Lexeo Therapeutics, Inc. · NASDAQ:LXEO
Lexeo Therapeutics — Investor Presentation (October 2024)
41 slides from Lexeo Therapeutics's investor presentation, Oct 9, 2024
Slide 1: Lexeo Therapeutics Corporate Overview October 2024
Lexeo Therapeutics Corporate Overview October 2024 Exhibit 99.1
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: Lexeo Therapeutics Team
Lexeo Therapeutics Team R. Nolan Townsend Chief Executive Officer Ronald Crystal, M.D. Founder & Chief Scientific Adviser Professor and Chairman, Weill Cornell Medicine Director, Belfer Gene Therapy Core Facility Steven Altschuler, M.D. Chairman Management team with broad leadership experience in ge
Slide 4: Revolutionizing Genetic Medicines for Cardiovascular Diseases and APOE4-Alzheimer's
Revolutionizing Genetic Medicines for Cardiovascular Diseases and APOE4-Alzheimer’s Genetic Variant or Disease Phenotype Targeted Delivery Platform Shift towards surrogate endpoints could circumvent need for large cardiovascular outcome trials Improvements in modern AAV delivery technology, includin
Slide 5: Lexeo Investment Highlights
Lexeo Investment Highlights Clinical-stage genetic medicine company addressing larger-rare and prevalent patient populations Cardiac Portfolio APOE4 Alzheimer’s Portfolio Ongoing Phase 1/2 trial for Friedreich ataxia cardiomyopathy with interim clinical results shared in July 2024 Mean reduction in
Slide 6: 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 7: Cardiovascular diseases
Cardiovascular diseases 7
Slide 8: Several Targets in Cardiac Organelles Dysregulated in Cardiomyopathy
Several Targets in Cardiac Organelles that are Dysregulated in Cardiomyopathy; Potential Readthrough to Other Therapeutic Indications Troponin LX2020 LX2021 LX2006 LX2022 Desmosome Mitochondria Gap junction PKP2 CX43 FXN TNNI3 Sarcomere
Slide 9: Utilizing AAVrh10 for Initial Genetic Cardiac Indications
Utilizing AAVrh10 for Initial Genetic Cardiac Indications Observed ~1.5x to 2.0x greater biodistribution in the heart compared to AAV9 in multiple large animal models Observed greater trends of functional improvements in PKP2-murine model compared to AAV9 AAVrh10 cardiac tropism may allow for lower
Slide 10: LX2006 (FA Cardiomyopathy)
LX2006 (FA Cardiomyopathy) 10
Slide 11: FA 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 12: Friedreich Ataxia Results from Frataxin Gene Mutations Impairing 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 13: LX2006 Mechanism: Potential to Treat 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 14: 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 15: Heart Muscle Dysfunction 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 16: Individuals with FA Demonstrate Concentric Hypertrophy and Elevated LVMI Predicting 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 17: LVMI is Elevated in 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 18: 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 19: Interim Data Update Supports LX2006 as Potential Treatment for FA Cardiomyopathy
Interim Data Update Supports LX2006 as Potential Treatment for FA Cardiomyopathy Data from Lexeo Sponsored SUNRISE-FA and Weil Cornell Medicine Investigator-Initiated Phase 1/2 Trials Program Status As of July 15, 2024, 13 participants dosed, including 1 participant in Cohort 3 SUNRISE-FA currently
Slide 20: SUNRISE-FA and Weill Cornell Trials Are Similarly Designed
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 21: 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
Slide 22: 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 23: 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 24: IHC Images Show Increased Frataxin Expression in Heart in All Participants
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 25: Percentage of Participants with LVMI Reduction >10% Increased Over Time
Across Participants With > 6 Months of Follow-Up, Percentage of Participants with LVMI Reduction >10% Increased 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
Slide 26: Meaningful LVMI Change from Baseline With Increased Improvement Over Time
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 27: Average Change from Baseline in Other Key Cardiac Measures
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 particip
Slide 28: 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 29: 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 (
Slide 30: LX2020 (PKP2-ACM)
LX2020 (PKP2-ACM) 30
Slide 31: ACM Caused by Mutations in PKP2 and How LX2020 is Designed to Treat It
ACM Caused by Mutations in PKP2 and How LX2020 is Designed to Treat It Arrhythmia Desmosomal Complex PKP2 gene PKP2 protein PKP2 gene PKP2 protein AAVrh10 Desmosomal Complex Delivering a functional PKP2 gene to cardiac muscle to increase desmosomal PKP2 protein levels, reassemble desmosomes and rest
Slide 32: IND Clearance Supported by Robust Preclinical Package
Note: PVC = premature ventricular contractions; VCN = vector copy number. IND Clearance Supported by Robust Preclinical Package IND-Enabling NHP: VCN in Various Heart Regions Robust Preclinical Package Murine studies utilizing CRISPR-Cas 9 edited model recapitulating PKP2-ACM disease features NHP sa
Slide 33: Quantitative MRI Showed Improvement in Cardiac Function in Mouse Model
Quantitative MRI Analysis Showed Improvement in Cardiac Function in Homozygous Mouse Model End-Diastolic Volume Quantitative MRI showed improved LV and RV ejection fraction and cardiac function in mid and high dose groups. RV improvements are most relevant as it is the primary ventricle impacted in
Slide 34: LX2020 Impacted All Modifiable Elements of ACM Diagnosis and Risk
In Preclinical Studies LX2020 Successfully Impacted All Modifiable Elements of ACM Diagnosis and Risk Calculator LX2020 Preclinical Evidence Arrhythmias Arrhythmia Burden Daily Premature Ventricular Contraction (PVC) Count Ectopic Beats (7/10 without PVC) Life-threatening Arrhythmia Events SCD, ICD
Slide 35: LX2020 PKP2-ACM Phase 1/2 (HEROIC-PKP2) Overview
LX2020 PKP2-ACM Phase 1/2 (HEROIC-PKP2) Overview Primary Endpoint: Safety Endpoints Additional Endpoints: Change in ventricular arrhythmias and associated clinical events Change in 12-lead ECG Change in cardiac MRI and ECHO Change in cardiac biomarkers (including troponin and BNP) Change in Patient
Slide 36: APOE4-Associated Alzheimer's Disease
APOE4-Associated Alzheimer’s Disease 36
Slide 37: APOE4 Homozygotes Represent a Patient Subgroup with Continued Unmet Need
APOE4 Homozygotes Represent a Patient Subgroup with Continued Unmet Need E4/E4 E3/E3 ~14.5x E4/E2 ~2.6x ~1.0x Alzheimer’s Disease Risk by APOE Genotype(1) E2/E2 ~0.6x ~15x more likely to develop AD than APOE3/E3 Unmet Need Persists Despite Recent Approvals Increased Incidence of Adverse Events(2) No
Slide 38: LX1001 Phase 1/2 Trial in APOE4 Homozygotes
LX1001 Phase 1/2 Trial in APOE4 Homozygotes Key Inclusion Criteria: ≥50 yr APOE4 homozygotes Mild cognitive impairment to moderate dementia with biomarkers consistent with Alzheimer’s disease Cohort 1 n=5 Cohort 2 n=4 Cohort 3 n=3 1.4x1010 vg/ml CSF 5.7x1012 Total VGs 4.4x1010 vg/ml CSF 1.8x1013 Tot
Slide 39: Initial LX1001 Low-Dose Cohort Data: CSF Core Biomarkers
Initial LX1001 Low-Dose Cohort Data: CSF Core Biomarkers Initial CSF core biomarker data for patients with 12-month follow-up(1) -20% -4% -9% -14% T-Tau P-Tau -22% -16% Baseline Month 12 -24% -33% Aβ42 stable Reduction in CSF total tau and phospho-tau were observed in all 3 patients, reduction in CS
Slide 40: Significant Catalysts Across Lead Programs Supported by Strong Balance Sheet
Significant Catalysts Across Lead Programs Supported by Strong Balance Sheet Program Upcoming Milestones US Prevalence Mid 2024: Interim Data Readout Year End 2024: Update on ongoing regulatory engagements ~5K Late Q1/Early Q2 2025: Interim Data Readout (Cohort 1) ~60K October 2024: Interim Phase 1/
Slide 41: Thank you
Thank you 41
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