If you wish to report an adverse event or product complaint, please call 1-800-LILLYRX (1-800-545-5979)
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 were the characteristics of ARIA in Kisunla™ (donanemab-azbt)-treated study participants?
In TRAILBLAZER-ALZ 2, ARIA occurred in 36% of donanemab-treated participants. While most ARIA is asymptomatic, fatal events have been observed in donanemab clinical trials. Most events occurred early in treatment but can occur at any time.
See important safety information, including boxed warning, in the attached prescribing information.
Warnings and Precautions: Amyloid-Related Imaging Abnormalities
The donanemab prescribing information recommends
- enhanced clinical vigilance for amyloid-related imaging abnormalities (ARIA) during the first 24 weeks of treatment with donanemab, and
- baseline brain magnetic resonance imaging (MRI) and periodic monitoring with MRI.1
Obtain a recent brain MRI at baseline prior to treatment initiation with donanemab;1 the prescribing clinician should use clinical judgment to determine what constitutes a "recent" MRI. In the TRAILBLAZER-ALZ 2 study, the baseline MRI was performed within 49 days of treatment initiation.2
Obtain additional MRIs
- prior to the second, third, fourth, and seventh infusions, and
- if symptoms suggestive of ARIA occur.1
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.1
Risk of ARIA, including symptomatic ARIA, was increased in apolipoprotein subtype E allele 4 (APOE ε4) homozygotes compared to heterozygotes and noncarriers. The risk of amyloid-related imaging abnormalities-edema (ARIA-E) and amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H) is increased in donanemab-treated patients with pretreatment microhemorrhages and/or superficial siderosis, findings which may be suggestive of cerebral amyloid angiopathy.1
The Appendix provides additional information on ARIA, including a description of the events, symptoms, and risk factors.
Amyloid-Related Imaging Abnormalities 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 Alzheimer's disease.2
Participants were randomized at the beginning of double-blind treatment in a 1:1 ratio to receive intravenous infusions every 4 weeks of either
The characteristics of ARIA in TRAILBLAZER-ALZ 2 provided below include
Incidence
More donanemab-treated participants experienced ARIA compared to participants receiving placebo (36% vs 14%) in TRAILBLAZER-ALZ 2.1
Overview of Amyloid-Related Imaging Abnormalities in TRAILBLAZER-ALZ 2 provides the incidence of ARIA-E, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and macrohemorrhage reported in TRAILBLAZER-ALZ 2.
ARIA-Ec |
ARIA-H Microhemorrhaged |
ARIA-H Superficial Siderosisd |
||||||
PBO |
DONA |
PBO |
DONA |
PBO |
DONA |
PBO |
DONA |
|
Total |
18 (2.1) |
205 (24.0) |
103 (11.8) |
220 (25.8) |
25 (2.9) |
134 (15.7) |
2 (0.2) |
3 (0.4) |
0 (0.0) |
1 (0.1) |
0 (0.0) |
1 (0.1) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
|
SAEs |
0 (0.0) |
13 (1.5) |
0 (0.0) |
4 (0.5) |
0 (0.0) |
0 (0.0) |
1 (0.1) |
1 (0.1) |
Study discontinuation |
2 (0.2) |
9 (1.1) |
1 (0.1) |
5 (0.6) |
0 (0.0) |
1 (0.1) |
1 (0.1) |
0 (0.0) |
Treatment discontinuation |
3 (0.3) |
21 (2.5) |
3 (0.3) |
7 (0.8) |
0 (0.0) |
3 (0.4) |
1 (0.1) |
2 (0.2) |
Symptomatich |
1 (0.1)i |
52 (6.1) |
NA |
NA |
NA |
NA |
NA |
NA |
Abbreviations: AE = adverse event; 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; DONA = donanemab; MedDRA = Medical Dictionary for Regulatory Activities; MRI = magnetic resonance imaging; NA = not available; PBO = placebo; SAE = serious adverse event.
aMedDRA version 25.1.
bThis analysis set includes participant data from the first dose of treatment to the end of treatment period plus 57 days. The incidence in this table may differ from the incidence in the United States Prescribing Information as those percentages were calculated using the last dose of treatment plus 57 days.
cAs assessed by MRI or TEAE cluster.
dAs assessed by MRI.
eMacrohemorrhage is defined as an intracerebral hemorrhage greater than 10 mm.
fDeaths are also included in SAEs and discontinuations due to AE.
gThere was a third death in a donanemab-treated participant with concurrent ARIA-E and ARIA-H.
hData on symptomatic ARIA-H was not collected.
iOne PBO-treated participant had ARIA-E during the placebo-controlled period; however, the participant developed symptoms during the long-term extension period.
Severity
The radiographic severity of ARIA was classified by the criteria shown in ARIA MRI Classification Criteria.
Most events (93.1%) of ARIA-E were of mild-to-moderate radiographic severity in donanemab-treated participants in TRAILBLAZER-ALZ 2.2 The maximum radiographic severity of ARIA-E in participants treated with donanemab was
- mild in 7%
- moderate in 15%, and
- severe in 2%.1
Isolated ARIA-E was most frequently of mild severity in both placebo (0.9%) and donanemab (2.7%) treatment groups.4
Macrohemorrhage was not assessed by severity category and was only assessed as present. The following information about radiographic severity refers to ARIA-H microhemorrhage and ARIA-H superficial siderosis.4
Radiographic severity of ARIA-H was most frequently reported as
- mild (15.8%) followed by severe (9.1%) in donanemab-treated participants, and
- mild (10.5%) followed by moderate (1.8%) in placebo-treated participants.4
The maximum radiographic severity of ARIA-H microhemorrhage in participants treated with donanemab was
- mild in 17%
- moderate in 4%, and
- severe in 5%.1
The maximum radiographic severity of ARIA-H superficial siderosis in participants treated with donanemab was
- mild in 6%
- moderate in 4%, and
- severe in 5%.1
Additionally,
- isolated ARIA-H was most frequently of mild severity in both placebo (10.0%) and donanemab (9.4%) treatment groups, and
- most concurrent ARIA-E and ARIA-H was moderate or severe in donanemab-treated participants.4
Onset and Resolution
The majority of first ARIA-E events occurred early in treatment (within the first 24 weeks), although ARIA can occur at any time and patients can have more than 1 episode.1 Specifically,
The mean resolution time for these first events of ARIA-E was
- 72.4 days for those receiving donanemab, and
- 63.5 days for those receiving placebo.2
Resolution on MRI after the first ARIA-E event in donanemab-treated participants occurred in
- 63% by 12 weeks
- 80% by 20 weeks, and
- 83% overall after detection.1
Of the 52 donanemab-treated participants who experienced symptomatic ARIA-E, approximately 85% had resolution of symptoms during the double-blind period.1
Recurrence
Limited data are available for dosing patients who have experienced recurrent episodes of ARIA-E. Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E.1
Deaths
A total of 3 participants in the donanemab treatment group reported serious ARIA and subsequently died. These deaths were attributed to
- ARIA-E (n=1)
- ARIA-H (n=1), and
- concurrent ARIA-E and ARIA-H (n=1).2
Further descriptions of each death are available in eTable 9 of supplement 3 in the TRAILBLAZER-ALZ 2 manuscript.2
Two additional ARIA-related deaths were reported in the ongoing, long-term extension of TRAILBLAZER-ALZ 2. One study participant died due to ARIA-E after the fifth donanemab dose. The other death occurred after thrombolytic administration for potential acute stroke-like symptoms. An MRI on the day of event showed severe ARIA-E; the participant subsequently died due to intracranial hemorrhage.5
Amyloid-Related Imaging Abnormalities in TRAILBLAZER-ALZ 6
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 standard dosing regimen (ie, the recommended dose as stated in the prescribing information).6
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.6
The study is ongoing. Results through 24 and 52 weeks have been published.6 Additional results from 18 months will be disclosed at a later date.
Compared with the standard dosing group at 24 weeks, participants in the modified titration group had lower
- frequency of ARIA-E and symptomatic ARIA-E (Overview of ARIA in TRAILBLAZER-ALZ 6), and
- radiographic severity of ARIA-E (Severity of ARIA-E Through Week 24 and 52: TRAILBLAZER-ALZ 6).6
These results were consistent at 52 weeks.6
Category |
24 Week Resultsa |
52 Week Results |
||
Standard |
Modified Titration |
Standard |
Modified Titration |
|
67 (32.4) |
50 (23.6) |
71 (34.3) |
61 (28.8) |
|
Any SAE of ARIA (-E or -H), n (%)e |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.5) |
Concurrent ARIA-E and ARIA-H, n (%)f |
32 (15.5) |
21 (9.9) |
34 (16.4) |
23 (10.8) |
49 (23.7) |
29 (13.7) |
50 (24.2) |
33 (15.6) |
|
10 (4.8) |
6 (2.8) |
10 (4.8) |
6 (2.8) |
|
SAE of ARIA-E, n (%)e |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.5) |
52 (25.1) |
42 (20.3) |
57 (27.5) |
53 (25.0) |
|
0 (0.0) |
1 (0.5) |
0 (0.0) |
1 (0.5) |
|
SAE of ARIA-H, n (%)e |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
Microhemorrhage, n (%)f |
41 (19.8) |
36 (17.0) |
44 (21.3) |
48 (22.6) |
Cortical superficial siderosis, n (%)f |
26 (12.6) |
14 (6.6) |
31 (15.0) |
18 (8.5) |
1 (0.5) |
2 (0.9) |
1 (0.5) |
2 (0.9) |
|
SAE of macrohemorrhage, n (%)e |
0 (0.0) |
1 (0.5) |
0 (0.0) |
1 (0.5) |
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; MRI = magnetic resonance imaging; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
aPrimary endpoint.
bBased on MRI or TEAE cluster.
cARIA-E TEAE cluster preferred terms: ARIA edema/effusion, brain edema, vasogenic cerebral edema.
dARIA-H TEAE cluster preferred terms: ARIA-microhemorrhage and hemosiderin deposits, brainstem microhemorrhage, cerebellar microhemorrhage, cerebral hemosiderin deposit, cerebral microhemorrhage, and cortical superficial siderosis of the central nervous system.
eBased on TEAE cluster.
fBased on MRI only.
gARIA-E TEAE cluster preferred terms are ARIA edema/effusion, brain edema, and vasogenic cerebral edema.
hSymptomatic ARIA-H low level term includes symptomatic ARIA-H, symptomatic ARIA-microhemorrhages and hemosiderin deposits, symptomatic ARIA-microhemorrhages and hemosiderin deposits, and symptomatic ARIA-superficial siderosis.
iSymptomatic ARIA-H low level term includes symptomatic ARIA-H, symptomatic ARIA-microhemorrhages and hemosiderin deposits, symptomatic ARIA microhemorrhages and hemosiderin deposits, and symptomatic ARIA-cortical superficial siderosis.
jMacrohemorrhage preferred terms are cerebral hemorrhage and hemorrhagic stroke.
Figure 1 description: Compared with the standard dosing arm, the severity of amyloid-related imaging abnormalities-edema (none, mild, moderate, and severe) was significantly shifted toward none or a less severe direction in the modified titration arm at week 24 (p=.011) and at week 52 (p=.015).
Abbreviations: ARIA-E = amyloid-related imaging abnormalities-edema observed on MRI as vasogenic cerebral edema or sulcal effusions; MRI = magnetic resonance imaging.
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Kisunla [package insert]. Indianapolis, IN: Eli Lilly and Company; 2024.
2Sims 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
3Solomon PR. TRAILBLAZER-ALZ 2: clinical background and study design. Abstract presented at: Alzheimer's Association International Conference (AAIC); July 16-20, 2023; Amsterdam, Netherlands.
4Data on file, Eli Lilly and Company and/or one of its subsidiaries.
5Zimmer 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. Published online March 10, 2025. https://doi.org/10.1001/jamaneurol.2025.0065
6Wang H, Nery ESM, Ardayfio P, et al. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimers Dement. Published online April 2, 2025. https://doi.org/10.1002/alz.70062
7Wang H, Nery ESM, Ardayfio P, et al. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction: 12 month results from TRAILBLAZER-ALZ 6. Presentation at: International Conference on Alzheimer's and Parkinson's Disease (AD/PD 2025); April 1-5, 2025; Vienna, Austria.
8Sperling 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
9Cogswell 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
10Ketter 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
11Carlson C, Siemers E, Hake A, et al. Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer’s disease. Alzheimers Dement. 2016;2(1):75-85. https://doi.org/10.1016/j.dadm.2016.02.004
12Salloway 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
13Arrighi HM, Barakos J, Barkhof F, et al. Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab: a historical, prospective secondary analysis. J Neurol Neurosurg Psychiatry. 2016;87(1):106-112. https://doi.org/10.1136/jnnp-2014-309493
14Cogswell 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. Published online August 23, 2024. https://dx.doi.org/10.3174/ajnr.A8469
Appendix
Amyloid-Related Imaging Abnormalities Overview
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.1,8 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.1,8,9
These are typically detected on different MRI sequences and are thought to share common underlying pathological mechanisms.8,9
Microhemorrhages and superficial siderosis (ie, ARIA-H) are often associated with ARIA-E1 and both are thought to be possibly related to removal of vascular amyloid beta or amyloid trafficking at the blood-brain barrier.9,10
Amyloid-related imaging abnormalities are 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.1
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.8-12
Risk factors for ARIA include
Overview of ARIA-E
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
Clinically symptomatic ARIA-E may require intervention beyond withholding treatment for management.4
Overview of ARIA-H
In ARIA-H, hemosiderin deposits are present on MRI, including
Clinically, symptomatic ARIA-H can be hard to distinguish from symptomatic ARIA-E. Therefore, the characterization of the symptoms focuses on those associated with ARIA-E.4
ARIA Severity
The radiographic severity of ARIA associated with donanemab was classified by the criteria shown in ARIA MRI Classification Criteria.1
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.
aHemosiderin 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.
bIncludes new or worsening superficial siderosis.
Date of Last Review: April 16, 2025