Donanemab (Kisunla) for Alzheimer's Disease
Also known as: Kisunla, LY3002813
Donanemab uniquely targets established amyloid plaques and allows treatment discontinuation once amyloid-negative, pioneering a 'treat-to-clear' approach.
Mechanism of Action
Donanemab targets pyroglutamate-modified amyloid-beta (N3pG-Aβ) found predominantly in established plaques rather than soluble species. This complement-mediated and microglial clearance approach can achieve amyloid negativity on PET in 68% of treated patients by 76 weeks, enabling treatment discontinuation.
General mechanism: Anti-N3pG-Aβ monoclonal antibody targeting pyroglutamate-modified amyloid in established plaques. 'Treat-to-clear' approach.
Current Evidence
TRAILBLAZER-ALZ 2 showed 35% slowing of cognitive decline in the combined tau-low + tau-intermediate population. 47% risk reduction in progression to next disease stage. Benefit was greatest in patients with lower baseline tau burden.
Clinical Status: FDA-approved (2024). Unique 'treat-to-clear' dosing paradigm. Treatment stops when amyloid PET shows clearance.
Safety Profile
ARIA in ~24% (edema + microhemorrhages). Three treatment-related deaths in trials. APOE4 homozygotes at highest ARIA risk. Infusion reactions.
Key Research Questions
- How durable is benefit after treatment discontinuation and amyloid clearance?
- Does donanemab's plaque-targeting complementary with lecanemab's protofibril-targeting suggest combination potential?
- Can tau biomarkers (PET or CSF) guide patient selection for optimal benefit?