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THE SAFETY OF KISUNLA IN CLINICAL TRIALS*

Adverse Reactions Reported In TRAILBLAZER-ALZ 6 At 52 Weeks1,2†‡

adverse reactions by dose chart desktop

aIn TRAILBLAZER-ALZ 6, placebo was given every other visit to preserve blinding for additional arms (not shown) to explore pharmacokinetics.3

bGradual-titration dosing was 350 mg for the first dose, 700 mg for the second dose, and 1050 mg for the third dose, followed by 1400 mg Q4W.1

†In TRAILBLAZER-ALZ 6, ARIA (including asymptomatic radiographic events) was observed in 34% of participants treated with the original dosing regimen compared with 29% of participants treated with gradual-titration dosing.2

‡Clinical symptoms associated with ARIA-E resolved in approximately 90% of patients in the original dosing arm compared to 67% of patients in the gradual-titration arm.4

The primary endpoint of TRAILBLAZER-ALZ 6 was the proportion of participants with any occurrence of ARIA-E1

  • Significant reduction of ARIA-E with gradual-titration dosing1
    • 16% of patients in the gradual-titration arm vs 25% of patients in the original dosing arm1
  • Approximately 84% of participants in the gradual-titration arm had no ARIA-E on MRI through week 525
  • Symptomatic ARIA-E was observed in 5% of patients in the original dosing arm compared to 3% of patients in the gradual-titration arm4
  • Less than 1% of patients treated with Kisunla experienced any ARIA that led to serious outcomes, such as hospitalization or medical intervention4

*The safety of Kisunla has been evaluated in 3727 patients with Alzheimer's disease (AD) who received at least 1 dose of Kisunla intravenously across 2 Phase 3 clinical trials.1

Adverse reactions reported in TRAILBLAZER-ALZ 2 at 76 weeks1

Adverse reactions reported in ≥5% of patients treated with Kisunla (n=853) and ≥2% higher than placebo (n=874) in TRAILBLAZER-ALZ 2 at 76 weeks. The incidence of ARIA-H in TRAILBLAZER-ALZ 2 was 31% in patients treated with Kisunla vs 13% in patients treated with placebo. ARIA-H microhemorrhage (25% vs 11%), amyloid-related imaging abnormalities-edema (ARIA-E) (24% vs 2%), ARIA-H superficial siderosis (15% vs 3%), headache (13% vs 10%), and infusion-related reactions (IRR) (9% vs 0.5%). ARIA (including asymptomatic radiographic events) was observed in 36% of participants treated with Kisunla compared to 14% of participants treated with placebo.1

  • Less than 2% of patients treated with Kisunla experienced ARIA that led to serious outcomes6
  • Symptomatic ARIA-E was observed in 6% of patients treated with Kisunla compared to 0% of patients treated with placebo1
  • Clinical symptoms associated with ARIA-E resolved in approximately 85% of patients taking Kisunla1

Original dosing was 700 mg for the first, second, and third dose (700/700/700 mg), followed by 1400 mg every 4 weeks (Q4W). This is the previously approved dosing regimen.1 Please refer to package insert for dosing instructions.

ARIA-E includes brain edema or sulcal effusions. ARIA-H most commonly includes macrohemorrhage and superficial siderosis.1

For your patients with early symptomatic Alzheimer’s disease (AD) and confirmed amyloid positivity1:

GRADUAL-TITRATION DOSING1

In TRAILBLAZER-ALZ 6, alternative dosing regimens with Kisunla were assessed. The primary endpoint was the proportion of participants with any occurrence of ARIA-E.1

Assessed the impact of gradual-titration dosing* on ARIA-E frequency and amyloid plaque reduction1

  • Participants (N=842) were randomized to 1 of 4 alternative Kisunla dosing regimens in a 1:1:1:1 ratio†, including:
  • Original dosing (N=207)‡: Consistent with TRAILBLAZER-ALZ 2
  • Gradual-titration dosing (N=212): 350 mg for the first dose, 700 mg for the second dose, 1050 mg for the third dose, followed by 1400 mg every 4 weeks (Q4W)

Inclusion and exclusion criteria were the same as TRAILBLAZER-ALZ 2 except that tau PET was not an inclusion criterion.1

*The treatment period was up to 72 weeks; treatment stopping criteria based on amyloid PET were the same as TRAILBLAZER-ALZ 2.1

†1:1:1:1 randomization stratified by ApoE ε4 carrier status and by baseline amyloid PET. For the original and gradual-titration dosing arms, placebo was given every other week for the first 16 weeks to preserve blinding for additional arms (not shown) to explore pharmacokinetics.3

‡Original dosing was 700 mg for the first, second, and third dose (700/700/700 mg), followed by 1400 mg Q4W.1

ApoE ε4=apolipoprotein E type 4 allele; ARIA=amyloid-related imaging abnormalities; ARIA-E=amyloid-related imaging abnormalities-edema; PET=positron emission tomography.

SELECT IMPORTANT SAFETY INFORMATION

Risk Factors for ARIA and Intracerebral Hemorrhages (ICH)

  • Radiographic Findings of Cerebral Amyloid Angiopathy (CAA): Neuroimaging findings that may indicate CAA include evidence of prior ICH, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk for ICH. The presence of an ApoE ε4 allele is also associated with CAA.
  • 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 for findings on neuroimaging of prior ICH >1 cm in diameter, >4 microhemorrhages, >1 area of superficial siderosis, severe white matter disease, and vasogenic edema.

ARIA=amyloid-related imaging abnormalities; ARIA-E=amyloid-related imaging abnormalities-edema; ARIA-H=amyloidrelated imaging abnormalities-hemosiderin deposition; MRI=magnetic resonance imaging.

In TRAILBLAZER-ALZ 6, gradual-titration dosing reduced the frequency of ARIA-E compared to the original dosing1

REDUCED ARIA-E RADIOGRAPHIC SEVERITY WAS SEEN IN THE GRADUAL-TITRATION* ARM COMPARED TO THE ORIGINAL DOSING† ARM IN TRAILBLAZER-ALZ 61

ARIA-E Severity Distribution Shifted Toward None or Less Severe in the Gradual-Titration Arm1,5


aDue to rounding, numbers presented may not add up to the totals indicated, and percentages may not reflect the absolute figures for the same reason.

In patients taking Kisunla in TRAILBLAZER-ALZ 6 at 52 weeks5:

  • Maximum radiographic severity of ARIA-H microhemorrhage and ARIA-H superficial siderosis in patients in the gradual-titration arm were, respectively: mild: 18% (37/212) and 4% (9/212); moderate: 3% (6/212) and 3% (6/212); and severe: 2% (5/212) and 1% (3/212)
  • Maximum radiographic severity of ARIA-H microhemorrhage and ARIA-H superficial siderosis in patients in the original dosing arm were, respectively: mild: 14% (28/207) and 9% (18/207); moderate: 5% (10/207) and 2% (4/207); and severe: 3% (6/207) and 4% (9/207)

In TRAILBLAZER-ALZ 2 at 76 weeks5:

  • Maximum radiographic severity of ARIA-E in patients taking Kisunla; mild: 7% (59/853); moderate: 15% (128/853); and severe: 2% (14/853). Maximum radiographic severity of ARIA-E in patients on placebo: mild: 2% (14/874); moderate: 0.3% (3/874); and severe: 0% (0/874)
  • Maximum radiographic severity of ARIA-H microhemorrhage and ARIA-H superficial siderosis for patients taking Kisunla, respectively: mild: 17% (143/853) and 6% (47/853); moderate: 4% (34/853) and 4% (32/853); and severe: 5% (40/853) and 5% (46/853). Maximum radiographic severity of ARIA-H microhemorrhage and ARIA-H superficial siderosis for patients on placebo, respectively: mild: 10% (88/874) and 2% (16/874); moderate: 1% (11/874) and 1% (5/874); and severe: 0.1% (1/874) and 0.2% (2/874)

*Gradual-titration dosing was 350 mg for the first dose, 700 mg for the second dose, and 1050 mg for the third dose, followed by 1400 mg Q4W.1

†Original dosing was 700 mg for the first, second, and third dose (700/700/700 mg), followed by 1400 mg Q4W. This is the previously approved dosing regimen.1 Please refer to the package insert for dosing instructions.

ARIA=amyloid-related imaging abnormalities; ARIA-E=amyloid-related imaging abnormalities-edema; ARIA-H=amyloid-related imaging abnormalities-hemosiderin deposition; MRI=magnetic resonance imaging.

SELECT IMPORTANT SAFETY INFORMATION

WARNING: 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) and ARIA with hemosiderin deposition (ARIA-H). ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events can occur. ARIA can be fatal. Serious intracerebral hemorrhages >1 cm, some of which have been fatal, have been observed in patients treated with this class of medications. 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.

ApoE ε4 Homozygotes: Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes treated with this class of medications, including Kisunla, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, the risk of ARIA across genotypes and implications of genetic testing results should be discussed with patients.

Consider the benefit for the treatment of Alzheimer's disease and risk of ARIA when deciding to treat with Kisunla.

RATES OF ARIA-E ACROSS ApoE ε4 GENOTYPES

TRAILBLAZER-ALZ 6 at 52 Weeks1

Percentage of participants with ARIA-E through 52 weeks

The small number of events and limited exposure in the ApoE ε4 subgroups limit definitive conclusions about the risk of ARIA-E.

In TRAILBLAZER-ALZ 6, ApoE ε4 homozygotes saw reduced rates of ARIA-E from 57% (original dosing) to 24% (gradual-titration dosing).1

In TRAILBLAZER-ALZ 2, of patients in the Kisunla arm (n=850), 17% (n=143) were ApoE ε4 homozygotes, 53% were heterozygotes (n=452), and 30% (n=255) were noncarriers. The incidence of ARIA through 76 weeks 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).1

Learn about ApoE ε4 genetic testing and the risk of ARIA

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ApoE ε4=apolipoprotein E type 4 allele; ARIA=amyloid- related imaging abnormalities; ARIA-E=amyloid-related imaging abnormalities-edema.

ARIA MANAGEMENT

Dosing Recommendations for Patients With ARIA-E1

aMild: discomfort noticed, but no disruption of normal daily activity; Moderate: discomfort sufficient to reduce or affect normal daily activity; Severe: incapacitating, with inability to work or to perform normal daily activity.1

bSuspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment.1



aSuspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification.1

bSuspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment when considering whether to continue treatment or permanently discontinue Kisunla.1

In patients who develop intracerebral hemorrhage >1 cm in diameter during treatment with Kisunla, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment when considering whether to continue treatment or permanently discontinue Kisunla after radiographic stabilization and resolution of symptoms.1

ARIA=amyloid-related imaging abnormalities; ARIA-E=amyloid-related imaging abnormalities-edema; ARIA-H=amyloid related imaging abnormalities-hemosiderin deposition; MRI=magnetic resonance imaging.

References:

  1. Kisunla (donanemab-azbt). Prescribing Information. Lilly USA, LLC.
  2. Data on File. Lilly USA, LLC. DOF-DN-US-0084.
  3. Wang H, Serap Monkul Nery E, Ardayfio P, et al. Alzheimers Dement. 2025;21(4):e70062. doi:10.1002/alz.70062
  4. Data on File. Lilly USA, LLC. DOF-DN-US-0085.
  5. Data on File. Lilly USA, LLC. DOF-DN-US-0081.
  6. Sims JR, Zimmer JA, Evans CD, et al; for TRAILBLAZER-ALZ 2 Investigators. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.

IMPORTANT SAFETY INFORMATION FOR Kisunla® (donanemab-azbt)

WARNING: 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) and ARIA with hemosiderin deposition (ARIA-H). ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events can occur. ARIA can be fatal. Serious intracerebral hemorrhages >1 cm, some of which have been fatal, have been observed in patients treated with this class of medications. 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.

ApoE ε4 Homozygotes: Patients treated with this class of medications, including Kisunla, who are apolipoprotein E ε4 (ApoE ε4) homozygotes (approximately 15% of Alzheimer’s disease patients) have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, the risk of ARIA across genotypes and the implications of genetic testing results should be discussed with patients.

Consider the benefit for treating Alzheimer's disease and risk of ARIA when deciding to treat with Kisunla.

Kisunla is contraindicated in patients with known serious hypersensitivity to donanemab-azbt or to any of the excipients. Reactions have included anaphylaxis.

Amyloid-Related Imaging Abnormalities (ARIA)

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 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).

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 resolved in approximately 85% of those patients.

Including asymptomatic radiographic events, ARIA, ARIA-E, and ARIA-H were observed with Kisunla: 36%, 24%, and 31% of patients treated with Kisunla, respectively compared to 14%, 2%, and 13% of patients on placebo. There was no increase in isolated ARIA-H for Kisunla vs 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 (ICH)

ICH >1 cm in diameter was reported in 0.5% of patients treated with Kisunla vs 0.2% on placebo in Study 1 and in 1% of patients treated with Kisunla in Study 2. Fatal events of ICH have been observed in patients taking Kisunla.

Risk Factors for ARIA and ICH

ApoE ε4 Carrier Status

The risk of ARIA, including symptomatic and serious ARIA, is increased in ApoE ε4 homozygotes.

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. An FDA-authorized test for detection of ApoE ε4 alleles is not currently available. Currently available tests may vary in accuracy and design.

Radiographic Findings of Cerebral Amyloid Angiopathy (CAA)

Neuroimaging findings that may indicate CAA include evidence of prior ICH, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk for ICH. The presence of an ApoE ε4 allele is also associated with CAA.

The baseline presence of at least 2 microhemorrhages or the presence of at least 1 area of superficial siderosis on magnetic resonance imaging (MRI), which may be suggestive of CAA, were identified as risk factors for ARIA. Patients were excluded from enrollment in Study 1 and Study 2 for findings on neuroimaging of prior ICH >1 cm in diameter, >4 microhemorrhages, >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 number of events and the limited exposure to non-aspirin antithrombotic medications limit definitive conclusions about the risk of ARIA or ICH in patients taking antithrombotic medications.

One fatal ICH 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. 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, and additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (eg, tissue plasminogen activator) to a patient being treated with Kisunla. Advise patients to carry information that they are being treated with Kisunla.

Caution should be exercised when considering the use of Kisunla in patients with factors that indicate an increased risk for ICH and in particular for patients who need to be on anticoagulant therapy or patients with findings on MRI that are suggestive of CAA.

Monitoring and Dose Management Guidelines

Obtain a recent baseline brain MRI prior to initiating treatment and prior to the 2nd, 3rd, 4th, and 7th infusions. 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.

Recommendations for dosing in patients with ARIA-E and ARIA-H depend on clinical symptoms and radiographic severity. Depending on ARIA severity, use clinical judgment in considering whether to continue dosing, interrupt treatment, or permanently discontinue Kisunla. See Prescribing Information for additional dosing considerations.

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.

Infusion-Related Reactions (IRR)

IRRs were observed with Kisunla with the majority occurring within the first 4 infusions. Most IRRs 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 IRRs 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 IRR, 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.

Adverse Reactions: The most common adverse reactions reported in ≥5% of patients treated with Kisunla and ≥2% higher than placebo were ARIA-H microhemorrhage, ARIA-E, ARIA-H superficial siderosis, headache, and IRRs.

Kisunla (donanemab-azbt) injection for intravenous use is available as a 350 mg/20 mL single-dose vial.

Please see full Prescribing Information, including Boxed Warning regarding ARIA, and Medication Guide.

DN HCP ISI 01JUL2025

INDICATION

Kisunla is indicated for the treatment of Alzheimer’s disease (AD). Treatment with Kisunla should be initiated in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in the clinical trials.