Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease

Budd Haeberlein, Samantha ; Aisen, P. S. ; Barkhof, F. ; Chalkias, S. ; Chen, T. ; Cohen, S. ; Dent, G. ; Hansson, O. LU orcid ; Harrison, K. and von Hehn, C. , et al. (2022) In Journal of Prevention of Alzheimer's Disease 9(2). p.197-210
Abstract

Background: Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. Objectives: We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease. Design: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease. Setting: These studies involved 348 sites in 20 countries. Participants: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical... (More)

Background: Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. Objectives: We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease. Design: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease. Setting: These studies involved 348 sites in 20 countries. Participants: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. Intervention: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. Measurements: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. Results: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. Conclusions: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose-and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.

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type
Contribution to journal
publication status
published
subject
keywords
Aducanumab, Alzheimer’s disease, amyloid beta
in
Journal of Prevention of Alzheimer's Disease
volume
9
issue
2
pages
14 pages
publisher
Springer
external identifiers
  • scopus:85126460709
  • pmid:35542991
ISSN
2274-5807
DOI
10.14283/jpad.2022.30
language
English
LU publication?
yes
id
2a6182ce-0a82-43c9-a953-f36a4d1da8b8
date added to LUP
2022-06-09 10:25:03
date last changed
2024-04-18 11:23:53
@article{2a6182ce-0a82-43c9-a953-f36a4d1da8b8,
  abstract     = {{<p>Background: Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. Objectives: We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease. Design: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease. Setting: These studies involved 348 sites in 20 countries. Participants: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. Intervention: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. Measurements: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. Results: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. Conclusions: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose-and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.</p>}},
  author       = {{Budd Haeberlein, Samantha and Aisen, P. S. and Barkhof, F. and Chalkias, S. and Chen, T. and Cohen, S. and Dent, G. and Hansson, O. and Harrison, K. and von Hehn, C. and Iwatsubo, T. and Mallinckrodt, C. and Mummery, C. J. and Muralidharan, K. K. and Nestorov, I. and Nisenbaum, L. and Rajagovindan, R. and Skordos, L. and Tian, Y. and van Dyck, C. H. and Vellas, B. and Wu, S. and Zhu, Y. and Sandrock, A.}},
  issn         = {{2274-5807}},
  keywords     = {{Aducanumab; Alzheimer’s disease; amyloid beta}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{197--210}},
  publisher    = {{Springer}},
  series       = {{Journal of Prevention of Alzheimer's Disease}},
  title        = {{Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease}},
  url          = {{http://dx.doi.org/10.14283/jpad.2022.30}},
  doi          = {{10.14283/jpad.2022.30}},
  volume       = {{9}},
  year         = {{2022}},
}