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Lexeo Therapeutics Corporate Overview June 2025 1
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2 Forward-Looking Statements This presentation contains “forward-looking statements” within the meaning of the federal securities laws, including, but not limited to, Lexeo’s expectations and plans regarding its current product candidates and programs and the timing for receipt and announcement of data from its clinical trials, the timing and likelihood of potential regulatory approval, and expectations regarding the time period over which Lexeo’s capital resources will be sufficient to fund its anticipated operations and estimates regarding Lexeo’s financial condition. Words such as “may,” “might,” “will,” “objective,” “intend,” “should,” “could,” “can,” “would,” “expect,” “believe,” “design,” “estimate,” “predict,” “potential,” “develop,” “plan” or the negative of these terms, and similar expressions, or statements regarding intent, belief, or current expectations, are forward-looking statements. While Lexeo believes these forward looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements. These forward-looking statements are based upon current information available to the company as well as certain estimates and assumptions and are subject to various risks and uncertainties (including, without limitation, those set forth in Lexeo’s filings with the U.S. Securities and Exchange Commission (SEC)), many of which are beyond the company’s control and subject to change. Actual results could be materially different from those indicated by such forward-looking statements as a result of many factors, including but not limited to: risks and uncertainties related to global macroeconomic conditions and related volatility; expectations regarding the initiation, progress, and expected results of Lexeo’s preclinical studies, clinical trials and research and development programs; the unpredictable relationship between preclinical study results and clinical study results; delays in submission of regulatory filings or failure to receive regulatory approval; liquidity and capital resources; and other risks and uncertainties identified in Lexeo’s Annual Report on Form 10-K for the annual period ended December 31, 2024, filed with the SEC on March 24, 2025, Quarterly Report on Form 10-Q for the quarterly period ended March 31, 2025, filed with the SEC on May 12, 2025, as amended, and subsequent future filings Lexeo may make with the SEC. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Lexeo claims the protection of the Safe Harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. Lexeo expressly disclaims any obligation to update or alter any statements whether as a result ofnew information, future events or otherwise, except as required by law.
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3 Lexeo: Advancing Cardiac Genetic Medicines In Diseases with High Unmet Need Leveraging gene therapy to address devastating cardiac diseaseswith no existing disease-modifying treatments Potential best-in-class treatment for PKP2-ACM; ~60K people in US with no disease-modifying treatment available Observed increased protein expression levels in two post-treatment cardiac biopsies and 67% reduction in PVCs from baseline in one participant that reached 6-months Only program in the clinic for the treatment of FA cardiomyopathy; the cause of death in 60-80% of individuals Latest interim clinical data show robust cardiac FXN expression in all participants, and clinically meaningful reductions in multiple cardiomyopathy markers FDA alignment on key elements of accelerated approval pathway based on LVMI reduction and protein expression LX2006: Friedreich Ataxia Cardiomyopathy LX2020: PKP2-ACM Focus Expect to initiate registrational study by early 2026 with potential efficacy readout in 2027 FA, Friedreich Ataxia; FXN, Frataxin; LVMI, Left Ventricular Mass Index; ACM, arrhythmogenic cardiomyopathy.
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Favorable Landscape for Cardiac Genetic Medicines Continues to Mature Evolving Regulatory Environment: Continued shift towards surrogate endpoints may circumvent need for larger cardiovascular outcome trials to achieve accelerated approval Improved Delivery Platforms: Improvements in modern AAV delivery technology, including AAVrh10, allow for greater targeting of the heart with lower doses 4 Increased Genetic Screening: Increased screening has potential to expand awareness and increase opportunity across genetic cardiac diseases Well-Established Biomarkers: Growing acceptance of cardiac biomarkers potentially allow for earlier signs of clinical activity Maturing AAVrh10 Safety Profile: Multiple gene therapies evaluated with AAVrh10 capsid in clinical trials, expanding the field’s safety understanding Favorable tailwinds supporting multi-billion $ commercial potential for cardiac genetic medicines
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Our Pipeline: Focused on Diseases with Significant Unmet Need and Clear Mechanisms 5 Clinical: Discovery Preclinical Phase 1/2 Phase 2/3 Preclinical: Indication:Programs: FA(1) Cardiomyopathy PKP2-ACM(2) FXN PKP2 Gene: LX2006 LX2020 (1) Friedreich ataxia. (2) Plakophilin 2 Arrhythmogenic Cardiomyopathy. (3) Desmoplakin. (4) Alzheimer’s disease; LXEO has two additional preclinical second-generation programs. CX43DSP(3) Cardiomyopathy Hypertrophic Cardiomyopathy TNNI3 LX2021 LX2022 APOE4-Associated AD(4) APOE2LX1001 CardiovascularAPOE4-AD Lexeo retains global rights across all programs Pursuing Partnership Opportunities for Continued Development ~5K US Prevalence ~60K US Prevalence ~35K US Prevalence ~25K US Prevalence
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– 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0% 16.0% AAVrh10 AAv9 Cardiac Tropism of AAVrh10 May Allow Lower Dosing for Cardiac Gene Therapy 6 AAVrh10 cardiac tropism may allow for lower doses compared to other vector serotypes while achieving targeted transgene biodistribution 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 has been utilized systemically across multiple Lexeo clinical programs with no clinically significant complement activation; both LX2006 and LX2020 have been generally well-tolerated to date AAVrh.10 AAV9 0 5000 10000 15000Copies/µg DNA Yucatan Minipig Biodistribution(1) NHP Biodistribution(2) I-124 Vector Levels (% total body) (1) Data presented at ASGCT 2023. (2) Ballon DJ et al, Human Gene Therapy, 2020. Compelling Cardiac Tropism Greater Trends of Functional Improvement Versus AAV9 in PKP2-ACM Model(1) Distribution to the heart ~1.5x higher with AAVrh10 than AAV9 AAVrh.10 AAV9 0 20 40 60EF% Vehicle WT AAVrh.10 AAV9 0 20 40 60EDV (µL) Vehicle WT AAVrh.10 AAV9 0 20 40 60ESV (µL) WT Vehicle Greater Increase in EF Greater Reduction in EDV Greater Reduction in ESV +61% +32% -28% -18% -37% -23% Note: PKP2 homozygous mouse model administered with human PKP2 (N = 5 mice / group).Copies / μg DNA Distribution to the heart ~2x higher with AAVrh10 than AAV9 AAVrh10 AAV9 AAVrh10 AAV9 AAVrh10 AAV9 AAVrh10 AAV9
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LX2006 (FA Cardiomyopathy)
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FA CardiomyopathyLX2006Cardiac Dysfunction is the Leading Cause of Death in Friedreich Ataxia 8 FA is a rare, devastating and progressive multi-system disordercaused by loss of function mutations in the FXNgene (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(1) Complications from FA-CM include blood clots or stroke, heart failure, and death from heart-related causes; hypertrophy in childhood appears associated with a more severe phenotype and earlier progression to end-stage disease(2) The only approved disease-specific treatment for FA demonstrated efficacy on neurological measures but was not evaluated for the treatment of cardiac dysfunction, leaving significant unmet need within FA cardiomyopathy Cardiac dysfunction is the cause of death in 60-80% of those with FA, often occurring by mid-30s(4)(5) ~15,000 individuals affected by FA worldwide(3) ~5,000 individuals affected by FA in the U.S.(3) FA, Friedreich Ataxia; FXN, Frataxin; LVMI, Left Ventricular Mass Index. (1) Regner S, et al. American Journal of Cardiology, 2012. (2) Norrish G., et al. Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study. Archives of disease in childhood, 107(5), 450–455, 2022. (3) Friedreich’s Ataxia Research Alliance, 2024. (4) Subramoney S, et al. MDA Clinical and Scientific Conference, 2023. (5) Pousset, F. et al. JAMA Neurol, 2015;72(11):1334-1341. (6) Clinical Management Guidelines for Friedreich Ataxia. Chapter 4. The heart and cardiovascular system in Friedreich ataxia. 2022. ~40% of adults with FA have left ventricular hypertrophy as defined by abnormal LVMI(5)(6)
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FA CardiomyopathyLX2006 Timely, Multidisciplinary Care is Critical to Diagnose and Manage FA Cardiomyopathy 9 Individuals with FA Typically Present with Cardiac Symptoms in Adolescence, and Face an Average Life Expectancy of 35-40 Years Ron and his son, Keith, who passed from FA cardiomyopathy at age 24 “There are no approved treatments for the cardiomyopathy of FA. Time is of the essence.” – Ron Bartek, Co-Founder of FARA Early signs often associated with the onset of ataxia ~5% of young children present with cardiac symptoms years before ataxia(2) Symptom Onset Journey to diagnosis with genetic test can take years Guidelines recommend an EKG and ECHO at diagnosis and annually (5) Almost all individuals with FA will develop cardiomyopathy or cardiac dysfunction during their lifetime(1) Cardiac dysfunction is the cause of death in 60-80% of those with FA, often occurring by mid-30s(3)(4) Journey to Diagnosis Life Expectancy Cardiac Dysfunction (1) Regner S, et al. American Journal of Cardiology, 2012. (2) Norrish G., et al. Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study. Archives of disease in childhood, 107(5), 450–455, 2022. (3) Subramoney S, et al. MDA Clinical and Scientific Conference, 2023. (4) Pousset, F. et al. JAMA Neurol, 2015;72(11):1334-1341. (5) Clinical Management Guidelines for Friedreich Ataxia. Chapter 4. The heart and cardiovascular system in Friedreich ataxia. 2022.
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FA CardiomyopathyLX2006 10 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 leads to deficient energy production in hypertrophic cardiomyocytes Mitochondria Cardiomyocyte AAV, Adeno-Associated Virus; CAG, Chicken Beta-Actin; cDNA, Copy DNA; FA, Friedreich Ataxia; FXN, Frataxin; Poly-A, Poly Adenosine. LX2006 Has the Potential to Treat the Root Cause of FA Cardiomyopathy: The Significant Decrease in Frataxin in the Heart Ubiquitous promoter FXN cDNA (full length gene) CAG FXN gene Poly-A Rabbit β-globin polyA LX2006 Construct AAVrh10.hFXN Iron cluster Frataxin with iron
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FA CardiomyopathyLX2006 Elevated LVMI Predicts Mortality in FA and is Not Expected to Significantly Decrease Without Intervention 11 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) HR, Hazard Ratio; CI, Confidence Internal; LVMI, Left Ventricular Mass Index. Note: 10g/m2 represents approximately 10% change in LVMI based on echocardiography measurements of upper bound of normal (105 g/m2). (1) Pousset, F. et al. JAMA Neurol, 2015;72(11):1334-1341. (2) Includes heart failure with preserved ejection fraction, Shah et al, Journal of American College of Cardiology, 2019; hypertensive cardiomyopathy, Muiesan et al, Hypertension, 2004; Fabry disease, Orsborne et al, Journal of American College of Cardiology, 2022; and obstructive hypertrophic cardiomyopathy, Hegde et al, Journal of American College of Cardiology, 2021. (3) Data on file. • Concentric hypertrophy, with increased left ventricular mass and increased left ventricular wall thickness, is a hallmark of FA cardiomyopathy (1) • In FA and many other cardiac diseases, LVMI is not expected to significantly decrease without intervention(1)(3) – and abnormal LVMI is closely correlated with outcomes such as death or hospitalization (2) • Reduction in LVMI may improve cardiac outcomes; FDA alignment as co-primary endpoint for potential pivotal trial in FA cardiomyopathy MRI of Individual With FA Cardiomyopathy Demonstrating Significant Hypertrophy
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FA CardiomyopathyLX2006LX2006 is Being Evaluated in Parallel Lexeo-Sponsored SUNRISE-FA and Weill Cornell Investigator Initiated Trials 12 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 Study Design & Objective Design: 52-week open-label study with a 4-year long term follow up Objective: To assess the safety and efficacy of LX2006 in individuals with cardiomyopathy associated with Friedreich ataxia Adults (18-50 years) Evidence of FA cardiomyopathy Neutralizing anti- AAVrh.10 titer cutoff Cardiac Structure & Function (LVMI, hsTnI, other measures) Functional / Reported Outcomes (mFARS, KCCQ) FXN Protein Expression Assessed Only in SUNRISE-FA CPET, Cardiopulmonary Exercise Testing; hsTnI, High Sensitivity Troponin I; IHC, Immunohistochemistry; LCMS, Liquid Chromatography Mass Spectrometry; LVMI, Left Ventricular Mass Index. Note: LX2006 is administered systemically; participants receive immune suppression with prednisone beginning on the day prior to treatment through 14 weeks following LX2006 administration. Note: In April 2024, Lexeo announced a license agreement with Cornell University for intellectual property rights including currentand future clinical data from the ongoing Weill Cornell Medicine investigator-initiated trial of AAVrh10.hFXN (LX2006). Lexeo-sponsored SUNRISE-FA trial and Weill Cornell Medicine investigator-initiated trial utilize identical drug product manufactured at Weill Cornell for these ongoing studies. Cohort 1 1.8x1011 vg/kg Cohort 2 5.6x1011 vg/kg Cohort 3 1.2x1012 vg/kg
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FA CardiomyopathyLX2006 FDA Alignment Guides Future Pivotal Study Inclusion Criteria and Co-Primary Endpoints to Support Accelerated Approval 13 FDA Alignment • Threshold of 10% reduction in LVMI as measured by cardiac MRI at 12 months ‒ Interim Phase 1/2 Results: participants with abnormal LVMI at baseline achieved a mean reduction of 25% in LVMI at 12 months or sooner visit (n=6) Co-primary Registrational Endpoints Target Reduction in LVMI Pivotal Trial Design Elements and Interim Phase 1/2 Results • Any increase from baseline in frataxin protein expression versus specific numerical threshold ‒ Interim Phase 1/2 Results: all participants showed increase in frataxin from baseline (n=8), assessed via LCMS at 3 months post treatment ‒ Lexeo expects to measure protein expression using liquid chromatography mass spectrometry (LCMS) assay in pivotal study • Enrollment of adult participants with abnormal LVMI at baseline • Estimated that approximately 40% of adults with FA have abnormal LVMI • 6 participants with abnormal baseline LVMI currently enrolled in ongoing Phase 1/2 trials Proposed Pivotal Trial Inclusion Criteria LVMI, Left Ventricular Mass Index; LCMS, Liquid chromatography mass spectrometry. Note: Abnormal LVMI defined as values 2 standard deviations (SD) above mean for respective gender (from healthy volunteers) as referenced in Kawel-Boehm et al. J Cardiovasc Magn Reson (2020) 22:87. Target Increase in Frataxin Expression
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FA CardiomyopathyLX2006 29% 187% 22% 35% 23% 120% 151% 198% 0% 100% 200% 300% 01-02-03 01-02-04 01-02-05 01-02-07 01-04-03 01-01-06 01-04-04 01-02-08 Participant #9 Increased Cardiac Frataxin Expression Across All Participants Evaluated at 3-Months Post Treatment Utilizing LCMS 14 Post-Treatment FXN Levels Increased in All Participants – Measured by LCMS Participant #6 Participant #10 Participant #11 Cohort 1 (n=1) Cohort 2 (n=3) Cohort 3 (n=4) Participant #12 Participant #14 Participant #15 Participant #16 Cohort 3: New DataPreviously Reported Cohort Avg. Inc. (%) C1 (n=1) 29% C2 (n=3) 69% C3 (n=4) 115% % Increase FXN from Baseline All participants show increase in frataxin expression vs. baseline Meeting FDA threshold for detecting any increase in frataxin expression Four biopsies from higher dose Cohort 3 show dose- responsive increases relative to Cohorts 1-2 +0.22 +1.81 +0.40 +0.29 +0.11 +0.91 +0.53 +0.60 FXN, Frataxin; LCMS, Liquid chromatography mass spectrometry. Research use only, assay validation in progress for registrational study. ng/mg total protein:
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FA CardiomyopathyLX2006Participants with Abnormal LVMI at Baseline: Improvements in Key Clinical Parameters at Latest Visit, with Latest Visit Average LVMI Reduction of 27% 15 Cohort Participant # | LVMI(1) at Baseline Latest Visit (months) ∆ LVMI (g/m2) Baseline LV ∆ LWT (cm) Baseline LV ∆ Hs-TNI (pg/ml) Baseline LV Cohort 1 (1.8E11 vg/kg) Participant #1 (F) 24 -17.3% 81 67 -16.7% 1.2 1.0 -26.8% 224 164 Participant #2 (M) 24 -25.7% 109 81 -9.1% 1.1 1.0 -40.5% 148 88 Participant #6 (M) 24 -2.3% 86 84 -2.4% 0.9 0.8 -50.0% 22 11 Cohort 2 (5.6E11 vg/kg) Participant #11 (F) 9 -30.2% 100 70 -30.0% 0.9 0.6 -88.7% 115 13 Participant #13 (F) 6 -60.9% 110 43 -23.1% 1.31.0 -88.3% 2518 294 Cohort 3 (1.2E12 vg/kg) Participant #12 (M) 6 -12.1% 85 74 -13.1% 0.8 0.7 -72.0% 25 7 Future pivotal trial will only enroll people with abnormal(1) LVMI at baseline Note: Normal LVMI range for males: 39-85 g/m2 and normal LVMI range for females: 30-68 g/m2. (1) For cardiac imaging, abnormal defined as values 2 standard deviations (SD) above mean and high-normal defined as values 1SD above mean for respective gender (from healthy volunteers) as referenced in Kawel-Boehm et al. J Cardiovasc Magn Reson (2020) 22:87. Improved Stabilized Worsened 5 of 6 participants achieve FDA aligned threshold of >10% LVMI reduction
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FA CardiomyopathyLX2006 (70%) (60%) (50%) (40%) (30%) (20%) (10%) – BL 6 Mo 9 Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo Registrational Co-Primary Endpoint LVMI % Change Participants with Abnormal LVMI at Baseline: 5 of 6 Achieve >10% Reduction in LVMI by 12-Month or Sooner Visit with Trend of Deepening Improvement Over Time 16 Cohort 1 (n=3) Cohort 2 (n=2) Cohort 3 (n=1) Note: Participant had less elevated LVMI baseline 5 of 6 participants reach normal LVMI range at last follow up Majority of participants reach 10% LVMI reduction before 12 months LX2006 generally well tolerated to date with no clinically significant complement activation One previously disclosed, possibly treatment-related Grade 2 event of asymptomatic myocarditis was observed one year after dosing Mean LVMI Change Participants at 12-mo visit Cohort 1 only (n=3) -12% Participants at 12-mo visit or less All cohorts (n=6) -25% Change in LVMI (%) for Participants with Abnormal LVMI at Baseline 10070 8574 8166 10995 8681 11043
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FA CardiomyopathyLX2006Interim Data Inform Preliminary Pivotal Trial Design: Registrational Single Arm Study with External Comparator 17 Pivotal Phase 2 Study Design to Support Accelerated Approval Pathway • Dose: Anticipate 1.2E12 vg/kg (cohort 3) based on safety data from ongoing Phase 1/2 study • Key Eligibility Criteria: FA-CM with abnormal LVMI; LVEF ≥40% • Co-Primary Endpoints (AA): ‒ >10% LVMI Reduction at 12 months ‒ Increase in FXN expression over baseline at 3 months ‒ Intend to evaluate endpoints separately • Key Secondary Endpoints: Hs-Troponin I, left ventricular wall thickness, mFARS, KCCQ, event free survival (death/MACE) • Immune Suppression: Prednisone regimen for 14 weeks following LX2006 administration • Statistical Plan: Details to be disclosed following final FDA alignment but intend at least 12 adult participants with 90% power(1) >16yrs, n=~12-16(1) Co-Primary Endpoint Assessment >10% LVMI Reduction at 12 months Increase in FXN expression over baseline (LCMS) at 3 months 12-16yrs, n=~3(1) 6-12yrs, n=~3(1) Primary Endpoint: Safety 5 Year LTFU Pediatric Cohort Initiated after >3 months of safety in adolescents Adolescent Cohort Initiated after >3 months of safety in at least 50% of adults 5 Year LTFU 5 Year LTFU Adult Cohort Trial Design Elements Note: Abnormal LVMI defined as values 2 standard deviations (SD) above mean for respective gender (from healthy volunteers) as referenced in Kawel-Boehm et al. J Cardiovasc Magn Reson (2020) 22:87. (1) Lexeo internal estimates. FDA alignment on elements of registrational study design but full statistical plan not yet approved. Primary Endpoint: Safety Concurrent Natural History Study: CLARITY-FA
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LX2020 (PKP2-ACM)
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Arrhythmogenic cardiomyopathyLX2020Arrhythmogenic Cardiomyopathy Caused by Mutations in the PKP2 Gene: Devastating Genetic Heart Disease With Clearly Defined Mechanism of Disease 19 ACM, arrhythmogenic cardiomyopathy; ARVD/C, arrhythmogenic right ventricular dysplasia/cardiomyopathy; ICD implantable cardioverter defibrillator; SDC sudden cardiac death. (1) Cedars-Sinai ARVC overview. (2023). (2) Corrado et al. (2017). (3) Dalal et al. (2005). (4) Day, Circulation: CardiovascularGenetics (2012). PKP2-ACM is a rare, geneticcardiac disordercaused by loss of function mutations in the PKP2gene Progressive replacement of cardiac muscle with fatty fibrotic tissue, with an increased risk of ventricular arrhythmias and sudden cardiac death(SCD) due to disrupted cardiac electrical signals(1)(2) Approximately 23% of individuals experience SCD as the presenting symptomand individuals often suffer from anxiety and reduced quality of life(3)(4) ICDs are commonly utilized but do not halt disease progression. Individuals experience ongoing arrhythmias, along with both appropriate and inappropriate shocks necessitating escalating treatments, underscoring severe unmet need (2)(3) Current management methods are focused on relieving symptoms and preventing SCD, and do not address the underlying cause of myocardial dysfunction and ACM 23% individuals experience SCD as presenting symptom ~60,000 individuals affected by PKP2-ACM in the U.S.
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Arrhythmogenic cardiomyopathyLX2020LX2020 Has Potential to Treat PKP2-ACM by Delivering a Full-Length PKP2 Gene to Cardiomyocytes, Restoring the Desmosomal Complex 20 Cardiac-specific promoter Promoter PKP2 gene Poly-A Rabbit β-globin polyA LX2020 Construct AAVrh10.hPKP2 PKP2-ACM LX2020 Mechanism Absence of PKP2 results in impairment of cardiac desmosomes, leading to abnormal cardiac rhythms (arrhythmias) and onset of cardiac dysfunction DES DES Absent PKP2 Desmoglein-2 Desmocollin-2 Desmin Desmoplakin Plakoglobin DES DES PKP2 Desmoglein-2 Desmocollin-2 Desmin Desmoplakin Plakoglobin PKP2 expression is expected to restore the balance of desmosomal proteins by scaffolding adjacent cell-cell junctional proteins The restoration of PKP2 may lead to improvement in cardiac electrical and mechanical function as well as inhibit further structural damage AAVrh10 PKP2 cDNA (full length gene) Desmosomal Complex Desmosomal Complex ACM, arrhythmogenic cardiomyopathy.
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Arrhythmogenic cardiomyopathyLX2020 Robust Preclinical Package Supporting Ongoing Phase 1/2 Trial 21 PKP2 (LX2020) mRNA in WT NHP Robust Preclinical Package • Murine studies utilized CRISPR-Cas 9 edited homozygous (severe) and heterozygous models recapitulating PKP2- ACM disease features • NHP safety study showed no toxicity at highest evaluated dose level (1x1014 vg/kg) LX2020 Significantly Extended Survival in Severe Mouse Model Vehicle or LX2020 Quantification of PKP2 Expression in Heterozygous Mouse Model 2 high dose early deaths likely due to technical injection error 9/9 2/5 7/11 7/10 2/2 3/5 4/11 3/10 0 5 10 15# of mice Normal PVC 6E12 vg/kg VEHWT PVC Analysis in Severe Mouse Model VWT 6E12 vg/kg (n=12) 2E13 vg/kg (n=12) 6E13 vg/kg (n=12) Vehicle (n=12) Wt (n=9) 2E13 vg/kg 6E13 vg/kg 6E12 vg/kg 2E13 vg/kg 6E13 vg/kg PVC, Premature Ventricular Contractions L Vent R Vent Septum R Atrium L Atrium 0 1×105 2×105 3×105 1×106 2×106 3×106 PKP2 mRNA (Copies/μg Nucleic Acid) Vehicle 2E13 vg/kg 6E13 vg/kg 1E14 vg/kg
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Arrhythmogenic cardiomyopathyLX2020In Preclinical Studies, LX2020 Successfully Impacted All Modifiable Elements of ACM Diagnosis and Risk Calculator 22 LX2020 Preclinical Evidence Arrhythmias Arrhythmia Burden Daily Premature Ventricular Contraction (PVC) Count Ectopic Beats (7/10 without PVC) Life-threatening Arrhythmia Events SCD, ICD Shocks, VT/VF Events Survival (100%) Repolarization & Depolarization Depolarization/Repolarization Abnormalities T-wave Inversions/ QRS Complex QRS Interval (18% reduction) Cardiac Structure & Function Cardiac Contractility RV Dysfunction and Enlargement Cardiac Fxn/EF Cardiac Dilation Cardiac Structure/Function Myocardial Tissue Integrity (Fibrosis, Calcifications, Fragility) Fibrosis, Calcifications, & Tissue Tearing LX2020 preclinical data demonstrated improvement across key areas for determining ACM diagnosis and risk profile PVC, Premature Ventricular Contractions.
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Arrhythmogenic cardiomyopathyLX2020LX2020 is Being Evaluated in an Ongoing Phase 1/2 Study (HEROIC-PKP2); Dose-Expansion Cohort 3 Currently Enrolling 23 2 Key Inclusion Criteria 3 Key Measurements 1 Study Design & Objective Design: 52-week open-label study with a 4-year long term follow up Objective: To assess the safety and efficacy of LX2020 in individuals with PKP2-ACM Adults (18-65 years) Diagnosis of ACM with documented PKP2 mutation Existing ICD that is MRI compatible and minimum threshold of PVCs / 24-hr Neutralizing anti-AAVrh.10 titer cutoff Ventricular arrhythmias and associated clinical outcomes (PVCs and events) Cardiac Structure & Function (ECG, cMRI, hsTNI and others) Change in Symptoms (NYHA Class and PROs) PKP2 Protein Expression (quantitative WB) PVC, Premature Ventricular Contraction; hsTnI, High Sensitivity Troponin I; WB, Western Blot; ECG, Electrocardiogram; NYHA, New York Heart Association; PROs, Patient Reported Outcomes. Note: LX2020 is administered systemically; participants receive immune suppression with prednisone and sirolimus beginning on the day prior to treatment through 12 weeks following LX2020 administration. Cohort 1 n=3 2.0x1013 vg/kg 6.0x1013 vg/kg Cohort 2 n=3 52-Week Fully Enrolled Fully Enrolled Additional participants currently enrolling in Cohort 3 (dose-expansion cohort, n=4) with selected dose
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Arrhythmogenic cardiomyopathyLX2020 0.47 0.18 0.80 0.39 0.00 0.50 1.00 Cohort 1 Participant 1 Cohort 1 Participant 2 PKP2 Levels (ng/μg protein) GAPDH normalized Cardiac Biopsies from Cohort 1 Show Increased PKP2 Protein Expression Three Months Post-Treatment with a Generally Well-Tolerated Safety Profile 24 Cohort 1 Results to Date • After 3-months, cardiac biopsies (n=2) show increased protein and mRNA following LX2020 administration ‒ +71% and +115% increase in PKP2 versus pre-treatment baseline ‒ Participant 1 approaching 80% of normal PKP2 levels; Participant 2 with lower baseline approaching 40% of normal ‒ Both participants achieved meaningful expression of exogenous mRNA; present in post-dose sample indicating transduction of cardiomyocytes with LX2020 ‒ Participant 3 elected not to undergo a post-treatment biopsy LX2020 Safety • LX2020 has been generally well-tolerated to date ‒ No treatment-related serious adverse events LX2020 Protein Expression Normal PKP2 levels 1.0E+05 5.3E+04 0.0E+00 5.0E+04 1.0E+05 1.5E+05 Cohort 1 Participant 1 Cohort 1 Participant 2 PKP2 exogenous mRNA (Copies/μg Nucleic Acid) Pre-Dose Levels Post-Dose Levels Participant 1 Cohort 1 Participant 2 +71% increase +115% increase Participant 1 Cohort 1 Participant 2
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Arrhythmogenic cardiomyopathyLX2020Participant 1: Early Signs of Clinical Efficacy at 6-Months Post Treatment 25 Reduced PVC Burden QRS Duration Normalized -67% reduction in PVCs per day High PVC count is associated with arrhythmia burden and risk of cardiac events 861 284 0 200 400 600 800 1,000 Cohort 1 Participant 1 PVC / 24 hours 124 90 0 50 100 150 Cohort 1 Participant 1 Milliseconds Pre-Dose Levels Post-Dose Levels ARVC threshold Normal level Participant 1 Cohort 1 Participant 1 Cohort 1 -67% decrease QRS duration reduced 6 months after treatment with LX2020 QRS duration associated with outcomes in ARVC
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Significant Catalysts Across Lead Programs in 2025 Supported by Strong Balance Sheet 26 Clinical Stage Program Upcoming 2025 Milestones • Mid 2025: Regulatory update • Early 2026: Expect to initiate registrational study • 2H 2025: LX2020 program update (Cohort 1 and Cohort 2) • Pursuing partnership opportunities for continued development LX2006 LX2020 FA Cardiomyopathy PKP2-ACM (1) Cash, cash equivalents and investments in marketable securities of $106.9M as of March 31, 2025. Pro forma for expected $74 million net proceeds from equity financing announced in May 2025, unaudited. (2) Shares outstanding as of March 31, 2025, pro forma for approximately 20.8M additional shares of common stock expected from equity financing announced in May 2025. Pro forma cash and marketable securities(1) ~$181M Balance sheet as of March 31, 2025 pro forma for financing announced May 2025 Projected runway into 2028 Significant runway following key catalysts Pro forma shares of common stock(2) 54.0M Expected pro forma shares outstanding LX1001 APOE4-Associated AD
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Thank you