What is the incidence of cerebral hemorrhage with Donanemab (anti-amyloid beta antibody) treatment?

Incidence of Cerebral Hemorrhage with Donanemab Treatment

Donanemab treatment is associated with a cerebral hemorrhage incidence of approximately 13% in clinical trials, primarily manifesting as amyloid-related imaging abnormalities with microhemorrhages (ARIA-H). 1

Overview of Donanemab and ARIA

Donanemab (Kisunla) is an anti-amyloid beta monoclonal antibody that targets a modified form of deposited Aβ (pyroglutamate form) found exclusively in amyloid plaques. It received unanimous recommendation for traditional FDA approval in June 2024 2. Like other anti-amyloid therapies, donanemab is associated with amyloid-related imaging abnormalities (ARIA), which include:

1. ARIA-E: Edema or effusions
2. ARIA-H: Hemorrhagic manifestations (microhemorrhages and superficial siderosis)

Specific Incidence Data

In the pivotal TRAILBLAZER-ALZ 2 phase 3 trial:

• Microhemorrhages occurred in 6 out of 46 patients (13.0%) treated with donanemab 3
• Superficial siderosis events occurred in 2 out of 46 patients (4.3%) 3

In earlier studies:

• The phase 1b study reported cerebral microhemorrhage events in 6 patients (13.0%) and superficial siderosis events in 2 patients (4.3%) 3

Risk Factors for Cerebral Hemorrhage with Donanemab

Several factors increase the risk of cerebral hemorrhage with donanemab treatment:

• APOE ε4 carrier status: APOE ε4 carriers are 4 times more likely than non-carriers to experience ARIA-E events by 24 weeks, which can be associated with subsequent hemorrhage 4
• Pre-existing cerebral amyloid angiopathy: This condition predisposes patients to hemorrhagic complications 2
• Higher baseline amyloid plaque levels: Associated with greater risk of ARIA events 4

Clinical Implications and Monitoring

Given the risk of cerebral hemorrhage, the following monitoring approach is recommended:

1. Pre-treatment screening:

   • Brain MRI to assess for pre-existing microhemorrhages
   • APOE genotyping to identify high-risk patients 2

2. During treatment:

   • Regular MRI monitoring for early detection of ARIA
   • Close clinical monitoring for symptoms such as headache, confusion, or focal neurological deficits

3. Risk mitigation:

   • Consider dose adjustment or temporary discontinuation if ARIA is detected
   • Avoid concomitant anticoagulant medications when possible 2

Comparison to Other Anti-Amyloid Therapies

The incidence of cerebral hemorrhage with donanemab appears comparable to other anti-amyloid antibodies in this class:

• Lecanemab and aducanumab have similar ARIA-H profiles
• The mechanism of hemorrhage is likely related to the removal of amyloid from vessel walls, potentially compromising vascular integrity 2

Conclusion

The 13% incidence of cerebral microhemorrhages with donanemab treatment represents a significant clinical consideration when weighing the benefits and risks of therapy. Careful patient selection, monitoring, and management of ARIA events are essential to optimize the safety profile of this treatment.