From the Guidelines
Lecanemab and donanemab are monoclonal antibodies that specifically target aggregated forms of amyloid-beta protein in the brain, binding to amyloid plaques and promoting their clearance through immune-mediated mechanisms, thereby addressing the underlying pathology of Alzheimer's disease. These medications work by directly targeting one of the primary pathological hallmarks of Alzheimer's disease - amyloid plaque deposition. According to the most recent evidence from 1, lecanemab was the first disease-modifying treatment to receive traditional approval from the US Food & Drug Administration (FDA), followed by donanemab, and these new treatments act by lowering brain amyloid, indicated for patients with early symptomatic AD.
The mechanism of action of these medications involves binding to the amyloid plaques that accumulate in the brains of Alzheimer's patients, facilitating their removal through immune-mediated clearance mechanisms, as described in 1 and 1. This approach is distinct from other treatments that target neurotransmitter systems, such as cholinesterase inhibitors, or those that target tau proteins, which represent a different pathological feature of Alzheimer's.
Key points about lecanemab and donanemab include:
- They are monoclonal antibodies targeting amyloid-beta protein
- They bind to amyloid plaques and facilitate their removal
- They are indicated for early symptomatic AD, including mild cognitive impairment or mild dementia caused by AD
- Biomarker confirmation of amyloid pathology is required before initiation, as stated in 1 and 1
- They have demonstrated the ability to reduce amyloid plaque burden, though debate continues about the magnitude of their clinical benefits, as discussed in 1 and 1.
Overall, the use of lecanemab and donanemab represents a significant advancement in the treatment of Alzheimer's disease, offering a disease-modifying approach that targets the underlying pathology of the disease.
From the FDA Drug Label
Lecanemab-irmb is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. LEQEMBI reduces amyloid beta plaques, as evaluated in Study 1 and Study 2 A reduction in plasma p-tau181 (Table 6), CSF p-tau181, and CSF t-tau was observed with LEQEMBI 10 mg/kg every two weeks compared to placebo The adjusted mean change from baseline in tau PET SUVR, relative to placebo, was in favor of LEQEMBI in the medial temporal (P<0.01), meta temporal (P<0.05), and temporal (P<0. 05) regions.
The mechanism of action of lecanemab in Alzheimer's disease is through its action as a monoclonal antibody directed against amyloid beta plaques, reducing their accumulation in the brain. Additionally, lecanemab has been shown to reduce plasma p-tau181, CSF p-tau181, and CSF t-tau levels, and to have a positive effect on tau PET SUVR in certain brain regions. There is no information provided about donanemab in the given drug labels 2 2.
From the Research
Mechanism of Action of Lecanemab and Donanemab
- Lecanemab is an amyloid beta (Aβ)-directed antibody that binds with high affinity to soluble Aβ protofibrils, which are more toxic to neurons than monomers or insoluble fibrils 3, 4.
- Donanemab is an IgG1 antibody directed at an N‑terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques 5.
- Both lecanemab and donanemab have been shown to reduce the accumulation of beta-amyloid in the brain, with lecanemab acting as a novel disease-modifying anti-amyloid-beta (Aβ) human monoclonal antibody 4, 6.
- Donanemab has been found to demonstrate a rapid, robust, and sustained reduction in brain amyloid plaque load, even after a single dose 5.
Effects on Amyloid-Beta Plaques and Tau Proteins
- Lecanemab has been shown to reduce the accumulation of beta-amyloid plaques in the brain, which is a hallmark of Alzheimer's disease 3, 4.
- Donanemab has also been found to reduce brain amyloid plaque load, with some patients achieving complete amyloid clearance within 24-36 weeks of treatment 5.
- There is no mention of the effects of lecanemab or donanemab on tau proteins in the provided studies.
Safety and Tolerability
- Lecanemab has been generally well-tolerated, with the most common adverse events being infusion-related reactions, amyloid-related imaging abnormalities (ARIA), and headache 3, 4.
- Donanemab has also been found to be generally well-tolerated, but may have higher rates of severe side effects, such as ARIA, which could lead to death 5, 7.