Lexeo Therapeutics Reports Positive Interim Data for LX1001 Alzheimer's Gene Therapy at CTAD Conference

Lexeo Therapeutics, Inc., a company focused on advanced genetic medicine, has shared encouraging interim findings from their Phase 1/2 study of LX1001, aimed at treating APOE4-associated Alzheimer’s disease. This announcement was made at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, reflecting a significant step in Alzheimer’s research.

The study highlighted a dose-dependent increase in the expression of neuroprotective APOE2 protein among all participants. Crucially, the durability of this effect was observed up to 12 months. Furthermore, there were consistent reductions in cerebrospinal fluid (CSF) tau biomarkers and tau PET scans in the majority of participants. Importantly, LX1001 was well tolerated across all dose cohorts, with no reports of amyloid-related imaging abnormalities (ARIA).

Alzheimer's disease presents a major challenge, especially for individuals with the APOE4 gene variant, who have a 15-fold increased risk compared to the general population. They also experience faster disease progression and higher susceptibility to ARIA with current treatments. Dr. Kim Johnson from Duke University, a lead investigator in the study, emphasized the promising potential of LX1001 for this high-risk group. The data suggest that the drug could be an effective treatment option, with observed reductions in tau biomarkers indicating a potential impact on Alzheimer’s pathology.

LX1001 is a gene therapy candidate based on AAVrh10, designed to introduce the protective APOE2 allele into the central nervous system of patients who are homozygous for APOE4. APOE2 is linked with a significantly lower risk and slower progression of Alzheimer’s disease. The Phase 1/2 study, which concluded enrollment by the end of 2023, involved fifteen patients with mild cognitive impairment or mild to moderate Alzheimer’s. They received varying doses of LX1001, and the study’s primary focus was on safety and tolerability, while secondary outcomes included changes in CSF APOE2 protein expression and tau and amyloid biomarkers.

Dr. Sandi See Tai, Chief Development Officer at Lexeo Therapeutics, remarked on the significance of these findings. Given the rapid progression of Alzheimer’s in this population, the data underscore the therapeutic potential of APOE2 delivery. This approach can influence multiple mechanisms of the disease, potentially altering its course in a meaningful way.

The interim data provide several key insights:
- There was a measurable increase in CSF APOE2 protein expression in all participants, with dose- and time-dependent increases observed.
- Amyloid pathology was stabilized in most participants, with only minimal changes from baseline in the Aß42/40 ratio and amyloid PET scans.
- Consistent reductions were noted across various CSF tau biomarkers, including T-tau, P-tau181, P-tau217, and P-tau231, in over two-thirds of participants relative to baseline.
- Six-month data showed reductions in global tau PET SUVR in five out of six participants, with regional SUVR reductions in a majority across all brain regions.
- Participants with moderate Alzheimer’s disease generally demonstrated the most improvement across various biomarker endpoints.
- There were four serious adverse events reported, with three deemed unrelated to the treatment and one case of mild-moderate sensorineural hearing loss potentially related, pending further audiometric testing.

Lexeo Therapeutics has initiated discussions with the FDA regarding these findings and plans to provide an update on regulatory interactions and further development of LX1001 in 2025.

LX1001 represents a novel genetic approach to treating APOE4-homozygous Alzheimer’s disease. The protective APOE2 gene’s expression within the central nervous system of APOE4 homozygous patients may slow or halt disease progression. The FDA has granted Fast Track designation to LX1001, reflecting its potential to meet an urgent medical need.

Lexeo Therapeutics is a clinical-stage company based in New York City, dedicated to transforming healthcare through pioneering scientific approaches to genetically defined cardiovascular diseases and APOE4-associated Alzheimer’s disease. They aim to advance a pipeline of innovative treatments through a stepwise development approach, leveraging early functional and biomarker data.