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Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab

Mallinckrodt, C. ; Tian, Y. ; Aisen, P. S. ; Barkhof, F. ; Cohen, S. ; Dent, G. ; Hansson, O. LU orcid ; Harrison, K. ; Iwatsubo, T. and Mummery, C. J. , et al. (2023) In Journal of Prevention of Alzheimer's Disease 10. p.171-177
Abstract

Objectives: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer’s disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the highdose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies. Design: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind,... (More)

Objectives: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer’s disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the highdose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies. Design: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies. Setting: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries. Participants: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE. Intervention: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks. Measurements: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab. Results: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms. Conclusions: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aducanumab, Alzheimer’s disease, amyloid beta
in
Journal of Prevention of Alzheimer's Disease
volume
10
pages
7 pages
publisher
Springer
external identifiers
  • scopus:85146038935
  • pmid:36946443
ISSN
2274-5807
DOI
10.14283/jpad.2023.6
language
English
LU publication?
yes
id
3f685213-d2d6-4fcd-bfc3-10fcb74503c9
date added to LUP
2023-02-16 15:34:06
date last changed
2024-06-09 10:04:53
@article{3f685213-d2d6-4fcd-bfc3-10fcb74503c9,
  abstract     = {{<p>Objectives: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer’s disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the highdose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies. Design: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies. Setting: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries. Participants: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE. Intervention: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks. Measurements: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab. Results: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms. Conclusions: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.</p>}},
  author       = {{Mallinckrodt, C. and Tian, Y. and Aisen, P. S. and Barkhof, F. and Cohen, S. and Dent, G. and Hansson, O. and Harrison, K. and Iwatsubo, T. and Mummery, C. J. and Muralidharan, K. K. and Nestorov, I. and Nisenbaum, L. and Rajagovindan, R. and von Hehn, C. and van Dyck, C. H. and Vellas, B. and Wu, S. and Zhu, Y. and Sandrock, A. and Chen, T. and Budd Haeberlein, S.}},
  issn         = {{2274-5807}},
  keywords     = {{Aducanumab; Alzheimer’s disease; amyloid beta}},
  language     = {{eng}},
  pages        = {{171--177}},
  publisher    = {{Springer}},
  series       = {{Journal of Prevention of Alzheimer's Disease}},
  title        = {{Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab}},
  url          = {{http://dx.doi.org/10.14283/jpad.2023.6}},
  doi          = {{10.14283/jpad.2023.6}},
  volume       = {{10}},
  year         = {{2023}},
}