What is the current approach to using anti-amyloid monoclonal antibodies, such as Donanemab (aducanumab) and Lecanemab, in the treatment of Alzheimer's disease?

Current Approach to Anti-Amyloid Monoclonal Antibodies in Alzheimer's Disease Treatment

Anti-amyloid monoclonal antibodies (mAbs) such as lecanemab (Leqembi) and donanemab (Kisunla) are now FDA-approved disease-modifying therapies that should be offered to patients with early Alzheimer's disease (mild cognitive impairment or mild dementia) who have confirmed amyloid pathology, as these treatments can slow cognitive decline by approximately 30%. 1, 2

Approved Agents and Regulatory Status

• Lecanemab (Leqembi) received traditional (full) FDA approval in July 2023, with CMS agreeing to reimburse for its use when appropriate patients are registered in a CMS-approved patient registry 1
• Donanemab (Kisunla) received traditional FDA approval in July 2024 as the third plaque-lowering mAb 1
• Aducanumab (Aduhelm) received accelerated approval in 2021 but its development has been discontinued due to limited use after CMS did not support payment 1

Patient Selection Criteria

• Treatment is indicated specifically for patients with early symptomatic Alzheimer's disease, including those with mild cognitive impairment (MCI) or mild dementia due to AD 1, 3
• Confirmation of amyloid pathology is required before initiating treatment, which can be done through:
  • Amyloid PET imaging (now reimbursable for Medicare beneficiaries since October 2023) 1
  • CSF biomarkers (several new assays for amyloid and tau have received FDA clearance) 1
  • Blood-based biomarkers such as plasma p-tau217 are increasingly being used to identify appropriate candidates 3
• Optimal results are seen in patients with intermediate tau PET burden, with patient stratification based on tau burden being crucial for treatment success 3

Mechanism of Action and Clinical Effects

• These mAbs target and reduce aggregated forms of amyloid beta in the brain 4, 5
• Lecanemab is directed against aggregated soluble and insoluble forms of amyloid beta 4
• Donanemab specifically targets insoluble N-truncated pyroglutamate amyloid beta 5
• Both treatments lead to significant reductions in amyloid plaque levels in the brain in a time-dependent manner 4, 5
• Treatment with these agents also reduces plasma p-tau217 levels, indicating effects on tau pathophysiology beyond just amyloid clearance 3, 5

Efficacy and Clinical Outcomes

• Anti-amyloid mAbs slow cognitive and functional decline by approximately 30% over 18 months in clinical trials 2
• Clinical benefit is associated with reductions in amyloid plaque burden below a threshold of 15-25 Centiloids 2
• After Week 79 of treatment with lecanemab, 67% of patients had amyloid levels less than 30 Centiloids as measured by PET 4
• The magnitude of clinical benefit is considered clinically meaningful in terms of extended cognitive integrity and delay of onset of more severe dementia phases 6

Safety Considerations and Monitoring

• Amyloid-related imaging abnormalities (ARIA) are a significant concern requiring monitoring:
  • ARIA with edema (ARIA-E) occurred in 13% of lecanemab-treated patients 4
  • ARIA with hemosiderin deposition (ARIA-H) occurred in 14% of lecanemab-treated patients 4
  • APOE ε4 carriers have approximately 4 times higher risk of ARIA-E events by 24 weeks of treatment 3, 7
• Brain MRI scans are required for monitoring ARIA 1
• Infusion-related reactions occurred in 26% of patients treated with lecanemab 4
• Other common adverse reactions include headache (11%), superficial siderosis (6%), and rash (6%) 4

Implementation Challenges

• The healthcare system faces challenges in meeting the demand for timely detection, accurate diagnosis, and appropriate treatment options for early AD 1
• Providing treatment requires high proficiency and sufficient resources, including close collaborations with comprehensive multidisciplinary teams 1
• With too few specialists currently available, new models of hub-and-spoke dementia specialist–primary care collaborations and peer-to-peer consultation are being developed 1
• Health systems are forming new partnerships among community organizations, primary care clinicians, memory-care experienced nurses and nurse practitioners, and specialists 1

Health Equity Considerations

• Better access and inclusion of Black, Hispanic/Latino, Asian American, Pacific Islander, and Native American populations in clinical trials and treatment programs is crucial 1
• Some health systems have demonstrated elimination of racial disparities in modifiable risk factors for dementia, though disparities persist for Black populations 1
• Ongoing progress to raise awareness, diversify the practitioner workforce, and evolve clinical practices is needed to mitigate health inequities 1

Future Directions

• The percentage of patients achieving low amyloid levels is predicted to increase with continued treatment 4
• After initial treatment periods, reducing the frequency of administration (e.g., from every 2 weeks to every 4 weeks) may maintain the reduction in amyloid beta plaque levels 4
• Development of subcutaneous formulations and increased use of blood-based biomarkers for diagnosis and monitoring promises to increase accessibility and decrease demands on healthcare systems 2