Safety matters. The incidence and timing of amyloid-related imaging abnormalities (ARIA) vary among treatments1
What is ARIA?1
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ARIA is a potential side effect of monoclonal antibodies like LEQEMBI® and can occur spontaneously in patients with Alzheimer's disease (AD). ARIA can present in 2 ways:
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ARIA-E: Presents as temporary swelling in areas of the brain and usually resolves over time
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ARIA-H: Presents as small spots of bleeding in or on the surface of the brain; infrequently, larger areas of bleeding in the brain can occur
ARIA usually occurs early in treatment and is mostly asymptomatic1,2
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Symptomatic ARIA occurred in 3% (29/898) and serious symptoms associated with ARIA occurred in 0.7% (6/898) of patients treated with LEQEMBI. ARIA can be fatal1
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Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation1
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ARIA-H that occurred with ARIA-E tended to occur early (within 6 months)2,3
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Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes and in ~1% of heterozygotes and noncarriers1
| Incidence of ARIA1,3 | LEQEMBI | Placebo |
|---|---|---|
| ARIA incidence | (n=898) % (n) |
(n=897) % (n) |
| ARIA-E or ARIA-H* | 21 (191) | 9 (84) |
| ARIA-E | 13 (113) | 2 (15) |
| ARIA-H | 17 (152) | 9 (80) |
| Isolated ARIA-H | 8.9 (80) | 7.8 (70) |
*Including asymptomatic radiographic events.1
ARIA-E: ARIA with edema can be observed on MRI as brain edema or sulcal effusions.1
ARIA-H: ARIA with hemosiderin deposition includes microhemorrhage and superficial siderosis.1
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The most common adverse reactions reported in ≥5% with LEQEMBI infusion every 2 weeks and ≥2% higher than placebo were IRRs (LEQEMBI: 26%; placebo: 7%), ARIA-H (LEQEMBI: 14%; placebo: 8%), ARIA-E (LEQEMBI: 13%; placebo: 2%), headache (LEQEMBI: 11%; placebo: 8%), superficial siderosis of central nervous system (LEQEMBI: 6%; placebo: 3%), rash (LEQEMBI: 6%; placebo: 4%), and nausea/vomiting (LEQEMBI: 6%; placebo: 4%)1
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Safety profile of LEQEMBI IQLIK for maintenance treatment was similar to LEQEMBI infusion. Patients who received LEQEMBI IQLIK experienced localized and systemic (less frequent) injection-related reactions (mild to moderate in severity)1
Imaging requirements and genetic testing recommendations are in place to help you assess and manage ARIA risk1
ApoE, apolipoprotein E; ARIA-E, amyloid-related imaging abnormalities-edema; ARIA-H, amyloid-related imaging abnormalities-hemosiderin deposition; MRI, magnetic resonance imaging.
Use the LEQEMBI MRI and infusion schedule to help monitor for ARIAThe incidence of ARIA decreased after 12 months as patients continued therapy with LEQEMBI4
Clarity AD Core period and LTE: Rates of ARIA-E and ARIA-H by years*4
*Infusion only data.4
Cutoff: March 31, 2025.4
The LTE study is ongoing.5
LTE, long-term extension.
ARIA rates vary across ApoE ε4 carrier status1,2
The incidence of ARIA was lower in ApoE ε4 heterozygotes and noncarriers than in homozygotes
Patients treated with LEQEMBI ApoE ε4 status
(% patients)
Any ARIA
ARIA-H
ARIA-E
Symptomatic ARIA-E
Noncarriers
31% (278/898)
13% LEQEMBI
vs 4% placebo
12% LEQEMBI
vs 4% placebo
5% LEQEMBI
vs 0% placebo
1% LEQEMBI
Heterozygotes
53% (479/898)
19% LEQEMBI
vs 9% placebo
14% LEQEMBI
vs 9% placebo
11% LEQEMBI
vs 2% placebo
2% LEQEMBI
Homozygotes
16% (141/898)
45% LEQEMBI
vs 22% placebo
39% LEQEMBI
vs 21% placebo
33% LEQEMBI
vs 4% placebo
9% LEQEMBI
Patients treated with LEQEMBI ApoE ε4 status
(% patients)
Noncarriers
31% (278/898)
Heterozygotes
53% (479/898)
Homozygotes
16% (141/898)
Any ARIA
13% LEQEMBI
vs 4% placebo
19% LEQEMBI
vs 9% placebo
45% LEQEMBI
vs 22% placebo
ARIA-H
12% LEQEMBI
vs 4% placebo
14% LEQEMBI
vs 9% placebo
39% LEQEMBI
vs 21% placebo
ARIA-E
5% LEQEMBI
vs 0% placebo
11% LEQEMBI
vs 2% placebo
33% LEQEMBI
vs 4% placebo
Symptomatic ARIA-E
1% LEQEMBI
2% LEQEMBI
9% LEQEMBI
Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA.
Individualizing risk assessments for ARIA1
When deciding to initiate treatment with LEQEMBI, consider the potential risk of serious adverse events associated with ARIA and the benefit of LEQEMBI for the treatment of AD
Increased risk of ARIA in ApoE ε4 homozygotes
- Patients who are ApoE ε4 homozygotes (16% of Study 2) have a higher incidence of ARIA, including symptomatic and serious ARIA, compared with heterozygotes and noncarriers
Additional risk factors
- The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy, which has an increased risk for intracerebral hemorrhage
- Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy
Concomitant medications
- Most exposures to an antithrombotic medication were to aspirin
- Antithrombotic medications taken with LEQEMBI did not increase the risk of ARIA
- Intracerebral hemorrhage occurred in 0.9% (3/328) of patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event compared with 0.6% (3/545) of those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared with none in patients on placebo
- Because intracerebral hemorrhages >1 cm in diameter have been observed in patients taking LEQEMBI, 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 LEQEMBI
- Baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) was allowed in Study 2 if the patient was on a stable dose
Assess and Monitor ARIA Risk Flashcard
A quick guide to help you manage ARIA in your patients
Rates of ARIA with concurrent antiplatelet or anticoagulant use relative to LEQEMBI alone6
| antiplatelet or anticoagulant | LEQEMBI | ||
|---|---|---|---|
| ARIA-E with concurrent ARIA-H % (n/N) |
ARIA-H (microhemorrhage or superficial
siderosis) % (n/N) |
Intracerebral hemorrhage % (n/N) |
|
| No antiplatelet or anticoagulation at any time | 13.6 (74/545) |
17.1 (93/545) |
0.6 (3/545) |
| Event post any antiplatelet (aspirin or non-aspirin) |
11.1 (30/271) |
16.2 (44/271) |
0.4 (1/271) |
| Event post any anticoagulation (alone or with antiplatelet) |
5.1 (4/79) |
13.9 (11/79) |
2.5* (2/79) |
Limitations: Exploratory subgroup analyses with a small sample size; therefore, no conclusions can be drawn.
*Includes 1 case on placebo and 1 case on LEQEMBI with intracerebral hemorrhage >30 days after discontinuing study medication.6
Dosing interruptions for patients who experience ARIA1
Recommendations for dosing interruptions for patients with ARIA-E1
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Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity
| ARIA-E severity on MRI | |||
|---|---|---|---|
| Clinical symptom severity* | Mild | Moderate | Severe |
| Asymptomatic | May continue dosing | Suspend dosing† | Suspend dosing† |
| Mild | May continue dosing based on clinical judgment | ||
| Moderate or severe | Suspend dosing† | ||
*Mild: Discomfort noticed, but no disruption of normal daily activity. Moderate: Discomfort sufficient to reduce or affect normal daily activity. Severe: Incapacitating, with inability to work or to perform normal daily activity.1
†Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment.1
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Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E1
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There is no experience in patients who continued dosing through symptomatic ARIA-E or through asymptomatic but radiographically severe ARIA-E. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E1
Recommendations for dosing interruptions for patients with ARIA-H1
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Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity
| ARIA-H severity on MRI | |||
|---|---|---|---|
| Clinical symptom severity | Mild | Moderate | Severe |
| Asymptomatic | May continue dosing | Suspend dosing‡ | Suspend dosing§ |
| Symptomatic | Suspend dosing‡ | ||
‡Mild/moderate: Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification.1
§Severe: Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; use clinical judgment in considering whether to continue treatment or permanently discontinue LEQEMBI1
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In patients who develop intracerebral hemorrhage >1 cm in diameter during treatment with LEQEMBI, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment in considering whether to continue treatment after radiographic stabilization and resolution of symptoms or permanently discontinue LEQEMBI1
If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment. Dosing was able to be continued in most patients with ARIA.1