New Drug Review: Donanemab-azbt Approved for Early Symptomatic Alzheimer Disease

On July 2, 2024, the FDA approved donanemab-azbt (Kisunla) for the treatment of Alzheimer disease. Approval of donanemab-azbt, an antiamyloid monoclonal antibody, was based on results of a phase 3, double-blind, placebo-controlled, (TRAILBLAZER-ALZ 2 [NCT04437511]).^1,2 Donanemab-azbt can help the body remove the excessive buildup of amyloid plaques and slow the decline that may diminish people’s ability to remember new information, important dates, and appointments.^1,2

A total of 1736 patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia were included in the study. | image credit: BOJOShop / stock.adobe.com

Efficacy

In the efficacy study, a total of 1736 patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia were randomly assigned 1:1 to receive either 700 mg donanemab-azbt every 4 weeks for the first 3 doses, followed by 1400 mg donanemab-azbt every 4 weeks thereafter (n=860) or placebo (n=876) for a total of up to 72 weeks. Investigators assessed the reduction in clinical decline by using the Integrated Alzheimer’s Disease Rating Scale (iADRS) vs placebo, the Alzheimer’s Disease Assessment Scale—Cognitive Subscale (ADASCog), and the Alzheimer’s Disease Cooperative Study—Instrumental Activities of Daily Living Scale (ADCS-iADL) at week 76.²

Results showed a statistically significant reduction in clinical decline on the iADRS (2.92), the ADAS-Cog13 (–1.33), and the ADCS-iADL (1.70) vs placebo at week 76. Overall, the patients treated with donanemab-azbt demonstrated a statistically significant reduction in clinical decline of Alzheimer disease.^1,2

Safety

Donanemab-azbt carries a boxed warning for amyloid-related imaging abnormalities (ARIA), which can be caused by monoclonal antibodies directed against the aggregated forms of β-amyloid. ARIA is characterized as ARIA with edema or ARIA with hemosiderin deposition. ARIA with edema can cause focal neurologic deficits that can mimic an ischemic stroke; clinicians should be aware of such a possibility before giving thrombolytic therapy in a patient treated with donanemab-azbt.³

Patients who are apolipoprotein E ε4 (APOE ε4) homozygotes treated with donanemab-azbt may have a higher incidence of ARIA. A test should be performed before starting treatment to assess the risk of developing ARIA.³

Investigators for TRAILBLAZER-ALZ 2 identified the most common adverse effects of donanemab-azbt therapy, which include ARIA and headache.

Donanemab-azbt can cause serious allergic and infusion-related reactions including swelling of the face, lips, mouth, or eyelids, as well as problems breathing, hives, chills, skin irritation, nausea, vomiting, sweating, headache, or chest pain.^1,2 If a patient experiences an infusion-related reaction, the infusion rate may be reduced or discontinued. Pretreatment with antihistamines, acetaminophen, or corticosteroids before subsequent dosing may be considered.³

Dosing and Administration

Donanemab-azbt is dosed at 700 mg every 4 weeks for the first 3 doses and then 1400 mg every 4 weeks thereafter. Each infusion is administered over approximately 30 minutes.^1,3 Donanemab-azbt comes in 2 doses and requires dilution with 0.9% sodium chloride injection to the recommended total volume for a final concentration of 4-mg/mL and 10-mg/mL concentrations of donanemab-azbt.

Donanemab-azbt is supplied in 1 vial per carton as a single-dose vial of 350 mg/20 mL (17.5 mg/mL). Each unopened vial should be stored in the refrigerator (2-8°C [36-46°F]) and protected from light; do not freeze or shake. Vials may be stored at room temperature (20-25°C [68-77°F]) for up to 3 days.

Before administration, let donanemab-azbt reach room temperature and dilute with 0.9% sodium chloride. To reconstitute, withdraw the required volume and mix with 0.9% sodium chloride to the recommended final concentration volume. Gently invert the diluted donanemab-azbt solution to mix thoroughly. After dilution, donanemab-azbt can be refrigerated for 72 hours or at room temperature for 12 hours. Storage times include the duration of infusion.³

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References

1. Lilly’s Kisunla (donanemab-azbt) approved by the FDA for the treatment of early symptomatic Alzheimer’s disease. News release. Eli Lilly. July 2, 2024. Accessed November 4, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early 

2. FDA approves treatment for adults with Alzheimer’s disease. FDA. July 2, 2024. Accessed November 4, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-adults-alzheimers-disease 

3. Kisunla [package insert]. Eli Lilly and Company; (2024). November 4, 2024.https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf