Anti-amyloid immunotherapies represent a major therapeutic approach in Alzheimer's disease, targeting the amyloid-beta (Aβ) protein that is central to the amyloid hypothesis. This comparison matrix provides detailed information on six key immunotherapies: Lecanemab (Leqembi), Donanemab (Kisunla), Aducanumab (Aduhelm), Gantenerumab, Crenezumab, and SAR228810.
| Therapy | Brand Name | Mechanism | Primary Target | FDA Status | Approval Year |
|---|---|---|---|---|---|
| Lecanemab | Leqembi | Monoclonal antibody | Aβ protofibrils | Approved | 2023 |
| Donanemab | Kisunla | Monoclonal antibody | Aβ plaques | Approved | 2024 |
| Aducanumab | Aduhelm | Monoclonal antibody | Aβ plaques | Withdrawn | 2021 |
| Gantenerumab | - | Monoclonal antibody | Aβ plaques | Not approved | - |
| Crenezumab | - | Monoclonal antibody | Aβ oligomers | Not approved | - |
| SAR228810 | - | Monoclonal antibody | Aβ protofibrils | Not approved | - |
Mechanism of Action:
Lecanemab is a humanized IgG1 monoclonal antibody that selectively binds to Aβ protofibrils (soluble aggregated Aβ) with high affinity. It clears both protofibrils and plaques through Fc-mediated antibody-dependent cellular cytotoxicity (ADCC).
Target: Aβ protofibrils (soluble aggregates) and existing plaques
Phase 3 Trial - CLARITY-AD:
FDA Status: Full approval (2023); covered by Medicare with evidence requirements
ARIA Incidence:
Dosing Protocol:
Patient Selection Criteria:
Mechanism of Action:
Donanemab is a monoclonal antibody that targets a specific conformational epitope on Aβ plaques. It binds to Aβ plaques and recruits microglia for plaque clearance through the brain's innate immune system.
Target: N-terminally truncated Aβ plaques (pyroglutamate-modified Aβ)
Phase 3 Trial - TRAILBLAZER-ALZ 2:
FDA Status: Full approval (2024)
ARIA Incidence:
Dosing Protocol:
Patient Selection Criteria:
Mechanism of Action:
Aducanumab is a human IgG1 monoclonal antibody that binds to multiple forms of Aβ, including monomers, oligomers, and plaques. It was designed to engage the immune system to clear amyloid plaques.
Target: Aβ plaques (broad-spectrum)
Phase 3 Trials - EMERGE and ENGAGE:
FDA Status: Withdrawn from market (2024) - manufacturer discontinued commercial availability
Note: Historic importance in field; raised bar for future approvals
Mechanism of Action:
Gantenerumab is a fully human IgG1 monoclonal antibody that binds with high affinity to Aβ plaques. It engages microglia-mediated clearance but showed limited efficacy in trials.
Target: Aβ plaques
Phase 3 Trials - GRADUATE 1 and 2:
FDA Status: Not approved; development discontinued
Note: Demonstrated amyloid removal but insufficient efficacy
Mechanism of Action:
Crenezumab is a humanized IgG4 monoclonal antibody that preferentially targets Aβ oligomers and protofibrils. The IgG4 isotype reduces Fc-mediated effector functions, theoretically reducing ARIA risk.
Target: Aβ oligomers (soluble aggregated Aβ)
Phase 3 Trials - CREAD and CREAD2:
-did not meet primary endpoints
FDA Status: Not approved; development discontinued
Note: Interesting proof-of-concept for oligomer-targeting
Mechanism of Action:
SAR228810 is a monoclonal antibody targeting Aβ protofibrils with high specificity. Development focused on early AD prevention.
Target: Aβ protofibrils
Phase 1/2 Trials:
FDA Status: Not approved; development status unclear
| Therapy | CDR-SB Slowing | Amyloid Removal | ARIA-E Rate |
|---|---|---|---|
| Lecanemab | 27% (0.45 pts) | Significant (~60 Centiloids) | ~12.6% |
| Donanemab | 29-35% (iADRS) | Very high (~80+ Centiloids) | ~24% |
| Aducanumab | Marginal | Significant | ~35% |
| Gantenerumab | None | Modest | High |
| Crenezumab | None | Minimal | Low (~10%) |
| SAR228810 | TBD | TBD | TBD |
| Therapy | ARIA-E Risk | ARIA-H Risk | Monitoring Intensity |
|---|---|---|---|
| Lecanemab | Moderate (12.6%) | Moderate (17.3%) | Every 4-12 weeks |
| Donanemab | Higher (24%) | Higher (31%) | More intensive |
| Aducanumab | High (~35%) | High | Intensive |
| Gantenerumab | High | High | Very intensive |
| Crenezumab | Low (~10%) | Low | Less intensive |
| SAR228810 | TBD | TBD | TBD |
| Factor | All Anti-Amyloid Therapies | Lecanemab | Donanemab |
|---|---|---|---|
| Disease stage | Early AD (MCI-mild) | Early AD | Early AD |
| Amyloid confirmation | Required | Required | Required |
| Tau imaging | Recommended | May help predict | Recommended |
| Age | Generally <85 | Generally <85 | Generally <85 |
| ApoE4 status | Risk factor for ARIA | Risk factor for ARIA | Risk factor for ARIA |
| Anticoagulation | Caution | Caution | Caution |
| Therapy | Annual Cost (est.) | Medicare Coverage | Availability |
|---|---|---|---|
| Lecanemab | ~$28,000 | Yes, with restrictions | Widely available |
| Donanemab | ~$32,000 | Yes, with restrictions | Expanding |
| Aducanumab | ~$28,000 | Discontinued | Not available |
The main Alzheimer's Disease disease page should reference this comparison matrix for treatment options.