Slide 1: Interim Phase 1/2 Clinical Data of LX2006 for the Treatment of Friedreich Ataxia Cardiomyopathy
Interim Phase 1/2 Clinical Data of LX2006 for the Treatment of Friedreich Ataxia Cardiomyopathy July 15, 2024
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains “forward-looking statements” within the meaning of the federal securities laws, including, but not limited to, statements regarding Lexeo’s expectations and plans regarding its current product candidates and programs, including statements regardi
Slide 3: Advancing Genetic Medicines in Larger-Rare and Prevalent Patient Populations
Advancing Genetic Medicines in Larger-Rare and Prevalent Patient Populations Clinical: Discovery Preclinical Phase 1/2 Phase 2/3 Preclinical: Cardiovascular Indication: LX1001 LX1020 LX1021 Programs: Alzheimer’s: APOE4 homozygotes APOE4-Associated Alzheimer’s Disease FA(1) Cardiomyopathy PKP2-ACM(2)
Slide 4: Lexeo Therapeutics: Revolutionizing Genetic Medicines for Cardiovascular Diseases
Lexeo Therapeutics: Revolutionizing Genetic Medicines for Cardiovascular Diseases Multiple cardiac programs in preclinically validated targets with high unmet need Pipeline of Clinical Stage Genetic Medicine Candidates Favorable Clinical and Regulatory Environment Continued Validation of Cardiac Pre
Slide 5: Individuals with Friedreich Ataxia and their loved ones are at the center of everything we do
Individuals with Friedreich Ataxia and their loved ones are at the center of everything we do Lexeo continues to collaborate with advocacy groups to support those impacted by FA, increase screening and diagnosis, and advance research We hear directly from the FA community to better incorporate their
Slide 6: Friedreich Ataxia is a Devastating Rare Disease Impacting Both the Nervous System and the Heart
FA is a rare, devastating and progressive disorder caused by loss of function mutations in the FXN gene (GAA repeat expansion) With a typical age of onset between 10 and 15 years, people with FA experience a combination of neurological and cardiac manifestations, with ~80% developing cardiomyopathy(
Slide 7: Friedreich Ataxia is a Result of Mutations in the Frataxin Gene, Leading to Impaired Mitochondrial Function
Friedreich Ataxia is a Result of Mutations in the Frataxin Gene, Leading to Impaired Mitochondrial Function in the Heart FXN mutation FXN Deficiency Mitochondria FA Cardiomyopathy Cardiomyocyte FXN deficiency results in mitochondrial dysfunction and leads to deficient energy production in cardiomyoc
Slide 8: LX2006 Has the Potential to Treat the Root Cause of FA Cardiomyopathy
FXN mutation FXN Deficiency Mitochondria Functional FXN FA Cardiomyopathy LX2006 Mechanism Cardiomyocyte Transfer of FXN gene to cardiomyocytes is intended to increase frataxin levels in the mitochondria and improve cardiac muscle cell function FXN deficiency results in mitochondrial dysfunction and
Slide 9: Small Increases in Frataxin Following Treatment May Produce Clinical Benefits
Small Increases in Frataxin Following Treatment May Produce Clinical Benefits Modest FXN Levels Resulted in Near Normal Cardiac Function in FA Murine Model Moderate Restoration of Protein Function Correlates with Better Disease Prognosis and Physiological Improvement in Other Diseases Hemophilia B M
Slide 10: Dysfunction in Heart Muscle Cells Can Lead to Concentric Hypertrophy and Poorer Outcomes
Dysfunction in Heart Muscle Cells Can Lead to Concentric Hypertrophy and Poorer Outcomes in Multiple Cardiomyopathies Normal LVMI Normal LV Wall Thickness Normal hs-Troponin I LVMI LV Wall Thickness Hs-Troponin I Disease Progression Normal Heart Concentric Hypertrophy Measurements of Hypertrop
Slide 11: Individuals with FA Demonstrate Concentric Hypertrophy, Which Predicts Mortality
Individuals with FA Demonstrate Concentric Hypertrophy Including Increased Wall Thickness and Elevated LVMI, Which Predicts Mortality Increases in LVMI Independently Predict Mortality in Friedreich Ataxia (FA) Natural history study showed a 19% higher risk of death per 10g/m2 (HR 1.19; 95% CI)(1) Co
Slide 12: LVMI is Elevated in Individuals with FA Cardiomyopathy, and Not Expected to Decrease Without Intervention
LVMI is Elevated in Individuals with FA Cardiomyopathy, and Not Expected to Decrease Without Intervention In other cardiac diseases, LVMI does not significantly decrease without intervention Across Multiple Randomized Controlled Trials, No Significant Change Observed in LVMI or LV Mass (LVM) in Cont
Slide 13: High Sensitivity Troponin I: A Validated Biomarker Studied in Cardiomyopathy and Friedreich Ataxia
High Sensitivity Troponin I (hsTnI): A Validated Biomarker Studied in Cardiomyopathy and Specifically Friedreich Ataxia Utilization of Troponin I as Blood Biomarker(1)(2) Cardiac troponin I is a component of the contractile apparatus of myocardial cells expressed almost exclusively in the heart Circ
Slide 14: Recent LX2006 Program Updates
Recent LX2006 Program Updates In April 2024, Lexeo announced a license agreement with Cornell University for intellectual property rights including current and future clinical data from the ongoing Weill Cornell Medicine investigator-initiated trial of AAVrh10.hFXN (LX2006) Lexeo-sponsored SUNRISE-F
Slide 15: The SUNRISE-FA and Weill Cornell Trials Are Similarly Designed to Assess the Effect of LX2006
The SUNRISE-FA and Weill Cornell Trials Are Similarly Designed to Assess the Effect of LX2006 in Adults with FA Cardiomyopathy SUNRISE-FA and Weill Cornell trials share a similar study design, enabling data from the two studies to be evaluated together 2 Key Inclusion Criteria 3 Key Measurements 1 S
Slide 16: Both Studies Utilize Similar Metrics to Evaluate Safety and Efficacy
Both Studies Utilize Similar Metrics to Evaluate Safety and Efficacy Applicable to Both Studies Specific to SUNRISE-FA Baseline Month 6 1 Year Long Term Follow Up -- -- -- Cardiac Biopsy Cardiac Imaging Biomarkers and Labs CPET Open Label Study Period SUNRISE-FA Lexeo Sponsored Cohort 1: 1.8x1011 v
Slide 17: Baseline Characteristics and Follow-up Time by Dosing Cohort
Baseline Characteristics and Follow-up Time by Dosing Cohort Characteristic Statistic Cohort 1 (1.8x1011 vg/kg) N=6 Cohort 2 (5.6x1011 vg/kg) N=5 Age, years Mean (SD) Min, Max 30.3 (5.0) 24.0, 35.0 23.4 (4.2) 19.0, 30.0 Female N (%) 3 (50) 4 (80) GAA Repeats Mean (SD) Min, Max 731 (44.1) 695, 800 79
Slide 18: Baseline Characteristics Consistent with Cardiac Phenotype of FA
Baseline Characteristics Consistent with Cardiac Phenotype of FA Cohort 1 (1.8x1011 vg/kg) Cohort 2 (5.6x1011 vg/kg) Characteristic Participant 1 Participant 2 Participant 3 Participant 4 Participant 5 Participant 6 Participant 7 Participant 8 Participant 9 Participant 10 Participant 11 Gender F M F
Slide 19: Treatment with LX2006 Has Been Well Tolerated to Date
Treatment with LX2006 Has Been Well Tolerated to Date LX2006 has been well tolerated with no treatment-related serious adverse events No signs of complement activation or other immunogenicity No cardiac or hepatic safety signals All AEs were transient and resolved No participants discontinued from e
Slide 20: IHC Images from Cardiac Biopsies Demonstrated Increased Frataxin Expression in All Participants Evaluated
IHC images from Participant 10 Cardiac Biopsies Have Demonstrated Increased Frataxin Expression in Heart in All Participants Evaluated to Date Utilizing Two Measurement Techniques FXN Level (ng/mg protein ) Pre- and Post-Treatment FXN Levels (LCMS) Cohort 1 Participant 6 Cohort 2 Participant 9 Cohor
Slide 21: Proportion of Participants with LVMI Reduction Over Time
Proportion of Participants *Inclusive of participants with observed increases. LVMI, Left Ventricular Mass Index. Note: Elevated defined as 1 or 2 standard deviations above mean for respective gender (from healthy volunteers) as referenced in Kawel‑Boehm et al. J Cardiovasc Magn Reson (2020) 22:87.
Slide 22: Meaningful LVMI Change from Baseline in Participants with Elevated LVMI
Meaningful LVMI Change from Baseline With Pattern of Increased Improvement Over Time in Participants with Elevated LVMI N=4 N=2 N=5 N=4 N=2 N=5 N=3 N=2 N=0 Elevated LVMI at Baseline: Mean Change Elevated LVMI at Baseline: Median Change Normal LVMI at Baseline: Mean Change In participants with elevat
Slide 23: Average Change from Baseline in Other Key Cardiac Measures Demonstrates Pattern of Improvement
Average Change from Baseline in Other Key Cardiac Measures Demonstrates Pattern of Improvement with Increased Improvement Over Time N=8 N=5 N=2 Continued pattern of improvement with increased reduction from 6 to 12 months Reduction of >10% in lateral wall thickness from baseline in 4 of 6 participan
Slide 24: Peak VO2 May Be Challenging to Assess in Friedreich Ataxia
Peak VO2 May Be Challenging to Assess in Friedreich Ataxia as Neurologic Disease Causes Interference Peak VO2 is defined as the highest amount of oxygen that an individual utilizes during maximal exercise in CPET(1) This measure may not represent the true functional capacity in FA cardiomyopathy giv
Slide 25: Multiple Cardiac Assessments Have Regulatory Precedent as Approvable or Supportive Endpoints
Multiple Cardiac Assessments in Ongoing Studies of LX2006 Have Regulatory Precedent as Potentially Approvable or Supportive Endpoints Key Assessment Ability to Impact Assessment Method Timepoints Transgene Expression (LCMS and IHC) Regulatory Precedent as Approvable Endpoint Cardiac Biopsy 3 Month
Slide 26: Summary of Results and Next Steps for LX2006
Summary of Results and Next Steps for LX2006 LX2006 (AAVrh10.hFXN) has been well tolerated with no treatment-related serious adverse events to date Improvements in key clinical parameters observed at 12-months: 75% of participants with elevated LVMI at baseline experienced >10% reduction in LVMI (n=
Slide 27: Thank You and Q&A
Thank You and Q&A