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Kisunla ® (donanemab-azbt) injection, for intravenous infusion
350 mg/20 mL (17.5 mg/mL)
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What was the incidence of ARIA in Kisunla® (donanemab-azbt)-treated participants by APOE genotype?
Patients who are APOE ε4 homozygotes treated with donanemab have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers.
See important safety information, including boxed warning, in the attached prescribing information.
ARIA Frequency and APOE ε4 Status
Studies confirm that having the apolipoprotein subtype E allele 4 (APOE ε4) is a strong genetic risk for Alzheimer's disease (AD).1,2
The presence of APOE ε4 has also been recognized as a risk factor for developing amyloid-related imaging abnormalities-edema (ARIA-E) and amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H).3,4
The Appendix provides a brief overview of the APOE gene and amyloid-related imaging abnormalities (ARIA).
APOE Genotype Testing Should be Performed Before Initiating Donanemab Treatment
The recommendations for management of ARIA do not differ based on APOE ε4 carrier status.4
Testing for APOE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.4
Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and implications of genetic testing results.4
Prescribers should inform patients that if genotype testing is not performed, they can still be treated with donanemab; however, it cannot be determined if they are APOE ε4 homozygotes and at higher risk for ARIA.4
A Food and Drug Administration (FDA) authorized test for detection of APOE ε4 alleles to identify patients at higher risk of ARIA if treated with donanemab is not currently available. Currently available tests used to identify APOE ε4 alleles may vary in accuracy and design.4
ARIA Events by APOE ε4 Carrier Status in TRAILBLAZER-ALZ 2
A phase 3, placebo-controlled 72-week study, TRAILBLAZER-ALZ 2, evaluated the safety and efficacy of donanemab in adults aged 60 to 85 years with early symptomatic AD.5
Participants were randomized at the beginning of double-blind treatment in a 1:1 ratio to receive intravenous infusions every 4 weeks of either
- donanemab 700 mg for the first 3 doses and 1400 mg thereafter (n=860), or
- placebo (n=876; administered as saline).5,6
Among the donanemab-treated participants in TRAILBLAZER-ALZ 2,
- 17% were APOE ε4 homozygotes (ε4/ε4)
- 53% were APOE ε4 heterozygotes (ε2/ε4; ε3/ε4), and
- 30% were noncarriers.4
Risk of ARIA, including symptomatic ARIA, was increased in APOE ε4 homozygotes compared to heterozygotes and noncarriers.4
The incidence of ARIA in TRAILBLAZER-ALZ 2 through 18 months was
- 55% donanemab versus 22% placebo in APOE ε4 homozygotes
- 36% donanemab versus 13% placebo in APOE ε4 heterozygotes, and
- 25% donanemab versus 12% placebo in noncarriers.4
Among participants treated with donanemab,
- symptomatic ARIA-E occurred in 8% of APOE ε4 homozygotes, 7% of APOE ε4 heterozygotes, and 4% of noncarriers, and
- serious events of ARIA occurred in 3% of APOE ε4 homozygotes, 2% of APOE ε4 heterozygotes, and 1% of noncarriers.4
Table 1 and Table 2 provide the frequency of ARIA-E, ARIA-H, and macrohemorrhage by APOE ε4 carrier status in TRAILBLAZER-ALZ 2.
The radiographic severity of ARIA associated with donanemab was classified by the criteria shown in Table 3.4
ARIA Category Incidence and Maximum Radiographic Severitya |
Placebo |
Donanemab |
||||
|---|---|---|---|---|---|---|
Noncarrier |
Heterozygote |
Homozygote |
Noncarrier |
Heterozygote |
Homozygote |
|
ARIA-E |
2 (0.8) |
9 (1.9) |
5 (3.4) |
40 (15.7) |
102 (22.6) |
58 (40.6) |
Mild |
2 (0.8) |
8 (1.7) |
4 (2.7) |
13 (5.1) |
31 (6.9) |
14 (9.8) |
Moderate |
0 (0.0) |
1 (0.2) |
1 (0.7) |
26 (10.2) |
62 (13.7) |
40 (28.0) |
Severe |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.4) |
9 (2.0) |
4 (2.8) |
Serious ARIA-E |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.4) |
4 (0.9) |
3 (2.1) |
Abbreviations: APOE ε4 = apolipoprotein subtype E allele 4; ARIA-E = amyloid-related imaging abnormalities-edema observed on MRI as vasogenic cerebral edema or sulcal effusions; MRI = magnetic resonance imaging.
a This analysis set includes participant data from the first dose of treatment to the last treatment dose plus 57 days.
ARIA Category Incidence and Maximum Radiographic Severitya |
Placebo |
Donanemab |
||||
|---|---|---|---|---|---|---|
Noncarrier |
Heterozygote |
Homozygote |
Noncarrier |
Heterozygote |
Homozygote |
|
ARIA-H |
27 (10.8) |
54 (11.4) |
30 (20.5) |
48 (18.8) |
142 (31.4) |
72 (50.3) |
Mild |
22 (8.8) |
47 (9.9) |
23 (15.8) |
34 (13.3) |
70 (15.5) |
30 (21.0) |
Moderate |
3 (1.2) |
7 (1.5) |
6 (4.1) |
5 (2.0) |
34 (7.5) |
11 (7.7) |
Severe |
2 (0.8) |
0 (0.0) |
1 (0.7) |
9 (3.5) |
38 (8.4) |
31 (21.7) |
Serious ARIA-H |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
2 (1.4) |
ARIA-H microhemorrhageb |
26 (10.4) |
48 (10.1) |
26 (17.8) |
39 (15.3) |
117 (25.9) |
60 (42.0) |
ARIA-H superficial siderosisb |
2 (0.8) |
10 (2.1) |
11 (7.5) |
19 (7.5) |
70 (15.5) |
36 (25.2) |
Macrohemorrhagec |
0 (0.0) |
1 (0.2) |
0 (0.0) |
0 (0.0) |
3 (0.7) |
0 (0.0) |
Serious macrohemorrhage |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.2) |
0 (0.0) |
Abbreviations: APOE ε4 = apolipoprotein subtype E allele 4; ARIA-H = amyloid-related imaging abnormalities-hemosiderin deposition which includes microhemorrhage and superficial siderosis; MRI = magnetic resonance imaging.
a This analysis set includes participant data from the first dose of treatment to the last dose of treatment plus 57 days.
b Treatment-emergent microhemorrhage is based on new incidents of microhemorrhages. Treatment-emergent superficial siderosis is based on new or worsening superficial siderosis.
c A type of ARIA-H; intracerebral hemorrhage >1 cm in diameter.
Modified Titration Reduces ARIA Across APOE ε4 Genotypes
The TRAILBLAZER-ALZ 6 study investigated the impact of different donanemab dosing options on the frequency of ARIA-E in relation to amyloid reduction. All participants received a dosing regimen that includes donanemab, but at different dose levels and frequency of dosing. The modified titration regimen met the primary objective of >80% probability of achieving ≥20% reduction in relative risk of developing ARIA-E compared with the dosing regimen used in the TRAILBLAZER-ALZ 2 study (referred to as standard dosing in the TRAILBLAZER-ALZ 6 study).8 Therefore, the modified titration regimen is the recommended dosage for donanemab.4
In the modified titration regimen, participants received intravenous donanemab doses every 4 weeks as follows:
- 350 mg for infusion 1
- 700 mg for infusion 2
- 1050 mg for infusion 3, and
- 1400 mg for infusion 4 and beyond.8
The frequency of ARIA-E across APOE ε4 genotypes in the modified titration arm and the standard dosing arm is shown in Figure 1.9
The incidence of symptomatic ARIA-E across APOE ε4 genotypes is shown in Figure 2.7,9
Figure 1. Incidence of ARIA-E by APOE ε4 Genotype Through Weeks 24 and 76: TRAILBLAZER-ALZ 68,9
Figure 1 description: At 24 weeks, the incidence of amyloid-related imaging abnormalities-edema in the standard vs modified titration arm was 57% vs 19% in homozygotes, 23% vs 14% in heterozygotes, and 15% vs 12% in noncarriers. At 76 weeks, the incidence of amyloid-related imaging abnormalities-edema in the standard vs modified titration arm was 57% vs 24% in homozygotes, 24% vs 16% in heterozygotes, and 15% vs 13% in noncarriers.
Abbreviations: APOE ε4 = apolipoprotein subtype E allele 4; ARIA-E = amyloid-related imaging abnormalities-edema observed on MRI as vasogenic cerebral edema or sulcal effusions; MRI = magnetic resonance imaging.
Figure 2. Incidence of Symptomatic ARIA-E by APOE ε4 Genotype Through Weeks 24 and 76: TRAILBLAZER-ALZ 67,9
Figure 2 description: The frequency of symptomatic amyloid-related imaging abnormalities-edema in the standard dosing arm was 5% in homozygous, 8% in heterozygous and 0% in noncarrier participants at 24 and 76 weeks. The frequency of symptomatic amyloid-related imaging abnormalities-edema in the modified titration arm was 0% in homozygous, 4% in heterozygous, and 3% in noncarrier participants at 24 and 76 weeks.
Abbreviations: APOE ε4 = apolipoprotein subtype E allele 4; ARIA-E = amyloid-related imaging abnormalities-edema observed on MRI as vasogenic cerebral edema or sulcal effusions; MRI = magnetic resonance imaging.
The frequency of ARIA-H across APOE ε4 genotypes in the modified titration and standard dosing arms at 24 and 76 weeks is shown in Figure 3.7 The modified titration arm did not statistically significantly reduce the risk of ARIA-H in this study. Possible reasons for this outcome include
- the study is not powered to detect a significant reduction of ARIA-H given the rate of spontaneous ARIA-H in this population, and
- ARIA-H resulting from amyloid-targeting therapies tend to co-occur with ARIA-E.9
Figure 3. Incidence of ARIA-H by APOE ε4 Genotype Through Weeks 24 and 76: TRAILBLAZER-ALZ 67,8
Figure 3 description: At 24 weeks, the incidence of amyloid-related imaging abnormalities-hemosiderin deposition in the standard vs modified titration arm was 43% vs 29% in homozygotes, 28% vs 23% in heterozygotes, and 17% vs 15% in noncarriers. At 76 weeks, the incidence of amyloid-related imaging abnormalities-hemosiderin deposition in the standard vs modified titration arm was 48% vs 29% in homozygotes, 31% vs 29% in heterozygotes, and 14% vs 20% in noncarriers.
Abbreviations: APOE ε4 = apolipoprotein subtype E allele 4; ARIA-H = amyloid-related imaging abnormalities-hemosiderin deposition which includes microhemorrhage and superficial siderosis.
Enclosed Prescribing Information
KISUNLA® (donanemab-azbt) injection, for intravenous use, Lilly
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
- Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106-118. https://doi.org/10.1038/nrneurol.2012.263
- Alzheimer's Association. 2023 Alzheimer's disease facts and figures. Alzheimers Dement. 2023;19(4):1598-1695. https://doi.org/10.1002/alz.13016
- Sperling RA, Jack Jr CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7(4):367-385. https://doi.org/10.1016/j.jalz.2011.05.2351
- Kisunla [package insert]. Indianapolis, IN: Eli Lilly and Company; 2025.
- Sims JR, Zimmer JA, Evans CD, et al; TRAILBLAZER-ALZ 2 Investigators. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527. https://doi.org/10.1001/jama.2023.13239
- Solomon PR. TRAILBLAZER-ALZ 2: clinical background and study design. Abstract presented at: Alzheimer's Association International Conference (AAIC); July 16-20, 2023; Amsterdam, Netherlands.
- Data on file, Eli Lilly and Company and/or one of its subsidiaries.
- Wang H, Nery ESM, Ardayfio P, et al. The effect of modified donanemab titration on amyloid-related imaging abnormalities with edema/effusions and amyloid reduction: 18-month results from TRAILBLAZER-ALZ 6. J Prev Alzheimers Dis. 2025;21(8):100266. https://doi.org/10.1016/j.tjpad.2025.100266
- Wang H, Nery ESM, Ardayfio P, et al. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimers Dement. 2025;21(4):e70062. https://doi.org/10.1002/alz.70062
- Troutwine BR, Hamid L, Lysaker CR, et al. Apolipoprotein E and Alzheimer's disease. Acta Pharm Sin B. 2022;12(2):496-510. https://doi.org/10.1016/j.apsb.2021.10.002
- Cogswell PM, Barakos JA, Barkhof F, et al. Amyloid-related imaging abnormalities with emerging Alzheimer disease therapeutics: detection and reporting recommendations for clinical practice. AJNR Am J Neuroradiol. 2022;43(9):E19-E35. https://doi.org/10.3174/ajnr.A7586
- Ketter N, Brashear HR, Bogert J, et al. Central review of amyloid-related imaging abnormalities in two phase III clinical trials of bapineuzumab in mild-to-moderate Alzheimer’s disease patients. J Alzheimers Dis. 2017;57(2):557-573. https://doi.org/10.3233/JAD-160216
- Cogswell PM, Andrews TJ, Barakos JA, et al; ASNR Alzheimer’s, ARIA, and Dementia Study Group. Alzheimer's disease anti-amyloid immunotherapies: imaging recommendations and practice considerations for ARIA monitoring. AJNR Am J Neuroradiol. 2025;46(1):24-32. https://doi.org/10.3174/ajnr.A8469
Appendix
Overview of APOE and ARIA
The APOE gene is responsible for lipid homeostasis by facilitating lipid transport from tissue or cells, and is associated with hyperlipidemia and hypercholesterolemia. In the central nervous system, transport of cholesterol to neurons is facilitated by APOE receptors.1
The gene consists of 3 polymorphic alleles, ε2, ε3, and ε4. The prevalence of alleles is approximately
- 8% (ε2)
- 78% (ε3), and
- 14% (ε4).1
However, the frequency of ε4 alleles has been reported as being present in 40% to 80% of patients with AD.1,10
Amyloid-related imaging abnormalities can be detected by brain magnetic resonance imaging (MRI) and have been observed in clinical trials of monoclonal antibodies directed against aggregated forms of beta amyloid.3,4 The 2 forms of ARIA are
- ARIA-E, observed on MRI as vasogenic cerebral edema or sulcal effusions, and
- ARIA-H, which includes microhemorrhage and superficial siderosis.3,4,11
These are typically detected on different MRI sequences and are thought to share common underlying pathological mechanisms.3,11
Microhemorrhages and superficial siderosis (ie, ARIA-H) are often associated with ARIA-E4 and both are thought to be possibly related to removal of vascular amyloid beta or amyloid trafficking at the blood-brain barrier.11,12
Risk factors for ARIA include
- drug exposure
- being a carrier of APOE ε4, and
- pretreatment hemosiderin deposition consistent with cerebral amyloid angiopathy, microhemorrhages or superficial siderosis.4,11
ARIA Severity
The radiographic severity of ARIA associated with donanemab was classified by the criteria shown in Table 3.4
ARIA Type |
Radiographic Severity |
||
|---|---|---|---|
Mild |
Moderate |
Severe |
|
ARIA-E |
FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white matter in 1 location <5 cm. |
FLAIR hyperintensity 5 to 10 cm in single greatest dimension, or more than 1 site of involvement, each measuring <10 cm. |
FLAIR hyperintensity >10 cm with associated gyral swelling and sulcal effacement. One or more separate/independent sites of involvement may be noted. |
ARIA-H microhemorrhagea |
≤4 new incident microhemorrhages |
5 to 9 new incident microhemorrhages |
≥10 new incident microhemorrhages |
ARIA-H superficial siderosisa |
1 newb focal area of superficial siderosis |
2 new focal areas of superficial siderosis |
>2 new focal areas of superficial siderosis |
Abbreviations: ARIA = amyloid-related imaging abnormalities; ARIA-E = amyloid-related imaging abnormalities-edema observed on MRI as vasogenic cerebral edema or sulcal effusions; ARIA-H = amyloid-related imaging abnormalities-hemosiderin deposition which includes microhemorrhage and superficial siderosis; FLAIR = fluid attenuation inversion recovery; MRI = magnetic resonance imaging.
a Hemosiderin deposits (microhemorrhage and superficial siderosis) are seen on T2* gradient-recalled echo sequence on MRI. ARIA-H severity score is based on cumulative numbers of treatment-emergent microhemorrhages and regions of superficial siderosis compared with the baseline MRI.
b Includes new or worsening superficial siderosis.
Date of Last Review: July 24, 2025