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

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 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 highdose 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.

Cost-Effectiveness and Value-Based Pricing of Aducanumab for Patients With Early Alzheimer Disease

“…Consistent with population estimates, slightly more than half (55%) of the cohort started in the MCI due to AD health state, with the remaining cohort (45%) starting in the mild dementia due to AD health state. 22 Other characteristics of the population starting in the model mirrored the characteristics from the 2 phase III trials, 15,16 with an average age of 70 years and 52% female. Given that aducanumab involves weight-based dosing, the weight of the population modeled represented the average weight of patients with AD from the Aging National Alzheimer's Coordinating Center 2015-2020 data.…”

Alzheimer disease neuropathology in a patient previously treated with aducanumab

“…Aducanumab has been granted accelerated approval by the US Food and Drug Administration (FDA) for the treatment of AD based on Aβ plaque reduction. Aβ plaque reduction has been demonstrated in patients with early symptomatic stages of AD (mild cognitive impairment due to AD and mild AD dementia) via reductions in Amyloid PET standard uptake value ratios (SUVR) in a Phase 1b (NCT01677572) [ 31 ] and two Phase 3 trials (NCT02477800 and NCT02484547) [ 6 ]. Postmortem histological evidence of Aβ plaque reduction by aducanumab in humans had not yet been reported.…”

Performing Cost-Effectiveness Analyses to Support Policy Making

“…After consultation with stakeholders and reviewing evidence from other amyloid-targeted therapies, we assumed that the increased risk of ARIA was only during the first year of aducanumab treatment. Furthermore, in alignment with the discontinuation due to adverse events reported in the trials, 22 we assumed patients who experienced symptomatic ARIA would discontinue aducanumab treatment, although this assumption could change as more is understood about ARIA occurrence and management. Long-term observational studies and ongoing conversations with clinical experts could aid in reducing the uncertainty in ARIA-related assumptions.…”