Lexeo Therapeutics (LXEO) Study Update summary

Study background and rationale

• APOE4/4 homozygotes have a ~15x increased risk of Alzheimer's, earlier onset, and faster decline, representing ~15% of Alzheimer's cases and 900,000 US patients.

• APOE4 drives Alzheimer's via multiple pathways, including neurotoxicity, amyloid and tau pathology, and neuroinflammation.

• APOE2 is protective; increasing APOE2 in APOE4/4 patients may dilute APOE4 toxicity and slow disease progression.

Study design and patient population

• Phase 1/2 open-label, dose-ranging trial enrolled 15 APOE4 homozygotes with mild cognitive impairment to moderate Alzheimer's across four dose cohorts.

• Inclusion: ≥50 years, APOE4 homozygotes, MCI to moderate dementia, amyloid and CSF biomarkers consistent with Alzheimer's.

• Mean age 65.3 years; 80% female; all white; 47% MCI, 13% mild, 40% moderate dementia.

• Moderate dementia patients were mainly in cohorts one and three, with higher baseline tau and amyloid burden.

• 12-month safety and biomarker data were shared for cohorts one to three; six-month data for cohort four.

LX1001 therapy and objectives

• LX1001 is a gene therapy delivering APOE2 to the CNS of APOE4/4 Alzheimer's patients using an AAVrh10 vector.

• Primary endpoint: safety; secondary endpoints: APOE2 CSF expression, amyloid/tau biomarkers, PET imaging, cognitive testing.

• LX1001 is designed to deliver the protective APOE2 allele to the CNS, potentially slowing or halting disease progression.

• LX1001 has received FDA Fast Track designation.