What are the clinical effects of Leqembi (lecanemab) on patients with early-stage Alzheimer's disease?

Clinical Effects of Leqembi (Lecanemab) in Early Alzheimer's Disease

Leqembi (lecanemab) modestly slows cognitive decline in early Alzheimer's disease by reducing amyloid plaque burden, but has significant safety concerns including ARIA (Amyloid-Related Imaging Abnormalities) and does not show efficacy in certain populations such as women and APOE4 homozygotes.

Efficacy Profile

Lecanemab is an amyloid plaque-lowering monoclonal antibody that received traditional FDA approval in July 2023 for treatment of early Alzheimer's disease (mild cognitive impairment or mild dementia) 1. Its clinical effects include:

• Cognitive and Functional Outcomes:

  • Modest slowing of cognitive decline rather than improvement or symptom reversal
  • 27% reduction in clinical decline as measured by CDR-SB (Clinical Dementia Rating-Sum of Boxes) over 18 months
  • Difference of -0.45 points on CDR-SB between lecanemab and placebo groups 2
  • Improvements on other cognitive measures including ADAS-Cog14, ADCOMS, and ADCS-MCI-ADL 2

• Biomarker Effects:

  • Substantial reduction in amyloid plaque burden (approximately 73.5 centiloid reduction compared to placebo) 3
  • Targets soluble amyloid-beta protofibrils with high affinity 2

• Quality of Life Impact:

  • 49% less decline in EQ-5D-5L (patient-reported quality of life measure)
  • 56% less decline in QOL-AD (Quality of Life in Alzheimer's Disease) by patient report
  • 23% less decline in QOL-AD as rated by caregivers
  • 38% less increase in caregiver burden as measured by Zarit Burden Interview 4

Safety Concerns

Lecanemab treatment comes with significant safety considerations:

• ARIA (Amyloid-Related Imaging Abnormalities):

  • ARIA-E (edema): occurs in 12.6% of patients, primarily within first 3-6 months of treatment 2
  • ARIA-H (hemosiderin deposits/microhemorrhages): occurs in 16.0% of patients 5
  • Higher risk in APOE ε4 carriers (16.8%) and especially homozygotes (34.5%) 5
  • Requires regular MRI monitoring before the 5th, 7th, and 14th infusions 3

• Infusion-Related Reactions:

  • Occur in 26.4% of patients receiving lecanemab compared to 7% with placebo 6, 2

• Serious Adverse Events:

  • Risk of intracerebral hemorrhage, particularly in patients on anticoagulants or receiving thrombolytic therapy 3, 5

Population-Specific Considerations

The effectiveness of lecanemab varies significantly across different patient populations:

• APOE ε4 Status:

  • Limited efficacy in APOE ε4 carriers
  • May enhance cognitive decline in APOE ε4 homozygotes 7
  • APOE testing is recommended before initiating treatment 3

• Gender Differences:

  • Reduced efficacy in women, despite women having twice the risk of developing Alzheimer's disease 7

Treatment Protocol

For patients receiving lecanemab:

• Dosing Regimen:

  • 10 mg/kg intravenously every two weeks for the first 18 months
  • May transition to 10 mg/kg every four weeks after 18 months 3

• Patient Selection:

  • Confirmation of amyloid pathology via PET scan or CSF testing is required before initiating treatment 3
  • Intended for early Alzheimer's disease (mild cognitive impairment or mild dementia) 3
  • Baseline MMSE score between 22-30 3

• Monitoring Requirements:

  • Baseline brain MRI before starting treatment
  • Follow-up MRIs before the 5th, 7th, and 14th infusions
  • Additional MRIs if symptoms suggestive of ARIA develop 3
  • Regular cognitive assessments to determine continued benefit 8

Clinical Implications

Healthcare providers should consider:

• The modest clinical benefits must be weighed against safety concerns and monitoring requirements
• Treatment requires specialized resources and multidisciplinary teams 1
• Centers for Medicare & Medicaid Services (CMS) will reimburse for lecanemab when patients are registered in a CMS-approved registry 1
• The high prevalence of APOE ε4 carriers (60-75% of AD patients) and women among AD patients means many patients may have limited benefit 7

Conclusion

While lecanemab represents a disease-modifying approach to Alzheimer's treatment, its clinical effects are modest and come with significant safety considerations. The decision to initiate treatment should carefully weigh potential benefits against risks, particularly for women and APOE ε4 carriers, who may experience limited benefit or worsening outcomes.