Introduction
Kisunla (donanemab-azbt) is a monoclonal antibody therapy developed by Eli Lilly and Company for the treatment of Alzheimer's disease. Approved by the FDA in July 2024, Kisunla represents a significant advancement in the management of early symptomatic Alzheimer's disease, specifically targeting amyloid-beta plaques, a hallmark pathological feature of the condition. This immunoglobulin G1 monoclonal antibody binds to N-terminal pyroglutamate amyloid-beta plaques, facilitating their clearance from the brain.
Mechanism of Action
Kisunla exerts its therapeutic effect through targeted amyloid plaque clearance. The drug specifically binds to N-terminal pyroglutamate amyloid-beta deposits, which are insoluble fibrillar aggregates that accumulate in the brains of Alzheimer's patients. By binding to these plaques, Kisunla promotes their removal through Fc receptor-mediated phagocytosis by microglial cells. This mechanism reduces amyloid plaque burden, potentially slowing disease progression and cognitive decline in patients with early Alzheimer's disease.
Indications
Kisunla is indicated for the treatment of Alzheimer's disease in adults with:
- Mild cognitive impairment due to Alzheimer's disease
- Mild dementia stage of Alzheimer's disease
- Confirmed presence of amyloid beta pathology through appropriate diagnostic testing
Dosage and Administration
Standard dosing regimen:- Initial dose: 700 mg intravenous infusion every 4 weeks for the first 3 doses
- Maintenance dose: 1400 mg intravenous infusion every 4 weeks thereafter
- Administered via IV infusion over approximately 30 minutes
- Pre-treatment with antihistamines may be considered to reduce infusion-related reactions
- Dose adjustments may be necessary based on amyloid PET imaging results or ARIA findings
- Renal impairment: No dosage adjustment required
- Hepatic impairment: No specific recommendations; use with caution
- Elderly: No dosage adjustment required
- Pregnancy: Not recommended unless potential benefit justifies potential risk
Pharmacokinetics
Absorption: Administered intravenously, resulting in complete bioavailability Distribution: Steady-state volume of distribution approximately 3.5-4.2 L; crosses blood-brain barrier to target cerebral amyloid plaques Metabolism: Expected to be metabolized via proteolytic degradation pathways typical of monoclonal antibodies Elimination: Terminal half-life approximately 10-12 days; cleared primarily via intracellular catabolism Time to steady state: Approximately 12 weeks with every-4-week dosingContraindications
- Hypersensitivity to donanemab-azbt or any component of the formulation
- Patients without confirmed amyloid pathology
- Active acute intracranial hemorrhage
- Recent history of cerebral vascular accident or transient ischemic attack
Warnings and Precautions
Amyloid-Related Imaging Abnormalities (ARIA):- ARIA-E (edema) and ARIA-H (hemosiderin deposition) may occur
- Most ARIA cases are asymptomatic; some may present with headache, confusion, or visual changes
- MRI monitoring recommended at specified intervals during treatment
- May occur during or within 24 hours of infusion
- Symptoms may include fever, chills, nausea, vomiting, and hypotension
- Pre-medication with antihistamines may be considered
- May increase risk of cerebral microhemorrhages and superficial siderosis
- Caution in patients on anticoagulant or antiplatelet therapy
Drug Interactions
Anticoagulants/Antiplatelets: Increased risk of bleeding when combined with warfarin, direct oral anticoagulants, or antiplatelet agents Thrombolytics: Potential increased risk of intracranial hemorrhage Other amyloid-targeting therapies: Avoid concomitant use with other anti-amyloid antibodiesAdverse Effects
Most common adverse reactions (≥10%):- ARIA-E (amyloid-related imaging abnormalities-edema)
- Headache
- Infusion-related reactions
- ARIA-H (microhemorrhages and superficial siderosis)
- Serious infusion-related reactions
- Symptomatic ARIA
- Serious hypersensitivity reactions
- Intracranial hemorrhage
Monitoring Parameters
Baseline assessment:- Cognitive and functional assessment (MMSE, CDR, ADAS-Cog)
- Brain MRI to establish baseline and exclude contraindications
- Amyloid PET scan or CSF analysis to confirm amyloid pathology
- APOE ε4 genotype status (informs ARIA risk assessment)
- Serial brain MRI at 6, 12, and 18 months, and as clinically indicated
- Monitoring for signs and symptoms of ARIA
- Cognitive and functional assessments every 6 months
- Regular assessment of infusion-related reactions
- No specific routine laboratory monitoring required
- Clinical monitoring for bleeding tendencies
Patient Education
- Understand the potential benefits and risks of treatment
- Report any new neurological symptoms immediately (headache, confusion, vision changes)
- Inform all healthcare providers about Kisunla treatment
- Understand the importance of regular MRI monitoring
- Be aware of potential infusion-related reactions and report symptoms promptly
- Discuss any planned surgical procedures with healthcare provider
- Continue other prescribed Alzheimer's medications as directed
- Maintain regular follow-up appointments for safety monitoring
References
1. FDA prescribing information: Kisunla (donanemab-azbt). July 2024. 2. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021;384(18):1691-1704. 3. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527. 4. Cummings J, Apostolova L, Rabinovici GD, et al. Lecanemab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2023;10(3):362-377. 5. Sperling RA, Jack CR Jr, Black SE, et al. Amyloid-Related Imaging Abnormalities in Amyloid-Modifying Therapeutic Trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7(4):367-385.
Note: This monograph is based on current available evidence and may be updated as new clinical data emerge. Healthcare providers should consult the most recent prescribing information before initiating treatment.