Donanemab (Kisunla) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Donanemab (brand name Kisunla; donanemab-azbt) is a humanized IgG1 monoclonal antibody developed by Eli Lilly and Company that targets pyroglutamate-modified amyloid-beta (AbetapE3-42), a post-translationally modified form of Aβ found predominantly in mature amyloid plaques. Unlike lecanemab, which preferentially binds soluble amyloid protofibrils, donanemab is designed to engage deposited, insoluble plaque and promote its clearance through microglial phagocytosis. The U.S. Food and Drug Administration (FDA) granted full approval to Kisunla on July 2, 2024, for the treatment of early symptomatic Alzheimer's Disease in adults with confirmed amyloid pathology, based on the pivotal TRAILBLAZER-ALZ 2 Phase III trial (Sims et al., 2023). [1]
Donanemab's epitope is unique among anti-amyloid immunotherapies. The antibody specifically recognizes the N-terminally truncated, pyroglutamate-modified Abeta peptide at position 3 (AbetapE3), generated by the enzyme glutaminyl cyclase. AbetapE3-42 is: [2]
By targeting this modified species, donanemab engages established plaque deposits and promotes Fc-receptor-mediated microglial phagocytosis of opsonized amyloid, leading to rapid and near-complete plaque removal in most patients (Mintun et al., 2021). [4]
Donanemab binds to AbetapE3-42 epitopes on the surface of amyloid plaques, forming immune complexes that are recognized by Fc-gamma receptors on microglia and confirmed amyloid PET positivity (Sims et al., 2023)). [8]
| Outcome Measure | Low/Medium Tau Population | Combined Population |
|---|---|---|
| iADRS slowing vs. placebo | 35.1% (p < 0.001) | 22.3% (p < 0.001) |
| CDR-SB slowing vs. placebo | 36.0% (p < 0.001) | 28.9% (p < 0.001) |
| No decline at 1 year | 47% vs. 29% placebo | -- |
| amyloid PET clearance | 80% achieved amyloid-negative status | 76% achieved amyloid-negative status |
The low/medium tau subgroup demonstrated the strongest clinical benefit, with a 35% slowing of decline on the iADRS. The combined population (including high-tau participants) showed 22% slowing on iADRS and 29% slowing on CDR-SB. Importantly, 47% of donanemab-treated participants showed no clinical progression at one year, compared with 29% on placebo. [10]
Donanemab treatment produced substantial changes in fluid and imaging biomarkers: [12]
The dissociation between p-tau217/GFAP improvements and continued NfL rise highlights that amyloid clearance alone may be insufficient to halt all neurodegenerative processes.
Donanemab employs a distinctive treatment-to-target approach:
In February 2025, the FDA approved an updated label allowing a simplified dosing regimen. This treatment-to-target approach distinguishes donanemab from lecanemab, which requires continuous biweekly infusions, and may offer advantages in cost, patient convenience, and cumulative [ARIA] risk (Eli Lilly, 2024).
Amyloid-related imaging abnormalities (ARIA represent the principal safety concern with donanemab:
| ARIA Type | Donanemab | Placebo |
|---|---|---|
| ARIA-E (edema/effusions) | 24.0% | 2.1% |
| ARIA-H microhemorrhages | 31.4% | 13.6% |
| ARIA-H superficial siderosis | 14.0% | 3.0% |
| Symptomatic ARIA | 6.1% | 0.4% |
| Serious ARIA | 1.6% | -- |
Three deaths attributable to ARIA occurred during the trial, including two in APOE epsilon4/epsilon4 homozygotes. ARIA-E risk was highest in the first 24 weeks of treatment and in APOE4 carriers. The updated 2025 label includes recommendations for genotyping to identify APOE4 homozygotes, who should be counseled about elevated risk, and for MRI monitoring at defined intervals (Sperling et al., 2024).
| Feature | Donanemab (Kisunla) | lecanemab ([Leqembi] |
|---|---|---|
| Target | Pyroglutamate Abeta (AbetapE3-42) on plaques | Soluble Abeta protofibrils |
| Plaque engagement | Deposited, mature plaques | Soluble aggregates and protofibrils |
| Dosing | 1,400 mg IV every 4 weeks | 10 mg/kg IV every 2 weeks |
| Treatment duration | Finite (stop after amyloid clearance) | Continuous (indefinite treatment) |
| Efficacy (CDR-SB) | 36% slowing (low/medium tau | 27% slowing (overall) |
| Amyloid clearance | 76-80% reach amyloid-negative | 68% reach amyloid-negative |
| ARIA-E rate | 24.0% | 12.6% |
| ARIA-H rate | 31.4% | 17.3% |
| Deaths attributed to ARIA | 3 | 3 |
| FDA approval | July 2024 (full) | January 2023 (accelerated); July 2023 (full) |
| Patient selection | Amyloid-positive, low/medium tau preferred | Amyloid-positive early AD |
A 2025 indirect treatment comparison demonstrated that lecanemab had significantly lower risk of any ARIA compared with donanemab, with a risk difference-in-difference of -10.1%, particularly in [APOE epsilon4 carriers (Burke et al., 2025). However, donanemab achieves higher rates of complete amyloid clearance and offers the advantage of a finite treatment course.
Optimal patient selection is central to donanemab's clinical benefit:
The tau-based stratification reflects a biological principle: once tau pathology has spread extensively beyond the medial temporal lobe, amyloid clearance may be too late to substantially modify the downstream neurodegenerative cascade (Jack et al., 2018).
The deployment of donanemab in clinical practice faces significant logistical hurdles:
The TRAILBLAZER-ALZ 2 open-label extension demonstrated sustained clinical benefit at 3 years. Participants originally randomized to donanemab maintained their cognitive advantage over the delayed-start (originally placebo) group at 36 months, suggesting that early amyloid clearance provides durable disease modification even after treatment discontinuation. This supports the hypothesis that removing the amyloid trigger early in the disease course slows downstream tau spreading and neurodegeneration (Lilly, 2025).
The study of Donanemab (Kisunla) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.