A PHASE 3 STUDY THAT ASSESSED DISEASE PROGRESSION IN EARLY SYMPTOMATIC ALZHEIMER’S DISEASE (AD) BY REDUCING AMYLOID PLAQUES^1,2

Overall population and low-medium tau population image — Overall population (N=1736). Low-medium tau population (N=1182). Subset of overall population.^1,2 Kisunla was assessed in patients who had MCI or mild dementia due to Alzheimer’s disease (AD) and who were amyloid positive. The study was powered to test the results of Kisunla in the low-medium tau population* (N=1182) and allowed enrollment of participants with high tau levels so Kisunla could also be tested in the overall population (low-medium tau plus high tau levels) (N=1736). Participants were included in the study if they had confirmed presence of amyloid pathology and MCI or mild dementia. The primary efficacy endpoint was iADRS score (impact on cognitive and functional decline). Patients were randomized 1:1 to receive either Kisunla (n=860) 700 mg via once-monthly (Q4W) IV infusion (for up to 72 weeks), increased to 1400 mg at the fourth infusion, or placebo (n=876) treatment arms at week 0. Patients were treated until stopping criteria reached^† (assessed with amyloid PET scans at 24, 52, and 76 weeks), discontinuation, or study completion (76 weeks). ARIA-monitoring MRI was performed before infusions 1, 2, 4, and 7.^1,2‡

*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

^‡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.

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 TASKS^2,4,5

iADRS measurement breakdown — iADRS measures global Alzheimer’s disease (AD) severity and reflects the impact of cognitive loss on the ability to complete daily tasks. Elements of cognitive ability are measured using the ADAS-Cog₁₃, while elements of function are measured using the ADCS-iADL. Cognitive ability elements include memory, language, orientation, attention, and planning and execution of movements. Functional ability elements include clearing the dishes, disposing of garbage, making meals, obtaining beverages, using household appliances, writing, reading, keeping appointments, shopping, getting around, finding belongings, selecting clothes, engaging in hobbies, having conversations, using the telephone, talking about current events, watching television, and being left alone.^2,4,5

*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.

KISUNLA GIVES YOU THE POWER TO HELP SLOW COGNITIVE AND FUNCTIONAL DECLINE IN PATIENTS WITH EARLY SYMPTOMATIC AD^1,2,6

iADRS Change From Baseline Through 76 Weeks^1,2,6

Low-medium tau population: iADRS change from baseline through 76 weeks — Participants treated with Kisunla in the low-medium tau population had statistically significantly less decline in cognition/function than patients treated with placebo as assessed by the iADRS at week 76 (Kisunla: n=418; placebo: n=444). At week 76, adjusted mean change from baseline for patients treated with Kisunla was -6.0 vs -9.3 for placebo. The adjusted mean change difference from placebo was 3.3 (35%); P<0.0001.^1,2,6

Overall population: iADRS change from baseline through 76 weeks — Participants treated with Kisunla in the overall population had statistically significantly less decline in cognition/function than patients treated with placebo as assessed by the iADRS at week 76 (Kisunla: n=583; placebo: n=653). At week 76, adjusted mean change from baseline for patients treated with Kisunla was -10.2 vs -13.1 for placebo. The adjusted mean change difference from placebo was 2.9 (22%); P<0.0001.^1,2,6

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.

HELP KEEP YOUR PATIENTS IN THE EARLIER STAGES OF DISEASE LONGER²

Low-medium tau population: Reduction in risk of progression on CDR-GS — In the overall population, 37% reduced risk of progressing to the next stage of disease vs placebo through 76 weeks; P<0.001.²

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.

50% LOWER RISK OF PROGRESSING TO MODERATE OR SEVERE AD THROUGH 76 WEEKS^7,8

RISK OF PROGRESSION^* TO MODERATE OR SEVERE AD OVER 76 WEEKS (CDR-GS) IN THE OVERALL POPULATION^2,7,8

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

50% reduced risk of progressing to moderate or severe dementia graph

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).^2,7,8†

^*Progression to moderate or severe AD was defined as CDR-GS score of 2 or above at 2 consecutive visits.^7,8
^†HR=0.504; the HR is the relative risk reduction for substantial decline achieved by Kisunla vs placebo.^2,7

CDR-GS=Clinical Dementia Rating Scale-Global Score; 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.

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 WEEKS^1,2,5,9

Results for key clinical endpoints at 76 weeks — In the low-medium tau population (Kisunla: n=588 and placebo: n=594), statistical significance was achieved across 3 key secondary endpoints at 76 weeks. In the overall population (Kisunla: n=860 and placebo: n=876), statistical significance was also achieved across these 3 key secondary clinical endpoints at 76 weeks. The 3 scales were: CDR-SB, which measures cognition and function; ADCS-iADL, which measures complex function; and ADAS-Cog₁₃, which measures cognition.^1,2,5,7

In the low-medium tau population^2,7:

Kisunla slowed decline by 36% (-0.67)^b vs placebo for CDR-SB^a
Mean baseline: 3.72 for Kisunla and 3.64 for placebo

Change from baseline: 1.20 for Kisunla and 1.88 for placebo

Kisunla slowed decline by 40% (1.83)^b vs placebo on ADCS-iADL^d
Mean baseline: 48.20 for Kisunla and 48.56 for placebo

Change from baseline: -2.76 for Kisunla and -4.59 for placebo

Kisunla slowed decline by 32% (-1.52)^b vs placebo on ADAS-Cog₁₃^d
Mean baseline: 27.41 for Kisunla and 27.60 for placebo

Change from baseline: 3.17 for Kisunla and 4.69 for placebo

In the overall population¹:

Kisunla slowed decline by 29% (-0.70)^c vs placebo on CDR-SB^a
Mean baseline: 3.92 for Kisunla and 3.89 for placebo

Change from baseline: 1.72 for Kisunla and 2.42 for placebo

Kisunla slowed decline by 28% (1.70)^e vs placebo on ADCS-iADL^d
Mean baseline: 47.96 for Kisunla and 47.98 for placebo

Change from baseline: -4.42 for Kisunla and -6.13 for placebo

Kisunla slowed decline by 20% (-1.33)^f vs placebo on ADAS-Cog₁₃^d
Mean baseline: 28.53 for Kisunla and 29.16 for placebo

Change from baseline: 5.46 for Kisunla and 6.79 for placebo

^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 MONTHS^1,10

Amyloid Plaque Reduction From Baseline in the Overall Population in TRAILBLAZER-ALZ 2^1,10

Amyloid plaque reduction from baseline in overall population — Three images showing averages of 61% amyloid plaque reduction at 6 months, 80% at 12 months, and 84% at 18 months.^1,8

Patients treated with placebo had an average of <1% amyloid plaque reduction from baseline to 18 months.^1,10

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).^1,10

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 POINTS^1,11†

Percentage of patients who achieved stopping criteria at 6, 12, and 18 months — 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.^1,9

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.

SELECT IMPORTANT SAFETY INFORMATION

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, 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.

TREATMENT EFFECT IN PATIENTS WHO SWITCHED* TO PLACEBO^12†

OVERALL POPULATION: PATIENTS TAKING KISUNLA WHO SWITCHED TO PLACEBO AT EITHER 24 OR 52 WEEKS¹²

iADRS Change From Baseline Through 76 Weeks^12,a,b

Graph showing change in iADRS score from baseline through week 76 in the overall population of patients who switched to placebo at 24 or 52 weeks — Graph displaying the adjusted mean change from baseline through 76 weeks in iADRS score in the overall population of patients who switched to placebo at 24 or 52 weeks. At week 76 (Kisunla: n=268; placebo: n=653), the adjusted mean change from baseline for patients treated with Kisunla was -9.4 vs -12.9 for placebo. The adjusted mean change difference from placebo was 3.52 (27%).¹²

Mean treatment duration was 47 weeks.¹²

No statistical testing was performed, therefore results should be interpreted with caution.¹²

*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

^†Based on a post hoc analysis of patients who switched to placebo after a 6- or 12-month PET scan.¹²

Amyloid PET values may increase after treatment with Kisunla is stopped. There are no data beyond the 76-week duration of TRAILBLAZER-ALZ 2 to guide whether additional dosing with Kisunla may be needed for longer-term clinical benefit.¹

iADRS=integrated Alzheimer’s Disease Rating Scale; NCS2=natural cubic spline with 2 degrees of freedom; PET=positron emission tomography.

References:

Kisunla (donanemab-azbt). Prescribing Information. Lilly USA, LLC.
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.
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.
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
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
Data on File. Lilly USA, LLC. DOF-DN-US-0054.
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.
Data on File. Lilly USA, LLC. DOF-DN-US-0064.
Data on File. Lilly USA, LLC. DOF-DN-US-0053.
Data on File. Lilly USA, LLC. DOF-DN-US-0029.
Data on File. Lilly USA, LLC. DOF-DN-US-0049.
Data on File. Lilly USA, LLC. DOF-DN-US-0032.

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.

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.

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

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

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

HELP KEEP YOUR PATIENTS IN THE EARLIER STAGES OF DISEASE LONGER2

50% LOWER RISK OF PROGRESSING TO MODERATE OR SEVERE AD THROUGH 76 WEEKS7,8

SLOWING OF DECLINE WAS DEMONSTRATED ACROSS ALL SECONDARY CLINICAL ENDPOINTS1

KISUNLA DEMONSTRATED REDUCTION IN AMYLOID PLAQUES AS EARLY AS 6 MONTHS1,10

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

TREATMENT EFFECT IN PATIENTS WHO SWITCHED* TO PLACEBO12†

IMPORTANT SAFETY INFORMATION FOR Kisunla™ (donanemab-azbt)

INDICATION

A PHASE 3 STUDY THAT ASSESSED DISEASE PROGRESSION IN EARLY SYMPTOMATIC ALZHEIMER’S DISEASE (AD) BY REDUCING AMYLOID PLAQUES^1,2

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

KISUNLA GIVES YOU THE POWER TO HELP SLOW COGNITIVE AND FUNCTIONAL DECLINE IN PATIENTS WITH EARLY SYMPTOMATIC AD^1,2,6

HELP KEEP YOUR PATIENTS IN THE EARLIER STAGES OF DISEASE LONGER²

50% LOWER RISK OF PROGRESSING TO MODERATE OR SEVERE AD THROUGH 76 WEEKS^7,8

SLOWING OF DECLINE WAS DEMONSTRATED ACROSS ALL SECONDARY CLINICAL ENDPOINTS¹

KISUNLA DEMONSTRATED REDUCTION IN AMYLOID PLAQUES AS EARLY AS 6 MONTHS^1,10

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

TREATMENT EFFECT IN PATIENTS WHO SWITCHED* TO PLACEBO^12†

IMPORTANT SAFETY INFORMATION FOR Kisunla^™ (donanemab-azbt)