The landscape of Alzheimer's disease treatment has undergone a significant transformation with the recent approval of disease-modifying therapies. For years, treatments only addressed the symptoms of cognitive decline, but never the root cause of the neurodegenerative process. The emergence of monoclonal antibodies like lecanemab and donanemab marks a pivotal shift, offering a new approach by actively clearing the amyloid-beta plaques that are a hallmark of the disease.
Lecanemab (Leqembi)
Developed by Eisai and Biogen, lecanemab (marketed as Leqembi) was granted traditional FDA approval in July 2023. It was the first amyloid-beta directed antibody to receive full approval for the treatment of early Alzheimer's disease, following an earlier accelerated approval based on its ability to reduce amyloid plaques.
Lecanemab functions by targeting and binding to soluble aggregated amyloid-beta species, particularly protofibrils. Protofibrils are believed to be the most neurotoxic form of amyloid, and by binding to them, lecanemab marks them for removal by the body's immune system.
Clinical trials, including the Phase 3 CLARITY-AD study, demonstrated that lecanemab could moderately slow cognitive and functional decline in patients with early Alzheimer's disease. The treatment showed a 27% reduction in the rate of decline over an 18-month period compared to a placebo. Lecanemab is administered as an intravenous infusion every two weeks.
Donanemab (Kisunla)
Following the approval of lecanemab, Eli Lilly's donanemab (marketed as Kisunla) received traditional FDA approval in July 2024 for the treatment of early symptomatic Alzheimer's disease.
Unlike lecanemab, donanemab specifically targets a modified form of amyloid-beta called N3pG that is found in amyloid plaques. This targeted approach allows donanemab to actively clear established amyloid plaques from the brain.
The Phase 3 TRAILBLAZER-ALZ 2 trial demonstrated donanemab's efficacy, showing that it slowed cognitive decline by 35% over 18 months compared to placebo in participants with early-stage Alzheimer's and low-to-medium tau pathology. An interesting feature of donanemab is that treatment can potentially be stopped once amyloid levels in the brain are sufficiently cleared. The drug is administered as a monthly intravenous infusion.
Key Considerations for Treatment
For both lecanemab and donanemab, patient eligibility is a critical factor. The treatments are indicated for people in the early stages of Alzheimer's—those with mild cognitive impairment or mild dementia. A key prerequisite is confirmation of amyloid plaques in the brain, which is typically done through amyloid PET scans or cerebrospinal fluid analysis. These drugs have not been studied or approved for use in individuals with more advanced Alzheimer's.
Potential Side Effects
One of the most significant risks associated with anti-amyloid therapies is amyloid-related imaging abnormalities (ARIA). ARIA can appear in two forms:
- ARIA-E (edema): Brain swelling or fluid buildup.
- ARIA-H (hemorrhage): Small spots of bleeding in the brain.
While ARIA is often asymptomatic, it can cause symptoms such as headache, dizziness, nausea, confusion, and vision changes. In rare cases, it can be serious or life-threatening. The risk of ARIA is higher for individuals who carry the APOE ε4 gene, a known genetic risk factor for Alzheimer's. Regular MRI monitoring is required during treatment to check for these abnormalities. Other common side effects may include infusion-related reactions, headache, and flu-like symptoms.
Lecanemab vs. Donanemab: A Comparison
| Feature | Lecanemab (Leqembi) | Donanemab (Kisunla) |
|---|---|---|
| Manufacturer | Eisai / Biogen | Eli Lilly |
| Approval | Traditional Approval (July 2023) | Traditional Approval (July 2024) |
| Target | Soluble amyloid-beta protofibrils | Plaque-specific N3pG beta-amyloid |
| Administration | Intravenous (IV) infusion every two weeks | Intravenous (IV) infusion every four weeks |
| Trial Results | 27% reduction in cognitive decline over 18 months | Up to 35% slowing of cognitive decline over 18 months |
| Treatment Duration | Long-term, ongoing treatment | Potentially discontinued after achieving amyloid plaque clearance |
| Side Effects | ARIA (edema and hemorrhage), infusion reactions, headache | ARIA (edema and hemorrhage), infusion reactions, headache |
| Cost (approx. per year) | ~$26,500 | ~$32,000 |
The Role of Aducanumab (Aduhelm)
It is important to note that a third anti-amyloid drug, aducanumab (Aduhelm), received accelerated FDA approval in 2021. However, its approval was highly controversial due to mixed efficacy results in its clinical trials. The drugmaker later removed it from the market in early 2024 to focus on other Alzheimer's therapies. This history highlights the evolving scientific understanding of amyloid-targeting treatments and the high standards of evidence required for traditional approval.
Conclusion
The FDA approval of lecanemab and donanemab represents a monumental step forward in Alzheimer's treatment. For the first time, clinicians have tools to directly intervene in the disease's underlying pathology, offering a potential to slow progression and give patients and their families more time with retained cognitive function. However, these treatments are not cures and come with significant risks, logistical commitments, and cost implications. The decision to pursue anti-amyloid therapy requires careful consideration and discussion between patients, families, and their healthcare providers, based on a confirmed diagnosis and individual risk factors. As research continues to refine therapeutic approaches and explore new targets, lecanemab and donanemab solidify their place as pioneering treatments that have redefined the therapeutic landscape for Alzheimer's disease.
