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A PHASE 3 STUDY THAT ASSESSED DISEASE PROGRESSION IN EARLY SYMPTOMATIC ALZHEIMER’S DISEASE (AD) BY REDUCING AMYLOID PLAQUES1,2

*There were 2 primary analysis populations based on tau PET imaging with flortaucipir: 1) low-medium tau level population (SUVR of ≥1.10 and ≤1.46), and 2) combined population of low-medium plus high tau (SUVR >1.46).1

†In the protocol, if the amyloid plaque level was <11 Centiloids on a single PET scan or 11 to <25 Centiloids on 2 consecutive PET scans, the patient was eligible to be switched to placebo.1

‡The full Prescribing Information recommends ARIA-monitoring MRI before infusions 1, 2, 3, 4, and 7.1

For reference, <24.1 Centiloids on an amyloid PET scan is consistent with a negative visual read.3

ARIA=amyloid-related imaging abnormalities; iADRS=integrated Alzheimer’s Disease Rating Scale; IV=intravenous; MCI=mild cognitive impairment; MRI=magnetic resonance imaging; PET=positron emission tomography; Q4W=every 4 weeks; SUVR=standardized uptake value ratio.

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.

KISUNLA GIVES YOU THE POWER TO HELP SLOW COGNITIVE AND FUNCTIONAL DECLINE IN PATIENTS WITH EARLY SYMPTOMATIC AD1,2,4

iADRS scores range from 0 to 144 with lower scores indicating greater impairment.1

iADRS=integrated Alzheimer’s Disease Rating Scale; NCS2=natural cubic spline with 2 degrees of freedom; SE=standard error.

HELP KEEP YOUR PATIENTS IN THE EARLIER STAGES OF DISEASE LONGER2

Overall Population (N=1736): Reduction in Risk of Progression* on CDR-GS1

CDR-GS: Time to worsening of disease

  • HR: Overall population=0.63†; 95% CI: 0.51, 0.77; low-medium tau=0.61†; 95% CI: 0.47, 0.802
  • In the low-medium tau population, a 39% reduced risk vs placebo was observed through 76 weeks (N=1182); P<0.0012

*Progression to next clinical stage was defined as any increase in CDR-GS at 2 consecutive visits from baseline. 0=normal; 0.5=very mild dementia; 1=mild dementia; 2=moderate dementia; 3=severe dementia.2
†The HR is the relative risk reduction for substantial decline achieved by Kisunla vs placebo.2

CDR-GS=Clinical Dementia Rating Scale-Global Score; CI=confidence interval; HR=hazard ratio.

RISK OF PROGRESSION* TO MODERATE OR SEVERE ALZHEIMER’S DISEASE (AD) OVER 76 WEEKS IN THE OVERALL POPULATION5,6

Reduced Risk of Progression2,5,6

Limitations: This post hoc exploratory analysis was not adjusted for multiplicity; as such, no conclusions can be drawn.

aThe HR is the proportional risk for substantial decline achieved by Kisunla vs placebo.2,5

A post hoc analysis showed that participants treated with Kisunla in the overall population (n=784) had a 50% reduced risk of progressing to moderate or severe AD compared with participants treated with placebo (n=821).2,5,6

*Progression to moderate or severe AD was defined as CDR-GS score of 2 or above at 2 consecutive visits.5,6

CDR-GS=Clinical Dementia Rating-Global Score; HR=hazard ratio.

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.

A LONG-TERM EXTENSION STUDY ASSESSED EFFICACY AND SAFETY FOR UP TO 3 YEARS7

PHASE 3 LONG-TERM EXTENSION (LTE) PERIOD

TRAILBLAZER-ALZ 2 LTE is a Phase 3, double-blind, 78-week extension study evaluating the efficacy and safety of Kisunla for up to 154 weeks. Participants who completed TRAILBLAZER-ALZ 2 (Kisunla or placebo arm) and were eligible as determined at study initiation could continue in the LTE period. Participants on Kisunla in TRAILBLAZER-ALZ 2 continued into the LTE period receiving either Kisunla or placebo based on amyloid reduction to minimal levels* (n=550). Participants on placebo in TRAILBLAZER-ALZ 2 switched to Kisunla in the LTE period (n=657). Of those who received active treatment in the LTE period, participants received Kisunla with the same dosing, administration and stopping criteria as in TRAILBLAZER-ALZ 2.7

PET=positron emission tomography.

*In the study, if the amyloid plaque level was < 11 Centiloids on a single PET scan or 11 to <25 Centiloids on 2 consecutive PET scans, the patient was eligible to be switched to placebo.1
For reference, <24.1 Centiloids on an amyloid PET scan is consistent with a negative visual read.3

PATIENTS TREATED ON KISUNLA SHOWED INCREASING CDR‑SB SEPARATION OVER 3 YEARS8

85% of participants who started Kisunla in the Core Study and continued into the LTE met trial completion criteria based on amyloid PET within 3 years9

CDR-SB Change From Baseline In Cognition And Function Through 3 Years: Overall Population1,8

aIn the 76-week TRAILBLAZER-ALZ 2 Core Study, in the overall population, as assessed by MMRM analysis (Kisunla: n=860 and placebo: n=876), Kisunla slowed decline by 29% (-0.70) vs placebo on CDR-SB (P<0.0001 vs placebo). Mean baseline: 3.92 for Kisunla and 3.89 for placebo; change from baseline: 1.72 for Kisunla and 2.42 for placebo.1

The LTE has limitations, including no placebo control and patients remaining in the extension phase may be those with better results in the Core Study. This retrospective analysis was not a head-to-head study and conclusions cannot be drawn due to potential selection bias, small sample size, and lack of statistical powering.10

Alzheimer's Disease Neuroimaging Initiative (ADNI) is a US and Canadian research study that follows the natural progression of Alzheimer's disease. An ADNI cohort (N=268 at baseline, followed for 36 months) was selected to match participants from the Core Study population based on baseline demographic, clinical, and biomarker characteristics, as detected by cerebrospinal fluid, for use as a reference cohort in the TRAILBLAZER-ALZ 2 long-term extension study. ADNI participants were not enrolled in the TRAILBLAZER-ALZ 2 Core Study or its long-term extension; they were used exclusively as a historical control group.10

CDR-SB=Clinical Dementia Rating Scale-Sum of Boxes; CSF=cerebrospinal fluid; MMRM=mixed model for repeated measures; PET=positron emission tomography; SE=standard error.

SELECT IMPORTANT SAFETY INFORMATION

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

KISUNLA DEMONSTRATED REDUCTION IN AMYLOID PLAQUES AS EARLY AS 6 MONTHS1,13*

Amyloid Plaque Reduction From Baseline in the Overall Population in TRAILBLAZER-ALZ 21,13

Nearly half of patients were able to complete treatment course by 1 year based on removal of amyloid plaques to minimal levels on amyloid PET imaging.1,12 Patients treated with placebo had an average of <1% amyloid plaque reduction from baseline to 18 months.13

In patients treated with Kisunla: 17% (130/761) achieved stopping criteria at 6 months, 47% (313/672) at 12 months, and 69% (429/620) at 18 months. In the protocol, if the amyloid plaque level was <11 Centiloids on a single PET scan or 11 to <25 Centiloids on 2 consecutive PET scans, the patient was eligible to be switched to placebo. Amyloid PET values may increase after treatment with Kisunla is stopped. There is no data beyond the 76-week duration of the clinical trial to guide whether additional dosing with Kisunla may be needed for longer-term clinical benefit.1,12

*Mean baseline (n=712) amyloid plaque level for patients treated with Kisunla was 103.7 Centiloids (placebo was 101.4 Centiloids). The mean change from baseline was -62.8 Centiloids at 6 months (n=702), -82.8 Centiloids at 12 months (n=627), and -86.9 Centiloids at 18 months (n=571).1,11

For reference, <24.1 Centiloids on an amyloid PET scan is consistent with a negative visual read.3

PET=positron emission tomography.

NEARLY HALF OF PATIENTS WERE ABLE TO COMPLETE TREATMENT COURSE* BY 1 YEAR1

Percentage of Patients in the Overall Population That Completed Treatment Course* at 12 and 18 Months1,12†

Kisunla treatment course was completed based on removal of amyloid plaques to minimal levels on amyloid PET imaging in TRAILBLAZER-ALZ 2.1

*In the protocol, if the amyloid plaque level was <11 Centiloids on a single PET scan or 11 to <25 Centiloids on 2 consecutive PET scans, the patient was eligible to be switched to placebo. Amyloid PET values may increase after treatment with Kisunla is stopped. There are no data beyond the 76-week duration of the clinical trial to guide whether additional dosing with Kisunla may be needed for longer-term clinical benefit.1

For reference, <24.1 Centiloids on an amyloid PET scan is consistent with a negative visual read.3

†The mean baseline amyloid levels for patients treated with Kisunla were 103.5 Centiloids for the overall population, and 102.4 Centiloids for the low-medium tau population.2

PET=positron emission tomography.

PATIENTS WHO COMPLETED KISUNLA TREATMENT COURSE BY 1 YEAR IN THE CORE STUDY CONTINUED TO DEMONSTRATE SUSTAINED SEPARATION IN CDR-SB SCORES THROUGH 3 YEARS10

Nearly half of patients were able to complete treatment course* by 1 year in the Core Study1

CDR-SB Change From Baseline Score Among Participants Who Met Completion Criteria by 1 Year10,14

This exploratory subgroup analysis of the Core Study and long-term extension has limitations, including no placebo control and patients remaining in the extension phase may be those with better results in the Core Study. This retrospective analysis was not a head-to-head study, and conclusions cannot be drawn due to potential selection bias, small sample size, and lack of statistical powering.10

Alzheimer's Disease Neuroimaging Initiative (ADNI) is a US and Canadian research study that follows the natural progression of Alzheimer's disease. An ADNI cohort (N=268 at baseline, followed for 36 months) was selected to match participants from the Core Study population based on baseline demographic, clinical, and biomarker characteristics, as detected by cerebrospinal fluid, for use as a reference cohort in the TRAILBLAZER-ALZ 2 long-term extension study. ADNI participants were not enrolled in the TRAILBLAZER-ALZ 2 Core Study or its long-term extension; they were used exclusively as a historical control group.11

*In clinical trials, completion of active treatment was based on amyloid PET levels measured at week 24, week 52, and week 76. If amyloid plaque level was <11 Centiloids on a single PET scan or 11 to <25 Centiloids on 2 consecutive PET scans, subjects taking Kisunla were eligible to switch to placebo.1,2 The percentages of patients who completed treatment course based on amyloid PET levels at week 24 and week 52 were 17% and 47%.1

For reference, <24.1 Centiloids on an amyloid PET scan is consistent with a negative visual read.3

CDR-SB=Clinical Dementia Rating Scale-Sum of Boxes; PET=positron emission tomography.

SELECT IMPORTANT SAFETY INFORMATION

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.

References:

  1. Kisunla (donanemab-azbt). Prescribing Information. Lilly USA, LLC.
  2. 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.
  3. Navitsky M, Joshi AD, Kennedy I, et al. Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale. Alzheimers Dement. 2018;14(12):1565-1571.
  4. Data on File. Lilly USA, LLC. DOF-DN-US-0053.
  5. Zimmer J, Biffi A, Collins EC, et al. Insights from TRAILBLAZER-ALZ 2 (donanemab): potential clinical translation. Presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA.
  6. Data on File. Lilly USA, LLC. DOF-DN-US-0064.
  7. Data on File. Lilly USA, LLC. DOF-DN-US-0074.
  8. Data on File. Lilly USA, LLC. DOF-DN-US-0073.
  9. Data on File. Lilly USA, LLC. DOF-DN-US-0076.
  10. Zimmer JA, et al. J Prev Alzheimers Dis. Published online December 1, 2025(Incl suppl mat).
  11. Eli Lilly and Company. TRAILBLAZER-ALZ 2 long-term extension preliminary results. Presented at: AAIC; March 2025.
  12. Data on File. Lilly USA, LLC. DOF-DN-US-0049.
  13. Data on File. Lilly USA, LLC. DOF-DN-US-0029.
  14. Data on File. Lilly USA, LLC. DOF-DN-US-0091.

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.