Donanemab, approved by the FDA for the treatment of early-stage symptomatic Alzheimer's disease, is a monoclonal antibody that works by clearing amyloid-beta plaques from the brain. While it offers the potential to slow cognitive and functional decline, like other anti-amyloid therapies, it also comes with a notable safety profile that requires careful management. The primary concern is amyloid-related imaging abnormalities (ARIA), but other adverse events, including infusion-related reactions, are also important to recognize.
Amyloid-Related Imaging Abnormalities (ARIA)
ARIA is the most significant adverse event associated with donanemab and is detected through regular magnetic resonance imaging (MRI) scans. ARIA includes two types of abnormalities: ARIA with edema or effusion (ARIA-E) and ARIA with microhemorrhages or hemosiderin deposition (ARIA-H).
ARIA-E (Brain Swelling)
ARIA-E involves temporary swelling in certain areas of the brain. In clinical trials, ARIA-E occurred in up to 24.4% of participants treated with donanemab, with a majority being mild to moderate in severity. In most cases, the swelling resolves on its own over time. While many patients with ARIA-E do not experience symptoms, some may.
Common symptoms of ARIA-E include:
- Headache
- Confusion or altered mental state
- Dizziness
- Nausea
- Gait disturbances or difficulty walking
- Visual changes
Serious symptoms, though rare, can include:
- Seizures
- Significant encephalopathy
- Focal neurological deficits that can mimic a stroke
ARIA-H (Brain Bleeding)
ARIA-H involves small spots of bleeding in or on the brain's surface, which are detected on MRI scans. This form of ARIA occurred in over 31% of donanemab-treated patients in clinical trials, but a portion of this is also seen in placebo groups. Most ARIA-H events are asymptomatic and resolve, but in rare cases, they can lead to more serious, life-threatening brain hemorrhages.
Infusion-Related Reactions
Since donanemab is administered via intravenous infusion every four weeks, infusion-related reactions (IRRs) are another common side effect. These reactions most frequently occur during the first few infusions and typically subside over time. Healthcare providers monitor patients closely during and after infusions to manage these reactions.
Symptoms of an infusion-related reaction may include:
- Chills
- Fever
- Nausea or vomiting
- Headache
- Redness or flushing of the skin
- Dizziness
- Difficulty breathing or chest tightness
- Sweating
- Changes in blood pressure
In some cases, pretreatment with medications like antihistamines, acetaminophen, or corticosteroids may be used to help prevent future reactions.
Other Adverse Effects
Beyond ARIA and IRRs, other general adverse events have been reported in donanemab trials, though often at a lower incidence than placebo. These can include:
- Falls
- Hypersensitivity reactions, including rare cases of anaphylaxis
- Back pain and joint pain
- Cognitive symptoms like confusion, which can also be a sign of ARIA
- Elevated liver enzymes, though this has not been linked to significant liver injury
Risk Factors and Monitoring
The APOE ε4 Gene
Genetic predisposition plays a significant role in determining the risk of ARIA with donanemab. Carriers of the apolipoprotein E ε4 (APOE4) allele, particularly those who are homozygous (having two copies), have a higher incidence of ARIA, including symptomatic and severe cases. For this reason, genetic testing for the APOE4 status is recommended before starting treatment to inform the risk assessment. The FDA has included a boxed warning for donanemab use in APOE4 homozygotes due to this increased risk.
MRI Monitoring Schedule
Due to the risks of ARIA, a strict MRI monitoring schedule is required for patients on donanemab.
- Before treatment: A baseline MRI is necessary to assess for pre-existing conditions that might increase risk.
- During treatment: Regular surveillance MRIs are performed before the 2nd, 3rd, 4th, and 7th infusions. Additional scans may be considered for higher-risk individuals.
- With symptoms: An urgent MRI is required if a patient shows any new neurological symptoms potentially related to ARIA.
Other Risk Considerations
Patients on blood thinners (anticoagulants or antithrombotic medications) may have an increased risk of brain bleeding while on donanemab. Healthcare providers must carefully weigh these risks, and in many cases, anticoagulants are a contraindication for treatment. Severe white matter disease or a high number of microbleeds on the baseline MRI can also increase ARIA risk.
Donanemab vs. Lecanemab: Comparison of Side Effects
| Feature | Donanemab (Kisunla) | Lecanemab (Leqembi) |
|---|---|---|
| Mechanism | Targets N-terminally truncated forms of amyloid-beta in plaques. | Targets soluble amyloid-beta protofibrils. |
| Incidence of ARIA | Generally higher than lecanemab. Reported ARIA-E rates around 24% and ARIA-H around 31% in placebo-controlled trials. | Lower than donanemab. Reported ARIA-E rates around 12.6% and total ARIA around 21% in Phase 3 trial. |
| Infusion Reactions | Less frequent and often milder than lecanemab, though still occur. | Can be more common, particularly with initial infusions, causing flu-like symptoms. |
| APOE4 Risk | Higher risk of ARIA for carriers, especially homozygotes (boxed warning). | Also increases ARIA risk, but some evidence suggests less risk for APOE4 homozygotes than with donanemab. |
| Monitoring | Requires a set schedule of MRI scans, particularly early in treatment. | Requires a similar regimen of MRI monitoring. |
| Treatment Duration | May be discontinued once sufficient amyloid clearance is achieved. | Typically a long-term treatment. |
Management of Side Effects
If a patient experiences symptoms suggestive of ARIA or an infusion reaction, the healthcare team will take several steps. For IRRs, the infusion may be slowed or stopped, and supportive care is provided. For suspected ARIA, treatment may be temporarily suspended or permanently discontinued depending on the severity of the imaging abnormalities and associated symptoms. For example, radiographically severe or symptomatic ARIA typically requires discontinuation. Monitoring with repeated MRI scans is crucial to track the resolution or stabilization of ARIA events.
Conclusion
The most prominent and serious risk associated with donanemab is the development of amyloid-related imaging abnormalities (ARIA), which can involve brain swelling or bleeding. While often asymptomatic, ARIA can lead to significant neurological symptoms and, rarely, be life-threatening. Other side effects include common infusion-related reactions, typically during early treatments. A patient's APOE4 genetic status is a major factor influencing the risk level, and careful monitoring with regular MRI scans is mandatory for all patients. The decision to use donanemab involves a careful risk-benefit discussion between the patient, their caregivers, and their healthcare team, considering the potential to slow Alzheimer's progression against these significant risks.
For more detailed information, consult the official FDA prescribing information for Kisunla (donanemab), available on the Eli Lilly website.
