Kisunla From Eli Lilly

The FDA has approved donanemab-azbt (Kisunla; Eli Lilly and Company) to treat adults with early symptomatic Alzheimer disease (AD), including mild cognitive impairment or the mild dementia stage of AD, and confirmed amyloid pathology.^1,2 Excessive accumulation of amyloid can form plaques in the brain that may lead to symptoms associated with AD. Donanemab-azbt is an amyloid plaque–targeting therapy that can be discontinued based on amyloid plaque reduction.²

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PHARMACOLOGY AND PHARMACOKINETICS

Donanemab-azbt is a humanized IgG1 monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid ß (Aß) to reduce Aß plaques. It reaches a steady state after a single dose and displays a terminal elimination half life of approximately 12.1 days.¹

DOSAGE AND ADMINISTRATION

Before beginning treatment with donanemab-azbt, Aß pathology should be confirmed and a baseline brain MRI should be obtained. The recommended dose of donanemab-azbt is 700 mg intravenously every 4 weeks for the first 3 doses, then 1400 mg intravenously every 4 weeks, with each dose administered over approximately 30 minutes. An MRI should be obtained before the second, third, fourth, and seventh doses. Treatment may be discontinued if PET imaging shows that amyloid plaques are reduced to minimal levels.¹

CLINICAL TRIALS

Donanemab-azbt was evaluated in the double-blind, parallelgroup, placebo-controlled phase 3 TRAILBLAZER-ALZ 2 study (NCT04437511). Patients were randomly assigned 1:1 to receive donanemab-azbt 700 mg every 4 weeks for the first 3 doses, then 1400 mg every 4 weeks or placebo for a total of up to 72 weeks. Concomitant use of approved therapies was permitted during the study.

The study met its primary efficacy end point, which was change in the Integrated Alzheimer’s Disease Rating Scale score from baseline to 76 weeks. The overall study population using donanemab-azbt showed a significant slowing of decline by 22% compared with placebo, whereas those with less advanced disease demonstrated a significant slowing of decline by 35%. Additionally, patients using donanemab-azbt had up to a 39% lower risk of disease progression than those using placebo.

Throughout the study, dosing was continued or discontinued based on amyloid imaging. Patients were eligible to switch to placebo based on amyloid PET levels measured at weeks 24, 52, and 76, with 17%, 47%, and 69% eligible at each time point, respectively. On average, donanemab-azbt was shown to reduce amyloid plaques by 61% at 6 months, 80% at 12 months, and 84% at 18 months.^1,2

CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS

Donanemab-azbt carries a boxed warning stating that monoclonal antibodies directed against aggregated forms of Aß can cause amyloid-related imaging abnormalities (ARIAs), such as ARIA with edema (ARIA-E) or ARIA with hemosiderin (ARIA-H). Patients who are APOE ε4 homozygotes have a higher incidence of ARIAs, including symptomatic and serious ARIAs, as compared with heterozygotes and noncarriers when using this class of medication. Testing for APOE ε4 status should be completed before beginning treatment, and patients should be counseled regarding the risk of ARIAs across genotypes and the implications of genetic testing results. Treatment with donanemab-azbt is contraindicated in patients with a history of known serious hypersensitivity to the medication or any of its components.

Enhanced clinical vigilance for ARIAs is recommended during the first 24 weeks of treatment. The risk of ARIA-E and ARIA-H is increased in patients with pretreatment microhemorrhages and/or superficial siderosis. Infusion related reactions may be managed by slowing or discontinuing the infusion and initiating appropriate therapy. Pretreatment with acetaminophen, antihistamines, or corticosteroids may be considered before additional doses.

The most common adverse reactions are ARIA-E, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and headache.¹

REFERENCES

1. Kisunla. Prescribing information. Eli Lilly and Company; 2024. Accessed July 24, 2024. https://pi.lilly.com/us/kisunla-uspi.pdf?s=pi

2. Lilly’s Kisunla (donanemab-azbt) approved by the FDA for the treatment of early symptomatic Alzheimer’s disease. News release. Eli Lilly and Company. July 2, 2024. Accessed July 24, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early