NEW YORK – Lexeo Therapeutics is discussing with the US Food and Drug Administration positive interim data from its Phase I/II trial of LX1001, an investigational gene therapy for treating Alzheimer's disease associated with APOE4 gene alterations.
New York-based Lexeo said earlier this week that it expects to provide an update on regulatory interactions and LX1001 development plans next year.
Lexeo's therapeutic strategy homes in on versions of the APOE gene that modulate Alzheimer's risk. Patients with two copies of the APOE4 allele have an eightfold to twelvefold greater risk of developing Alzheimer's than those that don't have this genotype. The APOE2 allele, however, is thought to confer a protective effect, and carriers of this allele tend to have a lower risk of developing the neurodegenerative disease and a slower disease progression if they do, compared to those with the APOE4/4 genotype.
LX1001 uses an adeno-associated virus rh10 vector to deliver the APOE2 allele to the central nervous system of patients with two copies of the APOE4 allele. Lexeo is hoping to show that such a gene therapy will slow disease progression in Alzheimer's patients.
In a presentation this week at the Clinical Trials on Alzheimer's Disease Conference in Madrid, Lexeo said that within the Phase I/II study, in which 15 patients with early Alzheimer's received the gene therapy at one of four doses, treatment with LX1001 led to dose-dependent increases in APOE2 protein expression for up to a year following therapy administration. Most patients also experienced improvements in tau biomarkers associated with Alzheimer's and stabilization of beta-amyloid pathology compared to baseline.
The gene therapy was tolerated well across the four cohorts, without any reports of amyloid-related imaging abnormalities (ARIA), an adverse event observed in patients taking some recently approved Alzheimer's drugs, namely monoclonal antibodies that target beta-amyloid plaque. The FDA-approved labels for anti-amyloid drugs like Eisai and Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab) carry a boxed warning regarding the higher risk of ARIA, which can cause brain hemorrhaging, in Alzheimer's patients carrying two copies of the APOE4 allele.
Four serious adverse events have been reported in the Phase I/II trial of LX1001 so far, one of which — mild to moderate sensorineural hearing loss — investigators determined was possibly related to the treatment.
"APOE4 homozygotes are approximately 15 times more likely to develop Alzheimer's disease than the general population, have faster disease progression, and have an increased risk of ARIA with currently available therapies that can cause serious complications," Kim Johnson, division chief of memory disorders within Duke University's neurology department and a principal investigator in the Phase I/II study, said in a statement. She noted that there have been no reports of ARIA in patients receiving LX1001 so far.