FDA Approves Donanemab (Kisunla) for Early Symptomatic Alzheimer's Disease
Key Insights
The FDA has approved donanemab-azbt (Kisunla) for treating Alzheimer's disease by reducing amyloid plaques (search) and slowing cognitive decline.
A phase 3 trial showed statistically significant reduction in clinical decline using the iADRS, ADAS-Cog13, and ADCS-iADL scales at week 76 compared to placebo.
Donanemab-azbt carries a boxed warning for amyloid-related imaging abnormalities (ARIA); monitoring and genetic testing are recommended.
The FDA has granted approval to donanemab-azbt (Kisunla) for the treatment of early symptomatic Alzheimer's disease. This approval marks a significant advancement in Alzheimer's care, offering a new therapeutic option that targets the underlying pathology of the disease by removing amyloid plaques (search).
The approval of donanemab-azbt, an antiamyloid monoclonal antibody, is based on the results of the Phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511), a double-blind, placebo-controlled study. The trial demonstrated that donanemab-azbt can effectively reduce the excessive buildup of amyloid plaques (search) in the brain, which is believed to slow the cognitive decline associated with Alzheimer's disease. This offers hope for patients experiencing mild cognitive impairment or mild dementia due to Alzheimer's.
Efficacy Demonstrated in Clinical Trials
The TRAILBLAZER-ALZ 2 trial involved 1736 patients with confirmed amyloid pathology and either mild cognitive impairment or mild dementia. Participants were randomized in a 1:1 ratio to receive either donanemab-azbt (n=860) or placebo (n=876) for up to 72 weeks. The donanemab-azbt group received 700 mg every 4 weeks for the first three doses, followed by 1400 mg every 4 weeks thereafter.
The primary endpoint was the change from baseline in the Integrated Alzheimer’s Disease Rating Scale (iADRS) score. Secondary endpoints included the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study—Instrumental Activities of Daily Living Scale (ADCS-iADL) at week 76.
Results showed a statistically significant reduction in clinical decline in the donanemab-azbt group compared to placebo across all measured scales. Specifically, the iADRS score showed a 2.92-point difference, the ADAS-Cog13 showed a -1.33-point difference, and the ADCS-iADL showed a 1.70-point difference, all favoring donanemab-azbt at week 76. These results indicate that donanemab-azbt can significantly slow the progression of Alzheimer's disease in patients with early symptomatic stages.
Safety Profile and Warnings
Donanemab-azbt carries a boxed warning for amyloid-related imaging abnormalities (ARIA), a known risk associated with monoclonal antibodies targeting aggregated forms of β-amyloid. ARIA can manifest as ARIA with edema (ARIA-E) or ARIA with hemosiderin deposition (ARIA-H). ARIA-E can cause focal neurologic deficits, potentially mimicking ischemic stroke, necessitating caution in diagnosis and treatment.
Patients who are apolipoprotein E ε4 (APOE ε4) homozygotes may have a higher incidence of ARIA when treated with donanemab-azbt. Genetic testing to determine APOE ε4 status is recommended before initiating treatment to assess the risk of developing ARIA.
The most common adverse effects observed in the TRAILBLAZER-ALZ 2 trial were ARIA and headache. Other potential adverse reactions include serious allergic and infusion-related reactions, such as swelling of the face, lips, mouth, or eyelids, as well as breathing difficulties, hives, chills, skin irritation, nausea, vomiting, sweating, headache, or chest pain. Management of infusion-related reactions may involve reducing the infusion rate or discontinuing the infusion, with consideration given to pretreatment with antihistamines, acetaminophen, or corticosteroids before subsequent doses.
Dosage and Administration
The recommended dosage for donanemab-azbt is 700 mg administered intravenously every 4 weeks for the first three doses, followed by 1400 mg every 4 weeks thereafter. Each infusion should be administered over approximately 30 minutes.
Donanemab-azbt is available in single-dose vials containing 350 mg/20 mL (17.5 mg/mL). The drug requires dilution with 0.9% sodium chloride injection to achieve a final concentration of 4 mg/mL or 10 mg/mL. Unopened vials should be stored in the refrigerator (2-8°C [36-46°F]) and protected from light, and should not be frozen or shaken. Vials can be stored at room temperature (20-25°C [68-77°F]) for up to 3 days.
Prior to administration, donanemab-azbt should be brought to room temperature and diluted with 0.9% sodium chloride. The diluted solution can be refrigerated for up to 72 hours or stored at room temperature for up to 12 hours, including the duration of infusion.