Pipeline

LX2006 is a gene therapy candidate designed to deliver a functional frataxin (FXN) gene for the treatment of Friedreich ataxia cardiomyopathy, or FA-CM. FA affects approximately 5,000 individuals in the United States, and approximately 15,000 individuals worldwide. FA-CM is the most common cause of mortality in individuals with FA.

LX2006 is currently being evaluated in individuals with FA-CM in the SUNRISE-FA 2 registrational trial as well as in two open-label trials: the Lexeo-sponsored SUNRISE-FA Phase 1/2 clinical trial (SUNRISE-FA) and the Weill Cornell Medicine investigator-initiated Phase 1A trial (Weill Cornell). Lexeo is also enrolling a prospective natural history study, CLARITY-FA. LX2006 clinical data have shown sustained or deepening improvements across both cardiac and neurologic measures of FA. The SUNRISE-FA 2 trial is designed to evaluate these benefits through measures of cardiac structure (left ventricular mass index) and neurological function (mFARS).

LX2006 has been granted Breakthrough Therapy, Regenerative Medicine Advanced Therapy (RMAT), Rare Pediatric Disease, Orphan Drug, and Fast Track designations by the FDA, admitted into the FDA CMC Development and Readiness Pilot (CDRP) program, and granted Orphan Medicinal Product Designation by the European Commission.

LX3010 is a clinical stage, oral combination therapy designed to increase frataxin expression while addressing mitochondrial function and oxidative stress through complementary mechanisms (HDAC inhibition and NRf2). Early clinical data includes an approximately 6-point improvement in mFARS scores at 16 weeks and a mean nine-fold increase in frataxin protein levels from baseline in muscle biopsies across 11 FA patients.

Lexeo is currently evaluating two preclinical programs for the treatment of Friedreich ataxia (FA). LX3030 is an oral, tissue-penetrant small molecule (sub-500Da) designed to increase production of endogenous frataxin in the central nervous system. This third-generation benzamide HDAC inhibitor builds on published clinical work demonstrating oral benzamide HDACs increase frataxin in FA patients by epigenetic modulation and acetylation of chromatin. Preclinical studies of LX3030 have demonstrated robust increases in frataxin, supporting continued evaluation of LX3030 as a differentiated oral therapy.

LX3050 is a recombinant human frataxin fused to a proprietary anti-TfR1 Fab, intended to directly replace the deficient frataxin protein and utilize a TfR1-targeting brain shuttle designed to cross the blood-brain barrier and increase delivery of frataxin to the brain. In vitro studies have demonstrated dose-responsive improvements in measures of mitochondrial function, providing early support for the program’s proposed mechanism.

Lexeo is evaluating additional therapeutic modalities for Friedreich ataxia (FA) to treat the multisystem manifestations of the disease. Research is currently underway to evaluate a discovery stage ASO Fab conjugate program designed to stabilize FXN mRNA and thereby increase translation of endogenous frataxin protein. Lexeo is also evaluating cerebellar-targeted sequential dosing of frataxin gene therapy, designed to be complementary to systemically administered LX2006. This research is evaluating both intra-cisternal administration as well as a novel, intravenously administered, blood-brain barrier crossing capsid that is expected to enable a less invasive route of administration to the central nervous system following initial systemic administration of LX2006.

LX2020 is a gene therapy candidate designed to deliver a functional PKP2 gene to cardiac muscle for the treatment of PKP2 arrhythmogenic cardiomyopathy, or PKP2-ACM. PKP2 mutations are associated with approximately 75% of all genetic cases of ACM, and are estimated to affect approximately 60,000 individuals in the United States. PKP2 mutations can cause replacement of heart muscle with fibrotic and fatty tissue and are associated with severe arrhythmias, cardiac dysfunction, and sudden cardiac death.

LX2020 is designed to increase desmosomal PKP2 protein levels, reassemble desmosomes, and restore myocardial cell function. LX2020 is currently being evaluated in an open-label, dose-ascending Phase I/II clinical trial (HEROIC-PKP2).

The FDA has granted Orphan Drug, Fast Track, and RMAT designations to LX2020 for the treatment of PKP2-ACM.

LX2021 is a gene therapy candidate we are developing to deliver a functional copy of the gene encoding connexin 43 (Cx43), a critical gap junction protein in the heart. It is being developed to treat a group of inherited cardiac muscle disorders associated with a high risk of sudden cardiac death. We believe restoring the Cx43 protein can potentially treat multiple genetic causes of arrhythmogenic cardiomyopathy (ACM) because the cardiac loss of Cx43 is a molecular deficit generally observed in all ACM patient populations.

Our LX2021 program is initially targeting desmoplakin, or DSP, cardiomyopathy, a distinct form of ACM as well as a certain form of dilated cardiomyopathy, impacting up to approximately 35,000 individuals in the United States.

LX2022 is a gene therapy candidate we are developing to deliver a functional TNNI3 gene to myocardial cells to treat a distinct form of hypertrophic cardiomyopathy (HCM) due to mutations in the TNNI3 gene. TNNI3 is a critical component of the thin filament of the sarcomere. Mutations in the TNNI3 gene often result in left ventricular hypertrophy and restrictive cardiomyopathy, leading to arrhythmias and heart failure.

TNNI3 variants compose 3-5% of all HCM cases, impacting approximately 25,000 individuals in the United States.

LX1001 is a gene therapy candidate designed to deliver an APOE2 gene for the treatment of APOE4 homozygous patients with Alzheimer’s disease. Alzheimer’s disease is the leading cause of cognitive decline in late adult life and characterized by complex underlying pathology in the central nervous system, or CNS.

Individuals homozygous for APOE4, an allele of the gene APOE, are approximately 15 times more likely to develop Alzheimer’s disease than the general population, and it is estimated that there are 900,000 APOE4 homozygous patients with Alzheimer’s disease in the United States alone. Conversely, individuals with two copies of the APOE allele APOE2 are 40% less likely to develop Alzheimer’s disease than the general population, which along with other evidence suggest that APOE2 may play a neuroprotective role. LX1001 is designed to express the protective APOE2 gene in the CNS of APOE4 homozygous patients in order to halt or slow the progression of Alzheimer’s disease.

LX1001 is being evaluated in an ongoing open-label, dose-escalation Phase 1/2 clinical trial (LEAD). LX1001 has been granted Fast Track designation by the FDA for the treatment of patients with early Alzheimer’s disease who are APOE4 homozygous to slow disease progression.

LX1021 is a gene therapy candidate we are developing to deliver a Christchurch mutation-modified APOE2 allele for the treatment of APOE4 homozygous patients with Alzheimer’s disease. The Christchurch mutation has been recognized to protect individuals against Alzheimer’s disease even in the presence of significant amyloid pathology. The mechanism of this protection may relate to the fact that APOE, in the presence of the Christchurch mutation, binds poorly to heparan sulfate proteoglycans, which are molecules found on the surface of neurons that may inhibit the spread of tau between cells.

We believe this approach has the potential to enhance the protective effect of APOE2 in homozygous APOE4-associated Alzheimer’s disease.

LX1020 is a gene therapy candidate we are developing to deliver both the protective APOE2 allele and miRNA to suppress APOE4 for the treatment of APOE4 homozygous patients. We believe delivery of APOE2 with concurrent suppression of APOE4 will achieve a higher degree of conversion to the APOE4/E2 heterozygous profile, which should lead to greater therapeutic effect.