The Journal of Prevention of Alzheimer's Disease MARCH 16, 2022

Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease (EMERGE and ENGAGE)

Samantha Budd Haeberlein, et al.

Bottom Line

The phase 3 EMERGE and ENGAGE trials evaluated the efficacy of aducanumab in early Alzheimer's disease, with EMERGE demonstrating a statistically significant reduction in clinical decline with high-dose treatment, whereas ENGAGE failed to meet its primary endpoint.

Key Findings

1. In the EMERGE trial, high-dose aducanumab (10 mg/kg) resulted in a statistically significant 22% reduction in clinical decline compared to placebo, as measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB) at week 78 (difference: -0.39; 95% CI, -0.69 to -0.09; P=.012).

2. In the ENGAGE trial, no statistically significant benefit was observed in the high-dose aducanumab arm compared to placebo (difference: 0.03; 95% CI, -0.26 to 0.33; P=.833).

3. Biomarker substudies across both trials confirmed that aducanumab achieved target engagement, resulting in a dose- and time-dependent reduction in amyloid-beta plaque burden.

4. The most frequent adverse event observed was amyloid-related imaging abnormalities-edema (ARIA-E), occurring in approximately 35.2% of participants in the 10 mg/kg dose groups.

Study Design

Design

RCT

Double-Blind

Sample

3,285

Patients

Duration

78 wk

Median

Setting

Multicenter, global

Population Patients aged 50-85 years with early Alzheimer's disease (mild cognitive impairment or mild dementia) confirmed by positive amyloid pathology.

Intervention Aducanumab (high dose: 10 mg/kg or low dose: 3/6 mg/kg) administered via IV infusion every 4 weeks.

Comparator Placebo administered via IV infusion every 4 weeks.

Outcome Change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB).

Study Limitations

• The trials were terminated early due to a futility analysis, which complicated the interpretation of data and efficacy assessments.

• There was a notable inconsistency between the EMERGE and ENGAGE trial outcomes, despite identical study designs.

• Protocol amendments during the study changed the dosing regimens for a portion of the participants, which may have impacted the comparability of treatment groups.

• The reliance on clinical data post-futility analysis has been subject to significant scientific and statistical debate regarding the robustness of the evidence.

Clinical Significance

These trials represent a pivotal, albeit controversial, investigation into amyloid-targeting immunotherapy for early Alzheimer's disease; the findings served as the basis for the accelerated FDA approval of aducanumab, highlighting the challenges of using surrogate biomarker endpoints (amyloid clearance) to infer clinical benefit.

Historical Context

The EMERGE and ENGAGE trials are landmark studies in the history of Alzheimer's research as they were among the first large-scale phase 3 trials to show a statistically significant reduction in amyloid-beta plaques alongside potential slowing of clinical decline, fueling intense debate regarding the validity of the 'amyloid hypothesis' and the regulatory pathway for disease-modifying therapies in dementia.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Explain the 'Amyloid Hypothesis' as it relates to the pathophysiology of Alzheimer's disease and describe how the mechanism of action of aducanumab differs from symptomatic treatments like donepezil.

Key Response

Aducanumab is a human monoclonal antibody that selectively binds to amyloid-beta (Aβ) aggregates (oligomers and fibrils), aiming to clear plaques and potentially modify the disease course. In contrast, cholinesterase inhibitors like donepezil increase synaptic acetylcholine levels to provide temporary symptomatic relief for cognitive symptoms without altering the underlying neurodegenerative process or plaque burden.

Resident

What are Amyloid-Related Imaging Abnormalities (ARIA), and what specific MRI monitoring protocol and management steps should a clinician follow when a patient on aducanumab presents with new-onset headaches and focal cortical edema (ARIA-E)?

Key Response

ARIA-E (edema/effusion) and ARIA-H (hemorrhage) are key adverse effects. According to the FDA label and trial protocols, patients require MRI monitoring at baseline and prior to the 5th, 7th, 9th, and 12th doses. For symptomatic or severe ARIA, treatment should be suspended; it may be resumed only after the patient is asymptomatic and the MRI shows stabilization or resolution, typically starting back at the previous dose level.

Fellow

Critically analyze the impact of the 'Protocol Amendment 4' on the divergent results of the EMERGE and ENGAGE trials, specifically regarding the exposure of APOE ε4 carriers to high-dose aducanumab (10 mg/kg).

Key Response

Initially, APOE ε4 carriers (who are at higher risk for ARIA) were limited to lower doses. The protocol was later amended to allow them to titrate to the 10 mg/kg dose. Because EMERGE enrolled more patients later in the study cycle compared to ENGAGE, a higher proportion of its participants reached the 10 mg/kg target dose for a longer duration, which investigators argue explains why EMERGE met its primary endpoint while ENGAGE did not.

Attending

Given that the 22% reduction in clinical decline on the CDR-SB in EMERGE represents a difference of approximately 0.39 points on an 18-point scale, how do you communicate the 'clinical meaningfulness' of this result to a family considering the high cost and risk of ARIA?

Key Response

This question addresses the gap between statistical significance and clinical relevance. An attending must teach that while the slowing of decline is statistically significant in one trial, the actual difference in daily functioning may be subtle. Shared decision-making must balance the hope of 'buying time' in an early stage against the logistical burdens of monthly infusions and the roughly 35-40% risk of ARIA-E.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The EMERGE/ENGAGE trials were famously halted for futility based on an interim analysis that was later contradicted by the final dataset. What are the statistical limitations of using conditional power in interim analyses for neurodegenerative trials where treatment effects may be delayed or dose-dependent?

Key Response

Futility analyses often assume that the treatment effect remains constant over time. In aducanumab's case, the drug required a long titration period to reach a therapeutic dose. If the interim analysis occurs before a sufficient number of patients have reached the high-dose steady state, the 'futility' calculation will be biased toward the null, failing to account for the delayed onset of efficacy seen in the latter half of the trial.

Journal Editor

As a reviewer, how would you address the concern of 'functional unblinding' in the EMERGE trial, and does the high incidence of ARIA-E (which often leads to protocol-mandated dose interruptions and unmasked MRI results) compromise the integrity of the CDR-SB primary endpoint?

Key Response

ARIA-E occurred in 35% of the treatment group, often requiring unmasked clinical management. Because the primary endpoint (CDR-SB) is a subjective assessment based on interviews with patients and caregivers, knowledge of the side-effect profile or dose changes could lead to 'expectation bias.' A rigorous review must determine if the sensitivity analyses (e.g., comparing results of those with and without ARIA) sufficiently prove that efficacy was not driven by unblinding.

Guideline Committee

Should the conflicting data from EMERGE and ENGAGE lead to a change in the AAN or NIA-AA diagnostic and treatment guidelines, and how does the evidence strength for aducanumab compare to the standard of 'consistency' required for a Level A recommendation?

Key Response

Guideline committees typically require at least two consistent, high-quality RCTs for a strong recommendation. Because ENGAGE failed its primary endpoint and EMERGE was positive only in a post-hoc analysis following a futility halt, the evidence quality is often graded as 'Low' to 'Moderate' due to inconsistency. Current guidelines (like those from the ICER report or European Academy of Neurology) have remained cautious, often recommending use only in highly controlled research or specialized clinical settings rather than broad adoption.

Clinical Landscape

Noteworthy Related Trials

2017

EXPEDITION-3 Trial

n = 2,129 · NEJM

Tested

Solanezumab 400mg every 4 weeks

Population

Patients with mild Alzheimer's dementia

Comparator

Placebo

Endpoint

Change from baseline in ADAS-Cog14 score

Key result: The study failed to show a statistically significant difference in cognitive decline between the treatment and placebo groups.

2021

DIAN-TU-001 Trial

n = 194 · NEJM

Tested

Gantenerumab or Solanezumab

Population

Individuals with dominantly inherited Alzheimer's disease

Comparator

Placebo

Endpoint

Cognitive composite score

Key result: Neither gantenerumab nor solanezumab met the primary endpoint for clinical benefit in this specific genetic population.

2023

Clarity AD Trial

n = 1,795 · NEJM

Tested

Lecanemab 10 mg/kg biweekly

Population

Early Alzheimer's disease patients with confirmed amyloid pathology

Comparator

Placebo

Endpoint

Change in CDR-SB score at 18 months

Key result: Lecanemab resulted in moderately less decline on clinical dementia rating scales compared to placebo.

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