Lexeo Therapeutics (LXEO) Study Update summary

Study background and rationale

• LX1001 is a gene therapy delivering the protective APOE2 allele to APOE4 homozygotes with Alzheimer's disease using an AAVrh10 vector administered into the CNS.

• APOE4 homozygotes have a significantly higher risk, earlier onset, and faster decline in Alzheimer's, representing about 15% of cases and 900,000 US patients.

• APOE4 drives Alzheimer's via neurotoxicity, amyloid and tau pathology, and neuroinflammation, while APOE2 is hypothesized to dilute APOE4 toxicity and provide neuroprotection.

• The study targets a high unmet need population, as current therapies are less effective and riskier for APOE4 homozygotes.

• LX1001 is the first clinical-stage gene therapy addressing the genetic cause of APOE4-associated Alzheimer's with a single administration approach.

Study design and patient population

• Phase 1/2, 52-week, open-label, dose-ranging trial enrolled 15 APOE4 homozygotes with mild cognitive impairment to moderate dementia across four ascending dose cohorts.

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

• Baseline: mean age 65.3 years, 80% female, all white, 47% MCI, 13% mild, 40% moderate dementia; cohorts 1 and 3 included more advanced disease.

• High amyloid and tau burden observed at baseline; cognitive and PET measures varied by cohort.

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

Safety and tolerability

• LX1001 was well tolerated across all dose cohorts, with no reports of ARIA, a key safety concern in this population.

• Four serious adverse events occurred; three were unrelated, and one case of mild to moderate sensorineural hearing loss was possibly related but showed improvement.

• Transient CSF pleocytosis was observed in 12 participants.

• No safety signals were observed in cognitive testing scales, and rates of progression were consistent with expectations for early Alzheimer's with high tau burden.

• No new safety signals identified to date; most adverse events were unrelated to treatment.