CTAD 2025: Lecanemab Boosts CSF Aβ Protofibrils, Confirming Target Engagement and Pharmacodynamic Effect

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Eisai and Biogen announced new data confirming the pharmacological effect of lecanemab (LEQEMBI®) on amyloid-beta (Aβ) protofibrils (PF) in cerebrospinal fluid (CSF). The findings, from the first large-scale clinical study to measure lecanemab’s effect on PF in CSF, enable further understanding of how lecanemab slows Alzheimer disease (AD) progression by demonstrating a direct measure of its effect on neurotoxic protofibrils.

The findings were presented at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, being held December 1-4, 2025, in San Diego, California.

Key Quantitative Results from the Clarity AD Sub-Study

Data were analyzed from a CSF sub-cohort (n=410) of the Phase III Clarity AD study, which quantified total PF concentration in CSF using an ultrasensitive assay. The primary analysis demonstrated a statistically significant, albeit paradoxical, increase in CSF PF concentrations in the lecanemab arm compared to placebo at 12 months (p=0.0126).

A comparison of changes from baseline revealed the following:

• Placebo Group: Total CSF PF concentration increased by 19% at 12 months and 29% at 18 months.
• Lecanemab Group: Total CSF PF concentration increased by 59% at 12 months and 45% at 18 months.

Interpretation of Pharmacodynamic Effects

The observed increase in total CSF PF concentration in patients treated with lecanemab is interpreted as direct evidence of a pharmacodynamic effect. This seemingly counterintuitive result indicates successful target engagement and mobilization of neurotoxic PF from the brain parenchyma, where they cause harm, into the CSF for clearance. The data suggest that lecanemab binds to PF and facilitates its mobilization from the vicinity of Aβ plaques within the brain parenchyma into the CSF.

Further analysis revealed a key difference in biomarker correlations between the two groups. In the placebo group, a statistically significant correlation was found between changes in CSF PF and changes in biomarkers of neurodegeneration (total tau, neurogranin) and tau pathology (p-tau181, MTBR-tau243). This correlation was absent in the group treated with lecanemab. This decoupling suggests that while PF are being mobilized into the CSF, lecanemab's binding neutralizes their downstream neurotoxic effects on tau pathology and neuronal injury.

Broader Clinical Context and Significance

Alzheimer's disease is characterized as a progressive disease driven by a continuous neurotoxic process involving PF that begins before amyloid plaque accumulation and continues even after plaque is removed.¹,²,³ The data position LEQEMBI as a unique therapeutic that fights AD by targeting both protofibrils and amyloid plaque, thereby impacting downstream tau pathology.

These findings reinforce lecanemab as the only AD treatment that targets neurotoxic PF and Aβ plaques, resulting in slower tau tangle accumulation on PET imaging.

Background on Aβ Protofibrils and Lecanemab

The Role of Aβ Protofibrils in AD

Protofibrils are considered the most toxic species of Aβ and play a major role in the neuronal damage and cognitive decline characteristic of AD. They contribute to pathology through multiple mechanisms, including increasing the formation of insoluble Aβ plaques and directly damaging signaling between neurons and other cells.³ It is hypothesized that reducing protofibrils may mitigate neuronal damage and prevent the progression of AD.⁴

References

1. Iwatsubo T, Irizarry M, van Dyck C, Sabbagh M, Bateman RJ, Cohen S. Clarity AD: a phase 3 placebo-controlled, double-blind, parallel-group, 18-month study evaluating lecanemab in early Alzheimer's disease. Presented at: CTAD Conference; November 29-December 2, 2022; San Francisco, CA.
2. Hampel H, Hardy J, Blennow K, et al. The amyloid-β pathway in Alzheimer's disease. Mol Psychiatry. 2021;26(10):5481-5503.
3. Amin L, Harris DA. Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers. Nat Commun. 2021;12(1):3451. doi:10.1038/s41467-021-23507-z.
4. Ono K, Tsuji M. Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer’s Disease. Int J Mol Sci. 2020;21(3):952. doi:10.3390/ijms21030952. PMID: 32023927; PMCID: PMC7037706.
5. Horie K, Barthélemy NR, Sato C, et al. CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease. Nat Med. 2023;29(8):1954-1963. doi:10.1038/s41591-023-02443-z.