Lexeo Therapeutics has announced positive interim results from its Phase I/II study of LX1001, a gene therapy designed to treat Alzheimer's disease in patients carrying the APOE4 genetic variant. This therapy aims to address a critical unmet need, as this patient population faces limited treatment options due to the high risk of amyloid-related imaging abnormalities (ARIA) associated with existing antibody treatments.
Targeting APOE4-Related Alzheimer's
The APOE gene plays a significant role in Alzheimer's risk. While the APOE3 allele is most common and confers average risk, the APOE4 allele, present in 15-25% of the population, significantly increases the likelihood of developing Alzheimer's. Individuals with two copies of APOE4 are approximately 15 times more likely to develop Alzheimer's disease and experience faster disease progression. Current treatments like Leqembi (lecanemab) and Kisunla (donanemab) are less suitable for these patients due to the elevated ARIA risk.
LX1001: Delivering the Protective APOE2 Allele
LX1001 is designed to deliver a copy of the protective APOE2 allele into the brain and nervous system of Alzheimer's patients with two copies of the APOE4 allele. The goal is that the APOE2 protein will help slow or even stop disease progression. The study involved 15 patients with mild to moderate Alzheimer's symptoms treated across four dose-ascending cohorts.
Interim Results: Safety and Efficacy Signals
The interim data revealed only one possible treatment-associated adverse event: mild-moderate sensorineural hearing loss at 12 months. APOE2 was detected in the cerebrospinal fluid of all patients, confirming successful gene delivery. Amyloid pathology stabilized in most participants, and reductions in tau protein levels were also observed in the majority of patients.
"In light of the rapid progression of Alzheimer’s disease in this population, these data highlight the therapeutic potential of delivering APOE2, which can impact multiple mechanisms of Alzheimer’s disease upstream of any specific pathway and thereby meaningfully alter the devastating course of this complex disease," said Sandi See Tai, chief development officer of Lexeo Therapeutics.
Future Directions: LX1021 and LX1020
Lexeo is also developing other gene therapies targeting Alzheimer's. LX1021 contains APOE2 with an additional mutation believed to offer further protection. LX1020 is a more complex therapy designed to deliver protective APOE2 while simultaneously suppressing APOE4. Both programs are currently in early stages of development.
