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Kisunla ® (donanemab-azbt) injection, for intravenous infusion
350 mg/20 mL (17.5 mg/mL)
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.
What are the risk factors for ARIA?
Risk factors for ARIA include drug exposure, being an APOE ε4 allele carrier, and baseline superficial siderosis and microhemorrhages. In the donanemab studies, presence of APOE ε4 and baseline ARIA-H were associated with higher frequency of ARIA.
See important safety information, including boxed warning, in the attached prescribing information.
Amyloid-Related Imaging Abnormalities Overview
Amyloid-related imaging abnormalities (ARIA) 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.1,2 The 2 forms of ARIA are
- amyloid-related imaging abnormalities-edema (ARIA-E), observed on MRI as vasogenic cerebral edema or sulcal effusions, and
- amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis.1-3
These are typically detected on different MRI sequences and are thought to share common underlying pathological mechanisms.2,3
Amyloid-related imaging abnormalities are usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, can occur. Amyloid-related imaging abnormalities 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.1
Also known as vasogenic edema, the mechanism of ARIA-E is thought to be a function of increased permeability of brain capillary endothelial cells to serum proteins resulting in increased extracellular fluid volume. It is generally
- asymptomatic
- transient
- reversible, and
- not associated with cytotoxic edema, which results from cellular damage.2,3
In ARIA-H, hemosiderin deposits are present on MRI, including
- microhemorrhages: leakage of blood from a vessel into the parenchyma
- superficial siderosis: leakage of blood from a vessel into the adjacent subarachnoid space or peri adventitial compartment, and
- macrohemorrhages: intracerebral hemorrhage >1 cm in diameter.2,3
Microhemorrhages and superficial siderosis (ie, ARIA-H) are often associated with ARIA-E in the setting of anti-amyloid therapy treatment1 and both are thought to be possibly related to removal of vascular amyloid beta or amyloid trafficking at the blood-brain barrier.3,4
Risk Factors for Amyloid-Related Imaging Abnormalities
While ARIA-E and ARIA-H do occur during the natural course of Alzheimer's disease,1 anti-amyloid therapies have been associated with an increased risk of ARIA-E and ARIA-H.2-6
Risk factors for ARIA include
- drug exposure
- being a carrier of apolipoprotein subtype E allele 4 (APOE ε4), and
- pretreatment hemosiderin deposition consistent with cerebral amyloid angiopathy, microhemorrhages or superficial siderosis.1,3
Risk Factors for ARIA-E From Post Hoc Exploratory Analysis
A post hoc exploratory analysis of the phase 2 TRAILBLAZER-ALZ, phase 3 TRAILBLAZER-ALZ 2, and TRAILBLAZER-ALZ 2 addendum populations (N=2,031) found that the baseline risk factors associated with increased risk for developing ARIA-E were
- APOE ε4 carriership
- number of microhemorrhages at baseline, and
- presence of superficial siderosis at baseline.7
Additional baseline factors found to be associated with increased ARIA-E risk in this post hoc analysis were
- elevated mean arterial pressure (MAP), and
- amyloid plaque levels on positron emission tomography ≥108 centiloids.7
A separate post hoc exploratory analysis completed by modeling of the phase 2 TRAILBLAZER-ALZ and phase 3 TRAILBLAZER-ALZ 2 studies (donanemab-treated participants N=1993) also found that higher baseline MAP was associated with increased risk of ARIA-E.8
Risk Factors for ARIA in TRAILBLAZER-ALZ 2
In the phase 3 double-blind, placebo-controlled study, TRAILBLAZER-ALZ 2, risk factor analysis based on MRI shows that the frequency of ARIA was influenced by
- APOE ε4 carrier status, and
- presence of microhemorrhage and/or superficial siderosis at baseline, findings which may be suggestive of cerebral amyloid angiopathy.1
Events of ARIA were observed in participants using antithrombotic medications and those not using antithrombotic medications. The number of events and the limited exposure to non-aspirin antithrombotic medications limit definitive conclusions about the risk of ARIA or intracerebral hemorrhage in patients taking antithrombotic medications.1 Additional information regarding ARIA-E, ARIA-H, and macrohemorrhage in participants using antithrombotic medications and those not using antithrombotic medications is summarized here.
APOE ε4 Carrier Status
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.1
The frequency of any ARIA was influenced by APOE ε4 carrier status (Table 1).
The frequency of ARIA-E and ARIA-H in participants treated with donanemab was increased in APOE ε4 homozygotes compared with APOE ε4 heterozygotes and noncarriers.1
|
Placebo |
Donanemab |
|---|---|---|
ARIA-E incidence, n/N (%) |
||
Homozygote |
5/146 (3.4) |
58/143 (40.6) |
Heterozygote |
9/474 (1.9) |
103/452 (22.8) |
Noncarrier |
2/250 (0.8) |
40/255 (15.7) |
ARIA-H incidence, n/N (%) |
||
Homozygote |
30/146 (20.5) |
72/143 (50.3) |
Heterozygote |
57/474 (12.0) |
146/452 (32.3) |
Noncarrier |
28/250 (11.2) |
48/255 (18.8) |
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; ARIA-H = amyloid-related imaging abnormalities-hemosiderin deposition which includes microhemorrhage and superficial siderosis; MRI = magnetic resonance imaging.
Baseline Microhemorrhage or Superficial Siderosis
In donanemab-treated participants with the presence of both microhemorrhage and superficial siderosis at baseline, a higher frequency of both ARIA-E and ARIA-H was observed (Table 2).1,10
|
Placebo |
Donanemab |
|---|---|---|
ARIA-E incidence, n/N1 (%) |
||
mCH or SS |
7/161 (4.3) |
37/124 (29.8) |
mCH and SS |
0/6 (0.0) |
2/3 (66.7) |
No mCH or SS |
10/713 (1.4) |
165/729 (22.6) |
ARIA-H incidence, n/N1 (%) |
||
mCH or SS |
49/161 (30.4) |
58/124 (46.8) |
mCH and SS |
3/6 (50.0) |
3/3 (100.0) |
No mCH or SS |
66/713 (9.3) |
209/729 (28.7) |
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; mCH = microhemorrhage; MRI = magnetic resonance imaging; n = number of subjects within the specific imaging at baseline category with the specific ARIA event; N1 = number of subjects within the specific imaging at baseline category; SS = superficial siderosis.
Risk Factors for ARIA in TRAILBLAZER-ALZ 6
The effectiveness of donanemab for the treatment of Alzheimer’s disease was established by TRAILBLAZER-ALZ 2,9 which assessed a dosing regimen of 700 mg every 4 weeks for the first 3 doses, and then 1,400 mg every 4 weeks (referred to as standard dosing in TRAILBLAZER-ALZ 6). The TRAILBLAZER-ALZ 6 study11 was conducted to assess different titration regimens, including the modified dosing regimen (ie, currently approved dosing of every 4 weeks with 350 mg the first infusion, 700 mg the second infusion, 1,050 mg the third infusion, and then 1,400 mg thereafter). The currently approved dose demonstrated
- comparable pharmacodynamic effects on amyloid plaque reduction, and
- a reduced incidence of ARIA compared with the standard dosing regimen.1,11
APOE ε4 Carrier Status
Among the participants treated with the modified dosing regimen in TRAILBLAZER-ALZ 6,
- 10% were APOE ε4 homozygotes (ε4/ε4)
- 55% were APOE ε4 heterozygotes (ε2/ε4; ε3/ε4), and
- 36% were noncarriers.1
With modified titration compared with standard dosing, ARIA-E incidence was 23.8% vs 57.1% in APOE ε4 homozygotes and ARIA-H incidence in homozygotes was 28.6% vs 47.6% (Table 3).11
|
Standard |
Modified Titrationa |
|---|---|---|
ARIA-E incidence, n/N (%) |
||
Homozygote |
12/21 (57.1) |
5/21 (23.8) |
Heterozygote |
27/112 (24.1) |
18/115 (15.7) |
Noncarrier |
11/72 (15.3) |
10/75 (13.3) |
ARIA-H incidence, n/N (%) |
||
Homozygote |
10/21 (47.6) |
6/21 (28.6) |
Heterozygote |
35/112 (31.3) |
33/115 (28.7) |
Noncarrier |
10/72 (13.9) |
15/75 (20.0) |
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; ARIA-H = amyloid-related imaging abnormalities-hemosiderin deposition which includes microhemorrhage and superficial siderosis; MRI = magnetic resonance imaging.
a Modified titration is the recommended dosage for donanemab.
Baseline Microhemorrhage or Superficial Siderosis
In participants with the presence of both microhemorrhage and superficial siderosis at baseline, a higher frequency of both ARIA-E and ARIA-H was observed (Table 4).10
|
Standard |
Modified Titrationa |
|---|---|---|
ARIA-E incidence, n/N1 (%) |
||
mCH or SS |
15/51 (29.4) |
8/55 (14.5) |
mCH and SS |
1/2 (50.0) |
1/1 (100.0) |
No mCH or SS |
35/156 (22.4) |
25/157 (15.9) |
ARIA-H incidence, n/N1 (%) |
||
mCH or SS |
16/51 (31.4) |
18/55 (32.7) |
mCH and SS |
1/2 (50.0) |
1/1 (100.0) |
No mCH or SS |
39/156 (25.0) |
36/157 (22.9) |
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; mCH = microhemorrhage; MRI = magnetic resonance imaging; n = number of subjects within the specific imaging at baseline category with the specific ARIA event; N1 = number of subjects within the specific imaging at baseline category; SS = superficial siderosis.
a Modified titration is the recommended dosage for donanemab.
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).
- Kisunla [package insert]. Indianapolis, IN: Eli Lilly and Company; 2025.
- Sperling RA, Jack CR Jr, 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
- 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
- Carlson C, Siemers E, Hake A, et al. Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer’s disease. Alzheimers Dement (Amst). 2016;2(1):75-85. https://doi.org/10.1016/j.dadm.2016.02.004
- Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2022;79(1):13-21. https://doi.org/10.1001/jamaneurol.2021.4161
- Zimmer JA, Ardayfio P, Wang H, et al. Amyloid-related imaging abnormalities with donanemab in early symptomatic Alzheimer disease: secondary analysis of the TRAILBLAZER-ALZ and ALZ 2 randomized clinical trials. JAMA Neurol. 2025;82(5):461-469. https://doi.org/10.1001/jamaneurol.2025.0065
- Gueorguieva I, Chow K, Chua L, et al. Donanemab exposure-efficacy and exposure-safety (ARIA-E) relationships in participants with Alzheimer’s disease: results from the TRAILBLAZER-ALZ clinical program. Abstract presented at: International Conference on Alzheimer’s and Parkinson’s Disease; March 5-9, 2024; Lisbon Portugal.
- 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
- 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;12(8):100266. https://doi.org/10.1016/j.tjpad.2025.100266
Date of Last Review: July 07, 2025