Implications of the Approval of Lecanemab for Alzheimer Disease Patient Care: Incremental Step or Paradigm Shift?

Abstract

The amyloid cascade model of the pathogenesis of Alzheimer disease (AD) is well supported in observational studies. Its therapeutic corollary asserts that removal of amyloid-β peptide ("amyloid") would provide clinical benefits. After 2 decades of pursuing the strategy of amyloid removal without success, clinical trials of the antiamyloid monoclonal antibody (AAMA) donanemab and a phase 3 clinical trial of lecanemab have reported clinical benefits linked to amyloid removal. Lecanemab (trade name, Leqembi) is the first with published phase 3 trial results. When administered through IV every 2 weeks to patients with elevated brain amyloid and mild cognitive impairment or mild dementia, lecanemab delayed cognitive and functional worsening by approximately 5 months in an 18-month double-blind, placebo-controlled trial. The trial was well conducted, and the results favoring lecanemab were internally consistent. The demonstration that lecanemab treatment delayed clinical progression in persons with mild symptoms due to AD is a major conceptual achievement, but a better appreciation of the magnitude and durability of benefits for individual patients will require extended observations from clinical practice settings. Amyloid-related imaging abnormalities (ARIA) that were largely asymptomatic occurred in approximately 20%, slightly more than half of which were attributable to treatment and the rest to underlying AD-related amyloid angiopathy. Persons who were homozygous for the APOE ε4 allele had greater ARIA risks. Hemorrhagic complications with longer-term lecanemab use need to be better understood. Administration of lecanemab will place unprecedented pressures on dementia care personnel and infrastructure, both of which need to grow exponentially to meet the challenge.

Figure 1. Amyloid Cascade Hypothesis of Alzheimer Disease Pathogenesis and Its Related Therapeutic Conjectures

The model posits that elevations of aggregated amyloid-β peptide occur asymptomatically and induce downstream consequences including tauopathy and other neurodegenerative changes, eventually culminating in cognitive impairment. Blue arrows indicate clinically covert pathologic changes, the purple arrow indicates pathologic changes with early symptomatic consequences, and the red arrows indicate changes with overt clinical consequences. Green arrows indicate therapeutic intervention and hypothesized alterations in downstream pathologic and clinical consequences. The orange arrow indicates the influence of other cerebrovascular and non-Alzheimer neurodegenerative pathologic processes that modify the clinical expression of Alzheimer pathology.

Figure 2. Two Views of the Amyloid-β Removal Results of 4 AAMAs

(A) Groupwise adjusted mean declines in amyloid PET levels (y-axis) at different time points (x-axis) in centiloid values and (B) Percent of participants who achieved “complete” amyloid removal (y-axis) at different time points (x-axis). “Complete” removal levels were specified differently by each sponsor. Data were obtained from publications or presentations for aducanumab “Aduc” using 18F-florbetapir in ENGAGE and EMERGE trials, donanemab using 18F-florbetapir, gantenerumab using 18F-florbetapir “gant” GRADUATE I and II, and lecanemab using 18F-florbetaben, 18-F-florbetapir, or 18F-flutemetamol. Because each study used slightly different PET imaging methodologies and lecanemab allowed any of 3 tracers, centiloid scale values are difficult to compare precisely across different studies. Placebo group adjusted mean values, which in all trials showed small increases over time, are not shown. Percent of those exhibiting “complete removal” of amyloid in placebo groups also not shown (see text for lecanemab placebo group data). “●”—indicates a time point at which PET scan was performed. (Note: Donanemab trial scan was performed at week 24 but depicted here as week 26 for illustrative purposes). Aducanumab published SUVR data were transformed into centiloid values using the equation CL = 100*(SUVR – 1.0124)/0.4339.

Figure 3. Cumulative Survival Analysis for Time to Decline 1 Global CDR Point, From Phase 3 Lecanemab Trial

Time in months is on the x-axis, and proportion of participants worsening by 1 global CDR point is on the y-axis for placebo group (black line) and lecanemab-treated group (green line). The numbers of at-risk participants are given for each group at each time point, below the x-axis. A decline of 1 global CDR represents either a change from 0.5 to global CDR 1 or higher or from a global CDR 1 to a global CDR of 2 or higher. Because changes in disease severity across global CDRs are not equal and because the data in the figure include a mix of persons who started at global CDR of 0.5 (comprising approximately 81% of participants in each treatment group) and some who started at global CDR of 1 (comprising 19% of participants in each treatment group), the difference in curves might be more applicable to persons starting with a global CDR of 0.5.

Figure 4. Flow Diagram for Some of the Activities Involved in the Initial Screening of Patients for Suitability to Receive an Approved AAMA and Activities Needed to Initiate Treatment With an AAMA

Clinical expertise beyond dementia care neurology includes neuropsychologists, neuroradiologists, genetics counselors, and primary care physicians.