Gene Therapy LX1001 Showing Potential to Lower Tau Levels in Phase 1 Trial

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by Patricia Inacio, PhD |

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LX1001, a one-time gene therapy for Alzheimer’s disease being developed by Lexeo Therapeutics, raised levels of the protective APOE2 protein in the cerebrospinal fluid (CSF), early data from an ongoing Phase 1/2 trial shows.

Findings in a first patient group treated at low dose also showed the gene therapy reduced the levels of tau protein — a hallmark of Alzheimer’s. No serious adverse events have been reported, supporting the therapy’s safety.

The Phase 1/2 trial (NCT03634007), underway in Florida and New York, aims to recruit 15 Alzheimer’s patients, 50 or older, with two copies of the APOE4 gene and mild cognitive impairment or mild to moderate dementia due to the disease.

Eligible adults must also have abnormal amyloid protein deposits — called amyloid plaques — evident on brain scans and Alzheimer’s biomarkers in their cerebrospinal fluid, the liquid surrounding the brain and spinal cord. Contact information for those interested in learning more is available here.

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“Initial data have shown meaningful APOE2 target engagement and declines in cerebrospinal fluid biomarkers, which support our belief that LX1001 has therapeutic potential for APOE4-associated Alzheimer’s disease,” Jay A. Barth, MD, Lexeo’s executive vice president and chief medical officer, said in a press release.

LX1001 uses a harmless viral vector to deliver a version of the APOE gene, called APOE2, to cells in the central nervous system (the brain and spinal cord).

APOE2 is one of the three versions (alleles) of the APOE gene, the other two being APOE3 and APOE4. Every person inherits two copies of the APOE gene, one from each biological parent, and the combination received is associated with the risk of developing Alzheimer’s.

Broadly, the APOE2 allele is associated with a lower Alzheimer’s risk while the APOE4 allele is linked to an increased risk.

The open-label Phase 1/2 trial is testing three ascending doses — a low (5.0 x 1010 genome copies per mililiter, gc/ml), medium (1.6 x 10^11 gc/ml) and high dose (5.0 x 1011 gc/ml) — of LX1001 in patients with two APOE4 allele copies. Participants are assigned to one of these three dosing groups.

Its main goals are to assess LX1001’s safety profile and determine a maximum-tolerated dose (the highest dose that can be given without unacceptable safety risks). Secondary goals include evaluating the gene therapy’s effects on the APOE protein.

Data covering four patients in the low-dose group show that APOE2 protein levels in the CSF rose relative to the trial’s start (baseline measures). Two patients were followed for three months post-treatment and the other two for 12 months.

Tau protein levels in the CSF — both total tau and phosphorylated tau or pTau — declined in the two people with 12 months of follow-up data. Alzheimer’s is characterized by the formation of tangles of tau protein in the brain, with pTau being particularly prone to forming aggregates. These atypical clumps are thought to be toxic to brain cells, driving disease progression.

Early data from patients treated at medium dose and further findings in the low-dose group are expected by year’s end. Findings will be shared at a future medical conference.

The gene therapy was granted fast track designation by the U.S. Food and Drug Administration (FDA) in May 2021. The designation gives Lexeo, as the therapy’s developer, access to more frequent meetings with the FDA to support and speed the therapy’s development and to expedite its review.

“LX1001 is the lead program in our Alzheimer’s disease gene therapy portfolio. These encouraging data support our unique approach to target the genetics of Alzheimer’s disease with multiple gene therapy candidates,” said R. Nolan Townsend, CEO of Lexeo.

“There is an urgent need for new treatments for this devastating condition, and we are extremely grateful to patients, their families and caregivers, as well as investigators who are participating in the trial,” Barth added.