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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.2

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.

THE POWER OF KISUNLA WAS MEASURED ON A VALIDATED, INTEGRATED SCALE OF COGNITION AND FUNCTION2

iADRS: An integrated assessment of cognition and daily function2*

iADRS MEASURES AD SEVERITY AND REFLECTS THE IMPACT OF COGNITIVE LOSS ON THE ABILITY TO COMPLETE DAILY TASKS2,4,5

*The primary efficacy endpoint was change in the iADRS score from baseline to 76 weeks (18 months). The iADRS is a combination of 2 scores: the ADAS-Cog13 and the ADCS-iADL. The total score ranges from 0 to 144, with lower scores reflecting worsening cognitive and functional performance.2

ADAS-Cog13=Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-iADL=Alzheimer’s Disease Cooperative Study—instrumental Activities of Daily Living; iADRS=integrated Alzheimer’s Disease Rating Scale.

“The biggest fear anyone has of developing Alzheimer’s disease is losing their cognitive and functional abilities and becoming more reliant on others. When I talk to patients about amyloid-targeting treatments, they are encouraged by the results showing slowing in disease progression.”

Dr Rosemary Laird, MD, MHSA, AGSF
Founder and Chief Medical Officer, My Memory Clinic, LLC

Dr Laird was compensated for her commentary.

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KISUNLA GIVES YOU THE POWER TO HELP SLOW COGNITIVE AND FUNCTIONAL DECLINE IN PATIENTS WITH EARLY SYMPTOMATIC AD1,2,6

iADRS Change From Baseline Through 76 Weeks1,2,6

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

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

“After 25 years caring for individuals with cognitive impairment, I’m able to tell those in the early symptomatic stages of Alzheimer’s disease that we can slow down the disease progression with amyloid-targeting therapies.”

Dr Andrew Budson, MD
Boston University

Dr Budson was compensated for his commentary.

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HELP KEEP YOUR PATIENTS IN THE EARLIER STAGES OF DISEASE LONGER2

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.

“Because we can now slow down the disease progression, it’s critical to diagnose and start treatment at the first symptoms of Alzheimer’s. Starting early can help keep patients in the early stages of disease longer.”

Dr Andrew Budson, MD
Boston University

Dr Budson was compensated for his commentary.

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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 rarely can occur. 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, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results.

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

SLOWING OF DECLINE WAS DEMONSTRATED ACROSS ALL SECONDARY CLINICAL ENDPOINTS1

RESULTS FOR KEY SECONDARY ENDPOINTS AT 76 WEEKS1,2,5,7

aAssessed using MMRM analysis.1
bP<0.001 vs placebo.2
cP<0.0001 vs placebo.1
dAssessed using NCS2 analysis.1
eP=0.0001 vs placebo.1
fP=0.0006 vs placebo.1

ADAS-Cog13=Alzheimer’s Disease Assessment Scale—13-item Cognitive Subscale; ADCS-iADL=Alzheimer’s Disease Cooperative Study-instrumental Activities of Daily Living; CDR-SB=Clinical Dementia Rating Scale-Sum of Boxes; MMRM=mixed model for repeated measures; NCS2=natural cubic spline with 2 degrees of freedom.

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 MONTHS1,8

Amyloid Plaque Reduction From Baseline in the Overall Population in TRAILBLAZER-ALZ 21,8

Patients treated with placebo had an average of <1% amyloid plaque reduction from baseline to 18 months.1,8

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).1,8

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

PERCENTAGE OF PATIENTS IN THE OVERALL POPULATION ACHIEVING STOPPING CRITERIA* AT KEY TIME POINTS1,9†

Kisunla was stopped 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.

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. Wessels AM, Rentz DM, Case M, et al. Integrated Alzheimer’s Disease Rating Scale: clinically meaningful change estimates. Alzheimers Dement (N Y). 2022;8:e12312. doi:10.1002/trc2.12312
  5. Wessels AM, Dennehy EB, Dowsett SA, et al. Meaningful clinical changes in Alzheimer disease measured with the iADRS and illustrated using the donanemab TRAILBLAZER-ALZ study findings. Neurol Clin Pract. 2023;13(2):e200127. doi:10.1212/CPJ.0000000000200127
  6. Data on File. Lilly USA, LLC. DOF-DN-US-0053.
  7. Data on File. Lilly USA, LLC. DOF-DN-US-0054.
  8. Data on File. Lilly USA, LLC. DOF-DN-US-0029.
  9. Data on File. Lilly USA, LLC. DOF-DN-US-0049.

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 rarely can occur. 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 (approximately 15% of Alzheimer’s disease patients) 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, 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 higher risk for ARIA.

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.

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)

Kisunla can cause ARIA-E, which can be observed on magnetic resonance imaging (MRI) as brain edema or sulcal effusions, and ARIA-H, which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease (AD), particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhemorrhage or superficial siderosis. ARIA-H generally occurs with ARIA-E.

ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. 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 (ICH) >1 cm in diameter have occurred in patients treated with Kisunla.

Incidence of ARIA

Symptomatic ARIA occurred in 6% (52/853) of patients treated with Kisunla. Clinical symptoms associated with ARIA resolved in approximately 85% (44/52) of patients.

Including asymptomatic radiographic events, ARIA was observed with Kisunla: 36% (307/853); placebo: 14% (122/874). ARIA-E was observed with Kisunla: 24% (201/853); placebo: 2% (17/874). ARIA-H was observed with Kisunla: 31% (263/853); placebo: 13% (111/874). There was no increase in isolated ARIA-H for Kisunla vs placebo.

Incidence of ICH

ICH >1 cm in diameter was reported in 0.5% (4/853) of patients after treatment with Kisunla vs 0.2% (2/874) on placebo. Fatal events of ICH have been observed.

Risk Factors for ARIA and ICH

ApoE ε4 Carrier Status

The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes. 17% (143/850) of patients in the Kisunla arm were ApoE ε4 homozygotes, 53% (452/850) were heterozygotes, and 30% (255/850) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (Kisunla: 55%; placebo: 22%) than in heterozygotes (Kisunla: 36%; placebo: 13%) and noncarriers (Kisunla: 25%; placebo: 12%). 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.

The recommendations for management of ARIA do not differ between ApoE ε4 carriers and noncarriers. 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 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 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 incidence of ARIA-H was 30% (106/349) in patients taking Kisunla with a concomitant antithrombotic medication within 30 days vs 29% (148/504) in patients who did not receive an antithrombotic within 30 days of an ARIA-H event. The incidence of ICH >1 cm in diameter was 0.6% (2/349) in patients taking Kisunla with a concomitant antithrombotic medication vs 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 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. Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (eg, 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. 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.

Radiographic Severity

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. The maximum radiographic severity of ARIA-E in patients treated with Kisunla was mild in 7% (59/853), moderate in 15% (128/853), and severe in 2% (14/853). 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. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with Kisunla was mild in 17% (143/853), moderate in 4% (34/853), and severe in 5% (40/853). The maximum radiographic severity of ARIA-H superficial siderosis in patients treated with Kisunla was mild in 6% (47/853), moderate in 4% (32/853), and severe in 5% (46/853). Among patients treated with Kisunla, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 3% (4/143) vs heterozygotes 2% (9/452) or noncarriers 0.4% (1/255). The rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 22% (31/143) vs heterozygotes 8% (38/452) or noncarriers 4% (9/255).

Monitoring and Dose Management Guidelines

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.

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.

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 experienced recurrent episodes of ARIA-E.

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: 9% (74/853); placebo: 0.5% (4/874); the majority (70%, 52/74) occurred within the first 4 infusions. IRRs typically occur during infusion or within 30 minutes post-infusion. IRRs were mostly mild (57%) or moderate (39%) in severity. IRRs resulted in discontinuations in 4% (31/853). Signs and symptoms of IRRs include chills, erythema, nausea/vomiting, 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. Pretreatment with antihistamines, acetaminophen, or corticosteroids prior to subsequent dosing may be considered.

Adverse Reactions: The most common adverse reactions reported in ≥5% of patients treated with Kisunla (n=853) and ≥2% higher than placebo (n=874): ARIA-H microhemorrhage (25% vs 11%), ARIA-E (24% vs 2%), ARIA-H superficial siderosis (15% vs 3%), headache (13% vs 10%), IRRs (9% vs 0.5%).

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

DN HCP ISI APP

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.