The Science Behind Donanemab (Kisunla)
Alzheimer's disease is marked by the buildup of beta-amyloid plaques and tau protein tangles in the brain. Unlike older treatments that only addressed symptoms, donanemab is a newer therapy that targets the amyloid pathology. It's a humanized IgG1 monoclonal antibody designed to bind specifically to an altered form of beta-amyloid in established plaques.
Clearing Amyloid: The Mechanism of Action
When donanemab binds to the modified amyloid, it signals the brain's immune cells (microglia) to remove the plaques. This action helps reduce amyloid in the brain and can slow the decline in cognition and function. A notable feature of donanemab treatment is its limited duration; treatment can stop once amyloid plaques are reduced to minimal levels, confirmed by a PET scan. This could potentially lower costs and the need for frequent infusions.
Clinical Evidence for Efficacy
The efficacy of donanemab was demonstrated in clinical trials, including the Phase 3 TRAILBLAZER-ALZ 2 study with over 1,700 participants with early symptomatic Alzheimer's. The study showed that donanemab slowed cognitive and functional decline by up to 35% in a key participant group over 76 weeks. For the entire trial population, the slowdown was 22%. Further analysis indicated even greater benefits in patients treated earlier and those under 75. Data also showed that nearly half of patients treated with donanemab had no clinical progression after one year, with sustained benefits observed for up to three years in long-term extension data.
How Donanemab Compares to Other Treatments
Donanemab is one of several anti-amyloid therapies for early Alzheimer's. Lecanemab (Leqembi) is another FDA-approved monoclonal antibody that reduces amyloid plaques. The table below highlights some key differences:
| Feature | Kisunla (Donanemab) | Leqembi (Lecanemab) |
|---|---|---|
| Manufacturer | Eli Lilly | Eisai and Biogen |
| Mechanism | Targets N3pG-modified amyloid in established plaques | Targets soluble amyloid-beta protofibrils, precursors to plaques |
| Dosing Frequency | Monthly intravenous infusion | Bi-weekly intravenous infusion (in some cases) |
| Treatment Duration | Can be stopped once amyloid plaque clearance is confirmed | Requires ongoing treatment |
| ARIA Risk | Higher rate of ARIA (brain swelling/bleeding) observed in trials | Lower rate of ARIA compared to donanemab |
Important Safety Information and Risks
A significant risk associated with donanemab is Amyloid-Related Imaging Abnormalities (ARIA), which includes brain swelling (ARIA-E) and small areas of bleeding (ARIA-H). While ARIA is often without symptoms, it can cause severe issues like headaches, confusion, dizziness, seizures, and visual changes, and in rare cases, can be fatal.
Risk Factors and Monitoring
Having two copies of the APOE4 gene significantly increases the risk of ARIA. The FDA has issued a boxed warning about this, recommending genetic testing before starting treatment. Patients taking blood thinners may also have a higher risk of brain bleeding. To monitor for ARIA, regular MRI scans are necessary before and throughout treatment.
Infusion-Related Reactions
Some patients may experience reactions during the infusion, especially with early doses. Symptoms like headache, chills, nausea, and changes in blood pressure are possible and are usually managed by adjusting the infusion speed or using pre-medications.
Eligibility Criteria and Administration
To be eligible for donanemab, patients must meet specific criteria from clinical trials:
- Diagnosis of early symptomatic Alzheimer's (mild cognitive impairment or mild dementia).
- Confirmed presence of amyloid plaques through a PET scan or CSF test.
- No other neurological conditions affecting cognition.
- Ability to undergo regular MRI scans.
The treatment involves a 30-minute monthly IV infusion. It's important to note that the drug is for early-stage disease, so most individuals with late-stage Alzheimer's are not eligible.
Conclusion
Kisunla (donanemab) marks a significant step in treating Alzheimer's, offering a therapy that can slow cognitive decline in early-stage patients by clearing amyloid plaques. Its unique limited-duration dosing, guided by biomarker levels, is also noteworthy. However, the treatment carries risks, particularly ARIA, which requires careful patient selection, genetic testing, and ongoing MRI monitoring. Deciding on donanemab should be done in close consultation with a healthcare provider who can evaluate the benefits against the risks and monitoring needs. While not a cure, donanemab provides new hope in the fight against Alzheimer's.
For more detailed clinical trial information, ClinicalTrials.gov is an authoritative source.
