Lexeo Therapeutics (LXEO) Study Update summary

Background and Disease Overview

• Friedreich's ataxia (FA) is a rare, progressive disorder caused by frataxin (FXN) gene mutations, leading to neurological and cardiac complications, with cardiomyopathy as the leading cause of death in up to 80% of patients.

• FXN deficiency impairs mitochondrial function in cardiomyocytes, resulting in cardiac hypertrophy, cell death, and high mortality.

• No currently approved therapies exist for FA cardiomyopathy; omaveloxolone is approved for neurological symptoms but not cardiac complications.

• Cardiac biomarkers such as LVMI, wall thickness, and hs-troponin I are validated predictors of outcomes in FA and other cardiomyopathies.

• Preclinical models suggest even modest increases in frataxin (as low as 5% of normal) may yield clinical benefit.

Mechanism and Regulatory Status

• LX2006 is an AAVrh10-based gene therapy designed to deliver a functional frataxin gene to the heart, aiming to restore mitochondrial function and target the root cause of FA cardiomyopathy.

• FDA has granted Rare Pediatric Disease, Fast Track, and Orphan Drug designations for LX2006 in FA cardiomyopathy.

Study Design and Participant Characteristics

• Two ongoing Phase 1/2 trials: Lexeo-sponsored SUNRISE-FA and Weill Cornell Medicine investigator-initiated, both using identical LX2006 drug product and similar protocols.

• Open-label, 52-week studies with long-term follow-up, enrolling adults (18–50 years) with genetically confirmed FA and evidence of cardiomyopathy, excluding those with significant neutralizing antibodies to AAVrh10.

• Key endpoints include safety, cardiac MRI, echocardiography, CPET, LVMI, lateral wall thickness, hs-troponin I, and frataxin expression (via LCMS and IHC in SUNRISE-FA).

• As of July 15, 2024, 13 participants have been dosed across both studies, with baseline characteristics reflecting typical FA cardiac phenotype; most are in their 20s–30s with abnormal cardiac parameters.

• Cardiac biopsies for frataxin expression are performed only in the SUNRISE-FA trial.