Kisunla Drug Information

Amyloid Related Imaging Abnormalities Monoclonal antibodies directed against aggregated forms of beta

amyloid, including KISUNLA, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer's disease, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhemorrhage or superficial siderosis. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together.

ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, can occur. ARIA can be fatal. When present, reported symptoms associated with ARIA may include, but are not limited to, headache, confusion, visual changes, dizziness, nausea, and gait difficulty.

Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with KISUNLA. Consider the benefit of KISUNLA for the treatment of Alzheimer's disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with KISUNLA. Study 1 and Study 2 Overview In Study 1, safety was assessed in patients who received KISUNLA Dosing Regimen 1 (n = 853) compared to those who received placebo (n = 874). In Study 2, the effect of different dosing regimens of KISUNLA on ARIA was assessed, including in patients who received KISUNLA Dosing Regimen 2 (n=212), which is the recommended dosage and described below.

Incidence of ARIA A lower incidence of ARIA was observed with Dosing Regimen 2 as compared to Dosing Regimen 1. Therefore, Dosing Regimen 2 is the recommended dosage for KISUNLA. In Study 1, symptomatic ARIA-E occurred in 6% of patients through 18 months of treatment with KISUNLA . Clinical symptoms associated with ARIA-E resolved in approximately 85% of those patients. Including asymptomatic radiographic events, ARIA, ARIA-E, and ARIA-H were observed in 36%, 24%, and 31% of patients treated with KISUNLA, respectively, compared to 14%, 2%, and 13% of patients on placebo, respectively. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for KISUNLA compared to placebo.

In Study 2, symptomatic ARIA-E occurred in 3% of patients and symptomatic ARIA-H occurred in less than 1% of patients through 12 months of treatment with KISUNLA . Clinical symptoms associated with ARIA-E resolved in approximately 67% of patients at 12 months. Including asymptomatic radiographic events, ARIA, ARIA-E, and ARIA-H were observed in 29%, 16%, and 25% of patients treated with KISUNLA. Incidence of Intracerebral Hemorrhage Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% of patients treated with KISUNLA compared to 0.2% of patients on placebo in Study 1, and in 1% of patients treated with KISUNLA in Study 2. Fatal events of intracerebral hemorrhage in patients taking KISUNLA have been observed. Risk Factors for ARIA and Intracerebral Hemorrhage ApoE ε4 Carrier Status The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes, which include approximately 15% of Alzheimer's disease patients.

In Study 1, of patients in the KISUNLA arm (n=850), 17% were ApoE ε4 homozygotes, 53% were heterozygotes, and 30% were noncarriers. The incidence of ARIA through 18 months was higher in ApoE ε4 homozygotes (55% on KISUNLA vs. 22% on placebo) than in heterozygotes (36% on KISUNLA vs. 13% on placebo) and noncarriers (25% on KISUNLA vs. 12% on placebo). Among patients treated with KISUNLA, symptomatic ARIA-E occurred in 8% of ApoE ε4 homozygotes compared with 7% of heterozygotes and 4% of noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, 2% of heterozygotes, and 1% of noncarriers.

In Study 2, of patients treated with KISUNLA Dosing Regimen 2 (n=211), 10% were ApoE ε4 homozygotes, 55% were heterozygotes, and 36% were noncarriers. Symptomatic ARIA-E occurred in 0% of ApoE ε4 homozygotes compared with 4% of heterozygotes and 3% of noncarriers. The small number of events and limited exposure in the ApoE ε4 subgroups limit definitive conclusions about the risk of ARIA-E. The recommendations for management of ARIA do not differ based on ApoE ε4 carrier status . Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results.

Prescribers should inform patients that if genotype testing is not performed, they can still be treated with KISUNLA; however, it cannot be determined if they are ApoE ε4 homozygotes and at a higher risk for ARIA. An FDA-authorized test for detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with KISUNLA is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design. Radiographic Findings of Cerebral Amyloid Angiopathy (CAA) Neuroimaging findings that may indicate CAA include evidence of prior intracerebral hemorrhage, cerebral microhemorrhage, and cortical superficial siderosis.

CAA has an increased risk for intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy. In Study 1, the baseline presence of at least 2 microhemorrhages or the presence of at least 1 area of superficial siderosis on MRI, which may be suggestive of CAA, were identified as risk factors for ARIA. Patients were excluded from enrollment in Study 1 for findings on neuroimaging of prior intracerebral hemorrhage greater than 1 cm in diameter, more than 4 microhemorrhages, more than 1 area of superficial siderosis, severe white matter disease, and vasogenic edema.

Concomitant Antithrombotic or Thrombolytic Medication In Study 1, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking KISUNLA with a concomitant antithrombotic medication within 30 days compared to 29% (148/504) who did not receive an antithrombotic within 30 days of an ARIA-H event.

The incidence of intracerebral hemorrhage greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking KISUNLA with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. The number of events and the limited exposure to non-aspirin antithrombotic medications limit definitive conclusions about the risk of ARIA or intracerebral hemorrhage in patients taking antithrombotic medications. One fatal intracerebral hemorrhage occurred in a patient taking KISUNLA in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent in Study 1, and one fatal intracerebral hemorrhage occurred in the setting of ARIA and the use of a thrombolytic agent in Study 2. Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with KISUNLA. Because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy in a patient being treated with KISUNLA. Caution should be exercised when considering the use of KISUNLA in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy or patients with findings on MRI that are suggestive of cerebral amyloid angiopathy.

Radiographic Severity The radiographic severity of ARIA associated with KISUNLA was classified by the criteria shown in Table 5. Table 5: ARIA MRI Classification Criteria a Includes new or worsening superficial siderosis. ARIA Type Radiographic Severity Mild Moderate Severe ARIA-E FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white matter in one location <5 cm. FLAIR hyperintensity 5 to 10 cm in single greatest dimension, or more than 1 site of involvement, each measuring <10 cm.

FLAIR hyperintensity >10 cm with associated gyral swelling and sulcal effacement. One or more separate/independent sites of involvement may be noted. ARIA-H microhemorrhage Less than or equal to 4 new incident microhemorrhages 5 to 9 new incident microhemorrhages 10 or more new incident microhemorrhages ARIA-H superficial siderosis 1 new a focal area of superficial siderosis 2 new focal areas of superficial siderosis Greater than 2 new focal areas of superficial siderosis In Study 1, the majority of ARIA-E radiographic events occurred early in treatment (within the first 24 weeks), although ARIA can occur at any time and patients can have more than one episode.

Resolution on MRI after the first ARIA-E event occurred in 63% of patients treated with KISUNLA by 12 weeks, 80% by 20 weeks, and 83% overall after detection. Among patients treated with KISUNLA, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes (n=143) compared to heterozygotes (n=452) or noncarriers (n=255) at rates of 3%, 2%, and 0.4%, respectively. Among patients treated with KISUNLA, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes (n=143) compared to heterozygotes (n=452) or noncarriers (n=255) at rates of 22%, 8%, and 4%, respectively.

Table 6 shows the maximum radiographic severity for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis in Study 1 and Study 2. Table 6: Maximum Radiographic Severity in Patients Treated with KISUNLA in Study 1 Study 2 *Administered as Dosing Regimen 2 over 12 months of treatment Study 1 Dosing Regimen 1 N=853 % Study 2 Dosing Regimen 2 N=212 % Mild Moderate Severe Mild Moderate Severe ARIA-E 7 15 2 6 9 0 ARIA-H microhemorrhage 17 4 5 17 3 2 ARIA-H superficial siderosis 6 4 5 4 3 1 Monitoring and Dose Management Guidelines Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity . Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity . Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E. Baseline brain MRI and periodic monitoring with MRI are recommended . Enhanced clinical vigilance for ARIA is recommended during the first 24 weeks of treatment with KISUNLA. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data for dosing patients who have experienced recurrent episodes of ARIA-E. Providers should encourage patients to participate in real world data collection (e.g., registries) to help further the understanding of Alzheimer's disease and the impact of Alzheimer's disease treatments.

Providers and patients can contact 1-800-LillyRx (1-800-545-5979) for a list of currently enrolling programs.

Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients

who were treated with KISUNLA. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction and initiate appropriate therapy. KISUNLA is contraindicated in patients with a history of serious hypersensitivity to donanemab-azbt or to any of the excipients of KISUNLA.

Infusion-Related Reactions

In Study 1, infusion-related reactions were observed in 9% of patients treated with KISUNLA, the majority (70%) of which occurred within the first 4 infusions, compared to 0.5% of patients on placebo. Infusion-related reactions were mostly mild (57%) or moderate (39%) in severity. Infusion-related reactions resulted in discontinuations in 4% of patients treated with KISUNLA. In Study 2, infusion-related reactions associated with KISUNLA occurred in 16% of patients; the majority (88%) occurred within the first 4 infusions.

Infusion-related reactions were mostly mild (47%) or moderate (50%) in severity. Infusion-related reactions resulted in discontinuations in 2.8% of patients treated with KISUNLA. Most infusion-related reactions associated with KISUNLA occurred during the infusion or within 30 minutes after completion of the infusion, however some have occurred hours after an infusion. Signs and symptoms of infusion-related reactions include chills, erythema, nausea/vomiting, flushing, difficulty breathing/dyspnea, sweating, elevated blood pressure, headache, chest pain, and low blood pressure.

In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Consider pre-treatment with antihistamines, acetaminophen, or corticosteroids prior to subsequent dosing.