Gene Therapy: Lexeo Therapeutics’ LX1001 Shows Promise for APOE4-Associated Alzheimer’s Disease

Lexeo Therapeutics recently presented interim findings from its ongoing Phase 1/2 trial of LX1001, a gene therapy targeting Alzheimer’s disease in patients with two copies of the APOE4 allele, at the Clinical Trials on Alzheimer’s Disease (CTAD) conference. This allele is associated with a higher risk and faster progression of the disease.

Detailed Findings: Dose-Dependent APOE2 Expression and Biomarker Changes

LX1001 is designed to deliver the APOE2 gene into the central nervous system (CNS) of APOE4 homozygous patients, who otherwise produce only the APOE4 protein, linked to increased Alzheimer’s risk. The study included 15 patients across four dose cohorts, all with either mild cognitive impairment or mild-to-moderate Alzheimer’s. Findings reveal that:

• APOE2 Protein Expression: All participants showed increases in APOE2 protein in cerebrospinal fluid (CSF) that were both dose- and time-dependent, with durability observed out to 12 months in earlier cohorts.
• Tau Reduction: Key Alzheimer’s-related tau biomarkers, including CSF T-tau, P-tau181, P-tau217, and P-tau231, saw reductions in over two-thirds of participants when compared to baseline. Reductions in tau PET signal were observed at 6 months in 5 out of 6 participants evaluated.
• Amyloid Stability: The study showed minimal change in amyloid biomarkers (Aß42/40 ratio and amyloid PET imaging) across participants, indicating stabilization of amyloid pathology.

See also: Ups and Downs of Adenovirus and Adeno-Associated Virus Vectors in Gene Therapy

Safety Profile

LX1001 has demonstrated a favorable safety profile, with no reports of amyloid-related imaging abnormalities (ARIA), a concern in other Alzheimer’s treatments, particularly in APOE4 carriers. While four serious adverse events were noted, only one, mild-to-moderate sensorineural hearing loss, was possibly related to treatment and is under further review.

Patient Outcomes and Next Steps

• Best Responses in Moderate AD Participants: The patients with moderate Alzheimer’s disease (n=4) generally showed the strongest biomarker responses across tau and amyloid measures, hinting at a dose-response relationship.

Lexeo is now in discussions with the FDA regarding these initial results and anticipates sharing updates in 2025 as they continue with further cohort analysis and follow-ups. These findings contribute to the growing evidence on the potential of LX1001 as a gene therapy that may shift the underlying mechanisms of Alzheimer’s in high-risk populations.

Clinical trial: Gene Therapy for APOE4 Homozygote of Alzheimer's Disease

Topics: Clinical Trials