@article{8468d20041f441e9ae8db2fada1040bb,
title = "Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab",
abstract = "Objectives: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer{\textquoteright}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.",
keywords = "Aducanumab, Alzheimer{\textquoteright}s disease, amyloid beta",
author = "C. Mallinckrodt and Y. Tian and Aisen, {P. S.} and F. Barkhof and S. Cohen and G. Dent and O. Hansson and K. Harrison and T. Iwatsubo and Mummery, {C. J.} and Muralidharan, {K. K.} and I. Nestorov and L. Nisenbaum and R. Rajagovindan and {von Hehn}, C. and {van Dyck}, {C. H.} and B. Vellas and S. Wu and Y. Zhu and A. Sandrock and T. Chen and {Budd Haeberlein}, S.",
note = "Funding Information: Funding: The sponsor (Biogen) played a role in the design and conduct of these studies as well as the collection, analysis, and interpretation of data. Medical writing and editorial support were provided by MediTech Media, Ltd., in accordance with Good Publication Practice guidelines ( http://www.ismpp.org/gpp-2022 ) and were funded by Biogen. Funding Information: These studies were funded by Biogen. YT, GD, KH, KKM, IN, SW, YZ, TC, and SBH are employees and shareholders of Biogen. CvH, PB, CM, LN, RR, and AS are former employees of Biogen. CM is a current employee of Cortexyme. PSA was Chair of the Steering Committee; has received research support from Eisai, Eli Lilly, Janssen, the Alzheimer{\textquoteright}s Association, NIH, and FNIH; and has consulted for ImmunoBrain Checkpoint, Merck, and Roche. FB was supported by the NIHR Biomedical Research Centre at UCLH. He receives personal fees for consultancy from Bayer, Biogen, Combinostics, IXICO, Novartis, and Roche. SC was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is a consultant to Alnylam, Biogen, Cognivue, Cogstate, Eisai, Eli Lilly, INmune Bio, Novo Nordisk, ProMIS Neurosciences, RetiSpec, and Roche and receives research support (paid to institution) from AgeneBio, Alector, Alnylam, Anavex, Biogen, Eisai, Eli Lilly, Genentech, Novo Nordisk, RetiSpec, Roche, UCB, and Vielight. OH has acquired research support (for the institution) from Avid Radiopharmaceuticals, Biogen, Eisai, Eli Lilly, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, ALZPath, Biogen, Cerveau, and Roche. TI is a consultant to Eisai and Roche. CJM was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is supported by the NIHR Biomedical Research Centre at UCLH and has acted as a consultant to Biogen, Ionis, and Roche. CvD was an EMERGE trial site investigator. He is a consultant to Eisai and Roche and receives research support from Biogen, Biohaven, Eisai, Eli Lilly, Genentech, Janssen, Merck, Novartis, and Roche. BV was a trial site investigator and an Aducanumab Steering Committee member. He is supported by CHU-T and has acted as a consultant to Biogen, Eli Lilly, Merck, and Roche. Publisher Copyright: {\textcopyright} 2023, The Authors.",
year = "2023",
month = feb,
doi = "https://doi.org/10.14283/jpad.2023.6",
language = "English",
volume = "10",
pages = "171--177",
journal = "Journal of Prevention of Alzheimer's Disease",
issn = "2274-5807",
publisher = "Springer International Publishing AG",
number = "2",
}