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INVESTIGATING PARTIALLY DISCORDANT RESULTS IN PHASE 3 STUDIES OF ADUCANUMAB

C. Mallinckrodt, Y. Tian, P.S. Aisen, F. Barkhof, S. Cohen, G. Dent, O. Hansson, K. Harrison, T. Iwatsubo, C.J. Mummery, K.K. Muralidharan, I. Nestorov, L. Nisenbaum, R. Rajagovindan, C. von Hehn, C.H. van Dyck, B. Vellas, S. Wu, Y. Zhu, A. Sandrock, T. Chen, S. Budd Haeberlein

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 high-dose 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.

CITATION:
C. Mallinckrodt ; Y. Tian ; P.S. Aisen ; F. Barkhof ; S. Cohen ; G. Dent ; O. Hansson ; K. Harrison ; T. Iwatsubo ; C.J. Mummery ; K.K. Muralidharan ; I. Nestorov ; L. Nisenbaum ; R. Rajagovindan ; C. von Hehn ; C.H. van Dyck ; B. Vellas ; S. Wu ; Y. Zhu ; A. Sandrock ; T. Chen ; S. Budd Haeberlein ; (2023): Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.6

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