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

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.

Déclaration de conflit d'intérêts

These studies were funded by Biogen. SBH, YT, KKM, TC, SW, GD, KH, IN, and YZ are employees and shareholders of Biogen. SC (Dr Chalkias), AS, LN, RR, CvH, CM and LS were employees of Biogen at the time of this work. CM is a current employee of Cortexyme. LS and CvH are current employees of Takeda Pharmaceutical Co. SC is a current employee at Moderna. RR is a current employee at Vigil Neuro. PSA was chair of the Steering Committee and has consulted for Biogen, has received research support from Eli Lilly, Janssen, Eisai, the Alzheimer’s Association, the National Institutes of Health, and the Foundation for the National Institutes of Health; he has consulted for Merck, Roche and ImmunoBrain Checkpoint. PSA is co-editor in chief of JPAD with no personal compensation; he did not have a role in the editorial process/review for this manuscript. FB was supported by NIHR Biomedical Research Centre at UCLH. He receives personal fees for consultancy from Bayer, Biogen, Roche, IXICO Ltd, Novartis, and Combinostics. SC (Dr Cohen) was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is a consultant (no personal fees received) to Biogen, Cassava Sciences, Cogstate, INmune Bio, ProMIS Neuroscience, and RetiSpec and receives research support (paid to institution) from AgeneBio, Anavex, Biogen, Cassava, Eisai, Genentech, Green Valley, Eli Lilly, Janssen, RetiSpec, Roche, and Vielight. OH received research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, 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 NIHR Biomedical Research Centre at UCLH and has acted as a consultant to Biogen, Roche, and IONIS. CvD was an EMERGE trial site investigator. He is a consultant for Roche, Eisai, and Ono and receives research support from Biogen, Eisai, Roche, Genentech, Eli Lilly, Janssen, Merck, Novartis, and Biohaven. BV is an investigator in clinical trials sponsored by Biogen, Lilly, Roche, Eisai Pharmaceuticals, and the Toulouse University Hospital (Inspire Geroscience Program). He has served as SAB member for Biogen, Alzheon, Green Valey, Norvo Nordisk, Longeveron, but received no personal compensation. He has served as consultant and/or SAB member for Roche, Lilly, Eisai, TauX with personal compensation. His family members have equity ownership interest in Serdi. He is member of the Editorial Board of JPAD with no personal compensation. He did not have a role in the editorial or peer review for this manuscript at JPAD.