8-K
Lexeo Therapeutics, Inc. (LXEO)
UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
| Date of Report (Date of earliest event reported): January 12, 2026 |
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Lexeo Therapeutics, Inc.
(Exact name of Registrant as Specified in Its Charter)
| Delaware | 001-41855 | 85-4012572 |
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| (State or Other Jurisdiction<br>of Incorporation) | (Commission File Number) | (IRS Employer<br>Identification No.) |
| 345 Park Avenue South, Floor 6 | ||
| New York, New York | 10010 | |
| (Address of Principal Executive Offices) | (Zip Code) | |
| Registrant’s Telephone Number, Including Area Code: 212 547-9879 | ||
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| N/A | ||
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(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
☐Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
☐Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
☐Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
☐Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class | Trading<br>Symbol(s) | Name of each exchange on which registered |
|---|---|---|
| Common Stock, $0.0001 par value per share | LXEO | Nasdaq Global Market |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 7.01 Regulation FD Disclosure.
The corporate presentation to be used in connection with the webcast described in Item 8.01 below is attached as Exhibit 99.2 to this Current Report on Form 8-K and incorporated into this Item 7.01 by reference.
The information in this Item 7.01, including Exhibit 99.2 attached hereto, shall not be deemed “filed” for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities of that section, nor shall they be deemed incorporated by reference in any filing under the Securities Act, except as expressly set forth by specific reference in such filing.
Item 8.01 Other Events.
On January 12, 2026, Lexeo Therapeutics, Inc. (the “Company”) issued a press release announcing positive interim Phase 1/2 clinical data of LX2020 for the treatment of PKP2-associated arrhythmogenic cardiomyopathy (“PKP2-ACM”). As part of the press release, the Company announced that it would be hosting a conference call and webcast at 8:00 a.m. ET on January 12, 2026 to discuss the interim Phase 1/2 clinical data of LX2020 for the treatment of PKP2-ACM. The press release is attached hereto as Exhibit 99.1 and incorporated by reference herein.
Also on January 12, 2026, the Company posted on its website an updated corporate presentation (the “Corporate Presentation”). The Corporate Presentation will be used from time to time in meetings with investors and analysts. A copy of the Corporate Presentation is attached hereto as Exhibit 99.3 and is incorporated by reference herein.
Cautionary Note Regarding Forward-Looking Statements
This report contains certain forward-looking statements regarding the business of the Company that are not a description of historical facts within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements regarding the Company’s expected plans with respect to clinical trials of the Company’s gene therapy candidates and the timing for announcement of data from such trials. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, expectations regarding the initiation, progress, and expected results of the Company’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 and liquidity and capital resources. Additional risks and uncertainties that could cause actual results to differ materially from those contemplated by the forward-looking statements are included in the Company’s Annual Report on Form 10-K for the fiscal year ended December 31, 2024, Quarterly Report on Form 10-Q for the quarter ended September 30, 2025 and subsequent future filings the Company may make with the Securities and Exchange Commission from time to time that are available at www.sec.gov.
You are cautioned not to place undue reliance on forward-looking statements which are current only as of the date hereof. Except as required by applicable law, the Company undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
| Exhibit<br><br>Number | Description |
|---|---|
| 99.1 | Press release issued by the Company on January 12, 2026, announcing Positive Interim Phase 1/2 Clinical Data of LX2020 |
| 99.2 | Corporate Presentation (LX2020), dated January 12, 2026, furnished herewith |
| 99.3 | Corporate Presentation, dated January 12, 2026 |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Lexeo Therapeutics, Inc. | |||
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| Date: | January 12, 2026 | By: | /s/ R. Nolan Townsend |
| R. Nolan Townsend, Chief Executive Officer |
EX-99.1
Exhibit 99.1
Lexeo Therapeutics Announces Positive Interim Phase I/II Data for LX2020 for the Treatment of
PKP2-Associated Arrhythmogenic Cardiomyopathy
LX2020 generally well tolerated across ten participants with no clinically significant complement activation
LX2020 transduction, transcription, and increased protein expression observed across participants with dose-dependent response; mean increase in PKP2 protein of 93% in low-dose cohort and 162% in high-dose cohorts
Arrhythmia burden stabilized or improved in majority of participants with dose-dependent response in non-sustained ventricular tachycardia and premature ventricular contractions
Company to host webcast today at 8:00 AM ET / 5:00 AM PT
NEW YORK – January 12, 2026 (GLOBE NEWSWIRE) – Lexeo Therapeutics, Inc. (Nasdaq: LXEO), a clinical stage genetic medicine company dedicated to pioneering novel treatments for cardiovascular diseases, today announced preliminary data from the HEROIC-PKP2 Phase I/II clinical trial of LX2020 for the treatment of PKP2-associated arrhythmogenic cardiomyopathy (PKP2-ACM). Across dose cohorts, LX2020 was generally well tolerated and led to robust transduction, increased PKP2 protein expression, and clinically meaningful improvement or stabilization in measures of arrhythmia burden in the majority of participants.
“These interim data from ten participants reinforce the favorable safety profile of LX2020 and demonstrate promising trends in transduction, protein expression, and reduction in arrhythmia burden at the high dose,” said R. Nolan Townsend, Chief Executive Officer of Lexeo Therapeutics. “We are encouraged by these preliminary results and look forward to advancing development of LX2020 given its therapeutic potential and ability to address the underlying cause of cardiac dysfunction and disease progression in PKP2-ACM.”
LX2020 Interim Update
Ten participants have been dosed in the HEROIC-PKP2 Phase I/II clinical trial, including three participants in Cohort 1 at the low dose (2x1013 vg/kg) and seven participants in Cohorts 2 and 3 at the high dose (6x1013 vg/kg). Safety data are summarized for all ten participants dosed; efficacy data are inclusive of those participants with at least 6 months of follow-up as of the January 7, 2026 data cutoff date. Cardiac biopsy data are available for seven participants, as one participant in Cohort 1 declined post-dose biopsy.
Interim Safety Update (n=10)
- LX2020 generally well tolerated across ten participants dosed
- No clinically significant complement activation
- Elevations in liver function tests (LFT) observed in five participants at the high dose, treated successfully with re-introduction of low-dose prednisone in three participants and increased prednisone and sirolimus in two participants per the trial protocol. All elevations resolved without complication, hospitalization or other treatment
- No participants discontinued from the HEROIC-PKP2 Phase I/II study
- One previously disclosed Grade 3 serious adverse event of sustained ventricular tachycardia (VT) was observed three months after dosing in a single participant at the high dose and assessed as possibly treatment related. This event is consistent with the natural course of PKP2-ACM and its known clinical manifestations. The participant was successfully treated with anti-arrhythmic medication and discharged with no additional intervention required
PKP2 Transduction and Expression (n=7 with post-treatment cardiac biopsies at 3 months)
- Mean increase in PKP2 protein expression of 93% in the low-dose cohort (n=2) and 162% in the high-dose cohorts (n=5), assessed by western blot
- Mean exogenous mRNA of 7.9E+04 copies per microgram of nucleic acid in the low-dose cohort (n=2) and 2.7E+05 copies per microgram in the high-dose cohorts (n=5)
- Mean vector copy number (VCN) of 1.5 in the low-dose cohort (n=1) and 3.3 in the high-dose cohorts (n=5); insufficient cardiac biopsy tissue available for participant 1 in low-dose cohort for VCN analysis
- Appropriate PKP2 colocalization observed at cardiac intercalated discs via immunofluorescence staining
Clinical Data (n=8 with > 6 months of follow up)
- Non-sustained ventricular tachycardia (NSVT) reduced or stabilized in the majority of participants; 22% mean improvement in high-dose cohorts at latest visit (n=5)
- Premature ventricular contractions (PVCs) reduced or stabilized in the majority of participants; 14% mean improvement in high-dose cohorts at latest visit (n=5)
- 4 of 5 participants in high-dose cohorts report improvement relative to baseline on the Patient Global Impression of Change (PGIC) scale, a patient-reported outcome measure
- Participants stable across other clinical measures including QRS duration, T-wave inversion, right ventricular ejection fraction (RVEF) and New York Heart Association (NYHA) Class
Next Steps
- HEROIC-PKP2 enrollment completed in Q4 2025; biopsy results pending for participants 9 and 10
- 12-month data available for all high-dose participants in Q4 2026
- Regulatory engagement expected in 2026
Corporate Webcast Details Lexeo Therapeutics will host a webcast at 8:00 AM ET / 5:00 AM PT today, January 12, 2026. Analysts and investors can participate by accessing the webcast live on the News & Events page in the Investors section of Lexeo’s website, www.lexeotx.com. The webcast will be archived on the company’s website following the call.
About LX2020
LX2020 is an AAV-based gene therapy candidate for the treatment of plakophilin-2-associated arrhythmogenic cardiomyopathy (PKP2-ACM). Mutations in the PKP2 gene are the most common genetic cause of ACM, responsible for approximately 50% of cases and estimated to affect approximately 60,000 people in the United States. PKP2 deficiency in ACM can lead to myocardial cell death, fibrosis, heart dysfunction, rhythm abnormalities, and sudden cardiac death. LX2020 is designed to systemically deliver a functional, full-length PKP2 gene within an adeno-associated viral capsid, AAVrh10, to cardiomyocytes to restore the desmosomal complex and cell-to-cell adhesion. LX2020 is being evaluated in the single-arm, open-label, multi-center HEROIC-PKP2 Phase I/II clinical trial (NCT06109181). LX2020 has been granted Orphan Drug and Fast Track designations by the FDA.
About Lexeo Therapeutics
Lexeo Therapeutics is a New York City-based, clinical stage genetic medicine company dedicated to reshaping heart health by applying pioneering science to fundamentally change how cardiovascular diseases are treated. The company is advancing a portfolio of therapeutic candidates that take aim at the underlying genetic causes of conditions, including LX2006 in Friedreich ataxia (FA) cardiomyopathy, LX2020 in plakophilin-2 (PKP2) arrhythmogenic cardiomyopathy, and others in devastating diseases with high unmet need.
Cautionary Note Regarding Forward-Looking Statements Certain statements in this press release may constitute “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 anticipated benefits of its current product candidates. 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: 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 Quarterly Report on Form 10-Q for the quarterly period ended September 30, 2025, filed with the SEC on November 5, 2025, 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 of new information, future events or otherwise, except as required by law.
Media Response:
Media@lexeotx.com
Investor Response:
Ashley Kaplowitz
akaplowitz@lexeotx.com
Interim Clinical Data from the Phase 1/2 HEROIC-PKP2 Trial of LX2020 for Arrhythmogenic Cardiomyopathy Caused by Mutations in the PKP2 Gene January 12, 2026 Exhibit 99.2
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 regarding the timing, progress and results of preclinical and clinical trials of Lexeo’s gene therapy product candidates and the anticipated benefits of its current product candidates. 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 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 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 Quarterly Report on Form 10-Q for the quarterly period ended September 30, 2025, filed with the SEC on November 5, 2025, 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 of new information, future events or otherwise, except as required by law.
Preliminary Results Demonstrate Increased PKP2 Expression and Potential for LX2020 to Reduce Severe Arrhythmia Burden Mean decrease in non-sustained ventricular tachycardia (NSVT) of 20% across all participants at latest visit (n=8) and 22% at high dose (n=5); key arrhythmia measure correlated with VT risk Mean decrease in premature ventricular contractions (PVCs) of 4% across all participants at latest visit (n=8) and 14% at high dose (n=5) Improvements in Clinical Measures of Arrhythmia Burden PKP2, Plakophilin-2 protein; ACM, Arrhythmogenic Cardiomyopathy; VT, Ventricular Tachycardia. Generally well-tolerated across 10 participants dosed with no clinically significant complement activation Safety Profile Robust, dose-dependent trends in LX2020 transduction and PKP2 protein expression despite fibrotic and fatty cardiac tissue characteristic of ACM Mean increase in PKP2 protein of 93% in low-dose (n=2) and 162% in high dose (n=5) by western blot, assessed at 3 months post dosing Dose-dependent increases observed in mean vector copy number and exogenous mRNA; immunofluorescence demonstrates appropriate co-localization of PKP2 in desmosome Dose-Dependent Transduction and Protein Expression
Arrhythmogenic Cardiomyopathy Caused by Mutations in the PKP2 Gene: Devastating Genetic Heart Disease With Clearly Defined Mechanism of Disease 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: Cardiovascular Genetics (2012). PKP2-ACM is a rare, genetic cardiac disease caused by loss of function mutations in the PKP2 gene 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 symptom and 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 ACM 23% individuals experience SCD as presenting symptom ~60,000 individuals affected by PKP2-ACM in the U.S.
Individuals with ACM Experience High Arrhythmia Burden with a Spectrum of Severity Early indicator of electrical instability that can trigger more severe/sustained arrhythmia Potentially driven by calcium instability; may be improved with flecainide that blocks cardiac fast sodium channels1,2 PVC spikes are associated with worse outcomes including greater risk of sudden cardiac death (SCD)3 >3 ventricular beats in a row, lasting under 30 seconds; self-terminating Occurs when a PVC propagates as a reentry run due to slow conduction or block; slow conduction may be caused by reduced desmosomal integrity and lower cell-to-cell adhesion from PKP2 deficiency4,5 Closely associated with increased risk of sustained VT, ICD shock and SCD3; impacts patient anxiety and quality of life >3 ventricular beats in a row lasting over 30 seconds Can cause collapse, cardiac arrest or SCD; sustained VT may be terminated by ICD shock to restore normal rhythm May be treated with ablation but recurrence is common; 30% experience VT within 1 year of ablation and 50% within 5 years6 SCD, sudden cardiac death; ICD, implantable cardioverter defibrillator; VT, ventricular tachycardia. (1) Cerrone et al. Nature Comm, 2017. (2) Kim et al. Circulation, 2019. (3) Gasperetti A, et al. JAMA Cardiology, 2022; 7(4):378–385. (4) Sato P. et al. Circulation Research, 2009. (5) Oxford E.M et al. Circulation Research, 2007. (6) Daimee et al. Heart Rhythm, 2021 Aug ;18(8):1369-1376. Severity of Arrhythmias Premature Ventricular Contractions (PVCs) Non-Sustained Ventricular Tachycardia (NSVT) Sustained VT / ICD Shock Normal Sinus Rhythm Premature Ventricular Contraction (PVC) Compensatory Pause Ventricular Tachycardia Cardioversion Shock Sinus Rhythm
Premature Ventricular Contractions (PVCs) May Trigger Ventricular Tachycardia (VT); Measures Are Related But Driven by Potentially Different Mechanisms (1) Cerrone et al. Nature Comm, 2017. (2) Kim et al. Circulation, 2019. (3) Sato P. et al. Circulation Research, 2009. (4) Oxford E.M et al. Circulation Research, 2007. PVCs Are a Trigger That Can Precipitate More Severe Arrhythmias VT is Caused When a Trigger (PVC) Meets an Electrical or Structural Vulnerability PKP2 deficient myocytes demonstrate calcium instability; Ca2+ leak can disrupt refractory period and depolarization1,2 PVCs are not reentry loops but can trigger them Calcium instability due to PKP2 deficiency likely driven by downstream proteins, which may take more time to repair versus the desmosome with direct PKP2 function VT occurs when a PVC meets a vulnerability like slow electrical conduction, enabling the premature beat to propagate as a reentry loop3,4 Reentry loops are self-sustaining electrical circuits that override normal rhythm, consistently re-exciting the heart PKP2 deficiency causes electrical and structural vulnerabilities like slow conduction and scarring; hypothesis that VT could be reduced if vulnerabilities are improved even if PVCs persist Ventricular Depolarization Ca2+ Ca2+ Ca2+ PKP2 Deficiency Reduces Cell-to-Cell Adhesion, Slowing Electrical Conduction and Causing Reentry Loops: Absent PKP2 Desmoglein-2 Desmocollin-2 Desmin Desmoplakin Plakoglobin Desmosomal Complex
In People with ACM, Sustained VT Risk is Predicted by Increased PVC Burden and by Non-Sustained VT Events PVC burden in ACM decreases initially after diagnosis but persists long term1 Initial drop driven by lifestyle change (exercise modification) and medication PVCs remain elevated (>500/24h) and variable over disease course While lifestyle modification may reduce PVCs immediately following diagnosis, Lexeo-sponsored SNAPSHOT natural history data suggests that PVCs and NSVT may increase later in disease progression, both of which are associated with greater VT risk 1. Gasperetti A, et al. JAMA Cardiol. 2022;7(4):378–385 VT risk increases with PVCs and NSVT1 Prospective natural history SNAPSHOT (n=15) Participants mean 8 years after diagnosis Median PVC / 24h Median NSVT / 7d Quartile 1 +41% Quartile 3 +20% Quartile 1 Quartile 3
Mutations in the PKP2 Gene are the Most Common Genetic Cause of ACM; LX2020 Delivers a Full-Length PKP2 Gene to Cardiomyocytes, Restoring the Desmosome Cardiac-specific promoter Promoter PKP2 gene Poly-A Rabbit β-globin polyA LX2020 Construct AAVrh.10hPKP2 PKP2-ACM LX2020 Mechanism Absence of PKP2 results in impairment of cardiac desmosomes, leading to slow conduction, 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
LX2020 is Being Evaluated in an Ongoing Phase 1/2 Study (HEROIC-PKP2); Enrollment Completed in Q4 2025 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 measures (PVC, VT, QRS, T-wave inversion) Cardiac Structure & Function (EF, EDV, ESV) Change in Symptoms (NYHA Class and PROs) Vector Transduction / Expression (VCN, mRNA, quantitative WB) ICD, implantable cardioverter defibrillator; EF, ejection fraction; EDV, end-diastolic volume; ESV, end-systolic volume; NYHA, New York Heart Association; PROs, patient reported outcomes; VCN, vector copy number; WB, western blot. Note: LX2020 is administered systemically; participants receive immune suppression with prednisone and sirolimus on the day prior to treatment through ~12 weeks following LX2020 dosing. 2.0x1013 vg/kg 6.0x1013 vg/kg 6.0x1013 vg/kg Cohort 1 n=3 Cohort 2 n=3 Cohort 3 n=4 52-Week Fully Enrolled Fully Enrolled Fully Enrolled
Baseline Characteristics Consistent with PKP2 Arrhythmogenic Cardiomyopathy; More Advanced Disease Observed in High-Dose Cohorts Characteristic Statistic Low-Dose Cohort 1 2.0x1013 vg/kg, N=3 High Dose Cohorts 2 and 3 6.0x1013 vg/kg, N=7 Age, years Mean (SD) Min, Max 28 (6) 22, 34 38 (6.4) 28, 44 Years since diagnosis Mean (SD) Min, Max 3 (3.5) 1, 7 9 (5.4) 2, 15 Male N (%) 3 (100%) 3 (43%) PVC, mean count per 24 hours Mean (SD) Min, Max 2130 (1103) 861, 2859 4217 (1720) 873, 6309 NSVT, total / 7 days Mean (SD) Min, Max 6 (5.2) 2, 12 71 (73.2) 2, 169 T-wave inversion, leads Mean (SD) Min, Max 2 (2.5) 0, 5 3 (1.2) 0, 4 QRS duration, milliseconds Mean (SD) Min, Max 107 (20.5) 84, 124 93 (13.6) 68, 110 RV Function (%) Mean (SD) Min, Max 46 (5.5) 42, 52 40 (7.9) 31, 52 NYHA class Class I (%) Class II (%) 2 (67%) 1 (33%) 7 (100%) 0 (0%)
Baseline Characteristics Consistent with PKP2 Arrhythmogenic Cardiomyopathy, with More Advanced Disease in High-Dose Cohorts Cohort 1 (2.0x1013 vg/kg) Cohort 2 (6.0x1013 vg/kg) Cohort 3 (6.0x1013 vg/kg) Characteristic Participant 1 Participant 2 Participant 3 Participant 4 Participant 5 Participant 6 Participant 7 Participant 8 Participant 9 Participant 10 Age, years 34 22 29 44 43 30 41 41 28 39 Age at diagnosis 27 21 28 29 28 27 30 34 16 37 Gender M M M M F F F F M M PVC per 24h 861 2859 2669 4788 3362 5176 4362 6309 873 4647 NSVT per 7 days 2 3 12 169 22 119 154 2 13 19 T-wave inversion 5 0 2 3 3 3 3 3 4 0 QRS duration, ms 124 84 112 90 90 68 90 94 110 106 RV Function (%) 43 52 42 31 34 33 42 52 43 47 NYHA class I I II I I I I I I I Follow-up, months 12 12 12 9 9 6 6 6 <6 <6 Relevant medical history prior to study Sustained VT, ICD shock, ablation Sustained VT, syncope, ICD shock Sustained VT, syncope Sustained VT, VT storm, ICD shock, ablation Sustained VT, ICD shock Sustained VT, near syncope Sustained VT, syncope, ablation, stable use of flecainide at study start Sustained VT, VT storm, ICD shock, ablation Sustained VT, syncope Safety data summarized for all 10 participants; efficacy data inclusive of 8 participants with > 6 months of follow-up Participant 8 stable on flecainide at study start; no other participants taking background anti-arrhythmic drugs (AAD) at study start AAD, antiarrhythmic drugs.
Treatment with LX2020 Has Been Well Tolerated to Date LX2020 generally well tolerated across ten participants dosed No clinically significant complement activation Elevations in liver function tests (LFT) observed in five participants at the high-dose, treated successfully with modified immunosuppression per the trial protocol: Three participants’ elevations occurred following steroid tapering and resolved with re-introduction of low-dose prednisone Two participants’ elevations occurred prior to steroid tapering and resolved with increased prednisone and sirolimus treatment All elevations have since resolved without other complications or hospitalization, and no other medications were required for resolution No participants discontinued from study One previously disclosed Grade 3 serious adverse event of sustained ventricular tachycardia (VT) was observed three months after dosing in a single participant in the high dose cohort and assessed as possibly treatment related. The participant was successfully treated with anti-arrhythmic medication and discharged with no additional intervention required Interim Safety Update: 10 Participants Dosed
LX2020 Transduction and Transcription Observed in All Participants Post-Dose Levels1 Vector Copies / Diploid Genome LX2020 not detected in pre-dose VCN or mRNA samples as expected. Participant 3 elected not to undergo a post-treatment biopsy. Participant 1 VCN not performed due to insufficient remaining cardiac biopsy tissue following other analyses. Vector Copy Number (VCN) Low dose (n=1)2,3 High dose (n=5) Part. #2 Part. #4 Part. #5 Part. #6 Part. #7 Part. #8 Dose Mean Low dose 1.5 High dose 3.3 Dose-dependent increases observed in mean vector copy number and exogenous mRNA in all participants Exogenous PKP2 Increase (mRNA) Copies / μg Nucleic Acid Low dose (n=2)2 High dose (n=5) Part. #1 Part. #2 Part. #4 Part. #5 Part. #6 Part. #7 Part. #8 Dose Mean Low dose 7.9E+04 High dose 2.7E+05
Increased PKP2 Protein Observed Across Most Participants % Increase PKP2 (Western Blot, GAPDH Normalized) PKP2 expression increased across participants with greater mean response at high dose Fibrofatty tissue (characteristic of ACM) may have impacted biopsy samples from participants 4 and 5; other cardiac tissue samples for VCN and mRNA demonstrate LX2020 transduction and transcription ng/μg Protein Dose Mean Inc. (%) Low dose 93% High dose 162% Pre-Dose Levels Post-Dose Levels Low dose (n=3) High dose (n=5) Part. #1 Part. #2 Part. #3 Part. #4 Part. #5 Part. #6 Part. #7 Part. #8 Not Collected 71% 115% -47% -59% 121% 679% 117%
Appropriate Localization of PKP2 With Other Key Proteins at the Intercalated Disc Pre-Dose Following LX2020 administration, PKP2 protein colocalizes with Cx43 (a gap junction protein) and Ncad (a desmosomal adhesion protein) within cardiac intercalated discs Plakophilin–2 (PKP2) Connexin 43 (Cx43) N-cadherin (Ncad) Merged Merged Post-Dose Merged Merged Merged Participant 4 Participant 5
Improvements Observed Across Clinical Parameters at Latest Visit; PVCs and NSVT Reduced or Stable in Majority of Participants Cohort Part. # Latest Visit (months) ∆ PVC / 24H Baseline LV ∆ NSVT/7d Baseline LV ∆ RVEF2 Baseline LV ∆ PGIC Scale3 Baseline LV Cohort 1 (2E13 vg/kg) #1 (M) 12 861 345 -60% 2 2 0% 43 42 -2% 3 3 #2 (M) 12 2859 3569 +25% 3 1 -63% 52 49 -6% 3 3 #3 (M)1 12 2669 4795 +80% 12 20 +69% 42 41 -2% 3 4 Mean +36% +35% -3% 2/3 no change Cohort 2 Cohort 3 (6E13 vg/kg) #4 (M) 9 4788 5601 +17% 169 44 -74% 31 40 +29% 3 2 #5 (F) 9 3362 3451 +3% 22 18 -18% 34 33 -3% 3 2 #6 (F) 6 5176 4814 -7% 119 199 +67% 33 32 -3% 3 24 #7 (F)1 6 43624163 -5% 154 98 -36% 42 40 -5% 3 3 #8 (F) 6 6309 2532 -60% 2 4 +100% 52 47 -10% 3 1 Mean -14% -22% +2% 4/5 improved Participants started on background anti-arrhythmic therapy during study period to manage PVC spike and VT, respectively. RVEF assessed by cardiac MRI at 6- and 12-months only; RVEF data for participants 4 and 5 from 6-month visit. Patient Global Impression of Change (PGIC) 5-point scale, patient-reported outcome; 3 represents no change from baseline, 1 represents significant improvement, 5 represents significant worsening per patient perception. PGIC result assessed at 9-month visit although Holter data for participant 6 pending as of Jan. 7, 2026 data cut-off date.
Clinically Meaningful Reductions in Arrhythmia Burden Over Time Mean PVC Change: PVCs and NSVT reduced or stabilized in majority of participants with >6 months of follow up -14% mean improvement in PVCs and -22% mean improvement in NSVT at latest visit in high-dose cohort 4 of 5 high-dose participants report improvement relative to baseline on the Patient Global Impression of Change (PGIC) scale, a patient-reported outcome measure n=3 n=8 n=5 n=5 n=2 n=3 Mean NSVT Change: n=3 n=8 n=5 n=5 n=2 n=3 PVC / 24h NSVT / 7d
Summary of Results and Next Steps for LX2020 LX2020 generally well tolerated across 10 participants dosed Biopsies demonstrate robust LX2020 transduction and increased PKP2 expression at 3 months post treatment, with dose-dependent increases: Mean vector copy number of 1.5 at low dose (n=1) and 3.3 at high dose (n=5) Mean exogenous mRNA of 7.9E+04 at low dose (n=2) and 2.7E+05 at high dose (n=5) Mean increase in PKP2 protein expression of 93% at low dose (n=2) and 162% at high dose (n=5) Appropriate PKP2 colocalization observed at cardiac intercalated disc via immunofluorescence staining Improvements in key clinical parameters observed at latest visit, particularly in high-dose cohort: PVCs reduced or stable in majority of participants; 14% mean improvement in high-dose at latest visit NSVT reduced or stable in majority of participants; 22% mean improvement in high-dose at latest visit 4 of 5 high-dose participants report improvement relative to baseline on the Patient Global Impression of Change (PGIC) scale Participants stable across other clinical measures Enrollment completed in Q4 2025; further clinical updates expected in 2026 Biopsy results pending for last two participants in Cohort 3 12-month data available for all high-dose participants in Q4 2026
Lexeo Thanks the Arrhythmogenic Cardiomyopathy Community Individuals and families impacted by genetically mediated cardiovascular diseases are at the center of our mission Lexeo is grateful to the study participants, caregivers, investigators and other members of the ACM community who have helped us reach this exciting milestone We will continue to collaborate with those impacted by PKP2-ACM to increase screening and diagnosis and advance critical research
Thank you
Lexeo Therapeutics Corporate Overview January 2026 Exhibit 99.3
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 Quarterly Report on Form 10-Q for the quarterly period ended September 30, 2025, filed with the SEC on November 5, 2025, 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 of new information, future events or otherwise, except as required by law.
Dedicated to reshaping heart health by applying pioneering science to fundamentally change how cardiovascular disease is treated Genetic medicine leader with rare cardiac disease focus Proven experience in the clinic Platform designed for safety and scalability Individuals and families impacted by Friedreich ataxia
Building a leading cardiac gene therapy platform Differentiated AAVrh10 capsid Genetic cardiac disease expertise Innovative AAV manufacturing Operating experience Deep cardiac genetic medicine know-how, anchored by two clinical and two preclinical programs Strong financial position Cash runway into 2028, supporting multiple value creating milestones Proven cardiac tropism allows for lower doses and improved therapeutic index Optimized Sf9 baculovirus manufacturing platform designed to support future commercial scale-up Leader in genetic medicine for inherited cardiac diseases
Advancing cardiac genetic medicines in diseases with high unmet need Lexeo cardiac programs and expertise: Clinical: LX2006 Friedreich Ataxia Cardiomyopathy LX2020 PKP2 Arrhythmogenic Cardiomyopathy LX2021 Desmoplakin Cardiomyopathy LX2022 Hypertrophic Cardiomyopathy Cardiomyopathies have few disease-modifying therapies and high morbidity/mortality High unmet need Cardiac gene therapy is less competitive, offering opportunity to establish leadership White space Lexeo’s vision is to fundamentally change the course of inherited cardiac disease with a single infusion Transformative potential Proven clinical experience with 27 patients treated using AAVrh10 Deep expertise in genetic cardiac disease models and IND enabling studies Market opportunity: Pre-Clinical:
Majority of mortality and severe complement activation in gene therapy at doses ≥1.0E14 vg/kg Lexeo’s AAVrh10 is a highly differentiated capsid Strong expression in the heart AAVrh10 cardiac tropism No history of clinically significant complement activation Cardiac tropism can reduce systemic dose levels Reduced pre-dose immunosuppression Potentially improved safety profile Distribution to the heart ~1.5x to 2.0x higher with AAVrh10 than AAV9 Gene Therapy Dose Levels (vg/kg)3 3.5E+14 1.2E+12 LX2020 (AAVrh10) LX2006 (AAVrh10) AAV9 AAV8 AAVrh74 AAV9 AAV8 AAV9 Yucatan minipig biodistribution1 ~1.5x higher 5000 10000 0 AAVrh10 AAV9 NHP biodistribution2 ~2.0x higher 2.0% 6.0% 12.0% 10.0% 4.0% 8.0% 0 (1) Data presented at ASGCT 2023. (2) Ballon DJ et al, Human Gene Therapy, 2020. (3) Dose Levels (vg/kg): Lexeo LX2006 (1.2E+12), Lexeo LX2020 (6.0E+13), Zolgensma (1.1E+14), Astellas AT132 low dose (1.3E+14) and high dose (3.5+E14), Elevidys (1.3E+14), Neurogene NGN-401 high dose (3.0+E15 vg fixed, assumes patient weight of 20kg), Pfizer PF-06939926 (low dose 1.0E+14, high dose 3.0E+14, average shown). AAVrh10 AAV9 Copies / μg DNA I-124 Vector Levels (% total body)
Lexeo manufactures AAVrh10 utilizing an optimized Sf9 baculovirus process Innovative approach High yield, high quality Sf9 baculovirus manufacturing platform compared to conventional manufacturing (e.g. HEK based) Optimal potency Higher yields (1.0E15 vg/L) Greater downstream recovery (>55%) Fewer empty AAV capsids (<25%) Improved genomic purity owing to lack of plasmid transfections Scalable manufacturing Sustainable and defined starting materials, similar to therapeutic protein process (e.g. cell banks, virus banks) Low overall complexity Enables robust commercialization Poised to deliver an industry-leading and potentially transformational COGS profile LX2006 selected for FDA CDRP program, created to facilitate CMC registrational readiness and support faster patient access
2025 year in review Announced positive data from Phase I/II studies Completed enrollment in HEROIC Phase I/II study Completed two financings totaling $234M of capital; secured runway into 2028 Received FDA Breakthrough Designation Shared interim Phase I/II safety and efficacy data from low dose cohort Initiated CLARITY-FA natural history study Friedreich Ataxia Cardiomyopathy PKP2 Arrhythmogenic Cardiomyopathy LX2006 LX2020 Appointment of new CFO with commercial finance experience Partnership to advance novel cardiac RNA therapeutics
Our pipeline: focused on diseases with significant unmet need and clear mechanisms Programs: Indication: Gene: Phase I/II Phase II/III 2026 milestones: CARDIOVASCULAR FXN PKP2 CX43 TNNI3 Lexeo retains global rights across all programs. ~5K US prevalence ~60K US prevalence ~35K US prevalence ~25K US prevalence LX2006 LX2020 LX2021 LX2022 Clinical: Pre-clinical: Discovery Preclinical FA(1) Cardiomyopathy DSP(3) Cardiomyopathy PKP2-ACM(2) Hypertrophic Cardiomyopathy (1) Friedreich ataxia. (2) Plakophilin 2 Arrhythmogenic Cardiomyopathy. (3) Desmoplakin. Early 2026 Regulatory Update 1H-26 Initiate SUNRISE-FA 2 Pivotal Trial Q1-26 Data Update 2026 Regulatory Update Q4-26 Data Update Research collaboration with J&J to explore targeted cardiac delivery of AAV gene therapy IND enabling studies
Friedreich Ataxia Cardiomyopathy (FA-CM) LX2006
Cardiac complications are the leading cause of death in Friedreich Ataxia 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 Prevalence: Mortality: ~5,000 ~15,000 Global: US: Standard of care: (2) (2) Cardiac complications account for up to 80% of deaths in those with FA, with an average life expectancy of 35-40 years(1)(4) Omaveloxolone (SKYCLARYS®) is FDA-approved for FA based on neurologic endpoints; cardiac efficacy was not established(3) FA is a rare, progressive and devastating multisystem disease caused by a loss of function mutation in the FXN gene(1) With a typical age of onset between 5 and 15 years(2), individuals with FA experience cardiac and neurological manifestations Cardiac dysfunction in FA presents as cardiac hypertrophy and subsequent heart failure(1); with up to 40% of adults with FA having left ventricular hypertrophy as defined by abnormal LVMI(5)(6) The only approved disease-specific treatment for FA was not evaluated for the treatment of cardiac dysfunction in clinical trials, leaving significant unmet need within FA cardiomyopathy(3) FA, Friedreich Ataxia; FXN, Frataxin; LVMI, Left Ventricular Mass Index. (1) Payne R.M. JACC Basic Transl Sci, 2022;13;7(12):1267-1283. (2) Friedreich’s Ataxia Research Alliance, 2024. (3) Reetz, K., et al. Lancet Neurol, 2025;24(7):614-624. (4) Indelicato, E., et al. Mov Disord, 2024;39(3), 510–518. (5) Clinical Management Guidelines for Friedreich Ataxia. Chapter 4. The heart and cardiovascular system in Friedreich ataxia. 2022. (6) Lexeo Therapeutics, Data on File, 2025.
LX2006 has the potential to treat the root cause of FA cardiomyopathy: the significant decrease in frataxin in the heart AAVrh.10hFXN LX2006 construct: LX2006 mechanism: FXN deficiency results in mitochondrial dysfunction and leads to deficient energy production in hypertrophic cardiomyocytes Transfer of FXN gene to cardiomyocytes is intended to increase frataxin levels in the mitochondria and improve cardiac muscle cell function functional FXN Mitochondria Cardiomyocyte AAV, Adeno-Associated Virus; CAG, Chicken Beta-Actin; cDNA, Copy DNA; FA, Friedreich Ataxia; FXN, Frataxin; Poly-A, Poly Adenosine. Ubiquitous promoter FXN cDNA (full length gene) Rabbit β-globin polyA FA cardiomyopathy: Cardiomyocyte FXN mutations FXN deficiency Mitochondria CAG FXN gene Poly-A
Lexeo’s role in advancing FA cardiomyopathy research Objective: Assess the safety and efficacy of LX2006 in individuals with cardiomyopathy associated with FA Dose: 1.8E11 vg/kg (Cohort 1), 5.6E11 vg/kg (Cohort 2), 1.2E12 vg/kg (Cohort 3) Key Endpoints: frataxin expression, LVMI, lateral wall thickness, troponin, mFARS Status: Ongoing (fully enrolled) SUNRISE-FA and Weill Cornell trials share a similar study design, enabling data from the two studies to be evaluated together Objective: Learn about how heart disease develops and worsens in individuals with FA Dose: N/A Key Assessments: LVMI, lateral wall thickness, troponin, mFARS, other biomarkers, cMRI and functional measures Status: Ongoing (actively recruiting) Objective: Assess the safety and efficacy of LX2006 in individuals with cardiomyopathy associated with FA Dose: 1.2E12 vg/kg Primary Endpoints: Any increase from baseline frataxin expression and >10% LVMI reduction measured at time point earlier than 12 months Status: To be initiated in 1H-26 Phase I/II Trial Observational Natural History Study Phase III Pivotal Trial
LX2006 clinical data show sustained or deepening improvements in the majority of participants across both cardiac and neurologic measures of FA LX2006 generally well tolerated across 17 participants dosed with no Grade 3+ SAEs to date No clinically significant complement activation Minimal, transient LFT elevations; no participants above 3X upper limit of normal No signs of frataxin over-expression observed in cardiac tissue One previously disclosed, possibly treatment-related Grade 2 event of asymptomatic myocarditis observed one year after dosing FA-COMS Natural History(2) (16-40yrs Cohort) LX2006 (18-35yrs) Mean LVMI Change Participants at 12-mo visit -23% Participants at 6-mo visit1 (n=6) -18% Cohorts 2 and 3 at 12-mo visit -33% Cohorts 2 and 3 at 6-mo visit1 (n=3) -28% Mean FXN change from baseline FA functional improvement: mFARS Cardiac frataxin (FXN) increased by LCMS with dose-dependent response All subjects demonstrate an increase from baseline, exceeding FDA-aligned threshold for pivotal study 11 of 16 participants improved or stabilized relative to baseline mFARS at latest visit Evidence of neurological functional improvement, compared to natural history progression of disease LX2006 generally well tolerated Cardiac MRI Among participants with abnormal baseline LVMI (key inclusion criteria for pivotal study; n=6): Exceeding 10% FDA-aligned threshold for pivotal study at 12 months and earlier FXN, Frataxin; LCMS, Liquid chromatography mass spectrometry. FXN expression assessed with academic LCMS assay, assay validation in progress for pivotal study. Note: Natural history for illustrative purposes only. Differences exist between trial designs and participant characteristics, and caution should be exercised when comparing data across unrelated studies. (1) Participant 11 6-month visit not conducted due to hurricane; 3-month visit used for mean calculations. (2) Patel, M. et al. Ann Clin Transl Neurol, 2016. 3: 684-694. Progression of Friedreich ataxia: quantitative characterization over 5 years.https://doi.org/10.1002/acn3.332 n=16 n=16(1) n=13 n=8 n=4 % Increase FXN from Baseline Mean change from baseline
Plakophilin-2 Arrhythmogenic Cardiomyopathy (PKP2-ACM) LX2020
Arrhythmogenic cardiomyopathy caused by mutations in the PKP2 gene: devastating genetic heart disease with clearly defined mechanism PKP2-ACM is a rare, genetic cardiac disease caused by loss of function mutations in the PKP2 gene 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 symptom and 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) Prevalence: Mortality: ~60,000 US 23% Standard of care: of individuals experience SCD as presenting symptom Current management methods are focused on relieving symptoms and preventing SCD, and do not address the underlying cause of ACM. 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: Cardiovascular Genetics (2012).
Mutations in the PKP2 gene are the most common genetic cause of ACM; LX2020 delivers a full-length PKP2 gene to cardiomyocytes, restoring the desmosome PKP2 cDNA (full length gene) Rabbit β-globin polyA AAVrh.10hPKP2 LX2020 construct: PKP2-ACM: LX2020 mechanism: Cardiac-specific promoter Absence of PKP2 results in impairment of cardiac desmosomes, leading to abnormal cardiac rhythms (arrhythmias) and onset of cardiac dysfunction 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 Desmosomal сomplex AAVrh10 ACM, arrhythmogenic cardiomyopathy. Desmin Desmoplakin DES DES Plakoglobin PKP2 Desmoglein-2 Desmocollin-2 DES DES Desmosomal сomplex Absent PKP2 Desmoglein-2 Desmocollin-2 Desmin Desmoplakin Plakoglobin Promoter PKP2 gene Poly-A
Individuals with ACM experience high arrhythmia burden with a spectrum of severity Early indicator of electrical instability that can trigger more severe/sustained arrhythmia >3 ventricular beats in a row, lasting under 30 seconds; self-terminating Closely associated with increased risk of sustained VT, ICD shock and SCD1; impacts patient anxiety and quality of life >3 ventricular beats in a row lasting over 30 seconds Can cause collapse, cardiac arrest or SCD; sustained VT may be terminated by ICD shock to restore normal rhythm SCD, sudden cardiac death; ICD, implantable cardioverter defibrillator; VT, ventricular tachycardia. (1) Gasperetti A, et al. JAMA Cardiology, 2022; 7 Severity of Arrhythmias Premature Ventricular Contractions (PVCs) Non-Sustained Ventricular Tachycardia (NSVT) Sustained VT / ICD Shock Normal Sinus Rhythm Premature Ventricular Contraction (PVC) Compensatory Pause Ventricular Tachycardia Cardioversion Shock Sinus Rhythm
Phase I/II Trial Lexeo’s role in advancing PKP2-ACM research Retrospective EMR Review and Prospective Observational Natural History Study Objective: Assess the safety and efficacy of LX2020 in individuals with PKP2-ACM Dose: 2.0E13 vg/kg (Cohort 1), 6.0E13 vg/kg (Cohorts 2, 3) Key Endpoints: PKP2 expression, VT, PVC, QRS, T-wave inversion, cardiac function, PROs Status: Ongoing (fully enrolled, n=10) Objective: Evaluate the clinical burden of illness for patients with PKP2-ACM, and prospectively evaluate changes in key cardiac parameters and patient-reported outcome measures (PROs) associated with PKP2-ACM progression Dose: N/A Key Assessments: VT, PVC, QRS, T-wave inversion, cardiac function, PROs Status: Ongoing (actively recruiting)
Interim results demonstrate increased PKP2 expression and potential for LX2020 to reduce severe arrhythmia burden n=3 n=8 n=5 n=5 n=2 n=3 n=3 n=8 n=5 n=5 n=2 n=3 Mean PKP2 change from baseline (western blot, GAPDH normalized) Mean PVC change PVCs reduced or stabilized in majority of participants with >6 months of follow up -14% improvement in mean PVCs at latest visit in high-dose cohort Mean NSVT change NSVT reduced or stabilized in majority of participants with >6 months of follow up -22% improvement in mean NSVT at latest visit in high-dose cohort LX2020 generally well tolerated LX2020 generally well tolerated across ten participants dosed No clinically significant complement activation Elevations in liver function tests (LFT) observed in five participants at the high-dose, treated successfully per the trial protocol with no complications or hospitalization(2) No participants discontinued from study One previously disclosed Grade 3 serious adverse event of sustained ventricular tachycardia (VT) was observed three months after dosing. This event is consistent with the natural course of PKP2-ACM and its known clinical manifestations. The participant was successfully treated with anti-arrhythmic medication and discharged with no additional intervention required. (1) Participant 3 elected not to undergo a post-treatment biopsy (2) Three participants’ elevations occurred following steroid tapering and resolved with re-introduction of low-dose prednisone; two participants’ elevations occurred prior to steroid tapering and resolved with increased prednisone and sirolimus treatment; all elevations have since resolved without other complications or hospitalization, and no other medications were required for resolution Patient reported outcomes 4 of 5 participants at high dose report improvement relative to baseline on the Patient Global Impression of Change (PGIC) scale NSVT / 7d ng/μg Protein PVC / 24h
Lexeo is also advancing two preclinical cardiac gene therapy programs LX2021 +2026 research collaboration with Johnson & Johnson exploring novel routes of administration for cardiac AAV gene therapy to maximize safety and efficacy LX2021 Desmoplakin Cardiomyopathy LX2022 Hypertrophic Cardiomyopathy High unmet need characterized by extensive fibrosis, high arrhythmic risk, and high heart failure burden 30-50% mortality within 5 years of diagnosis for dilated phenotype ~35K patients in U.S. IND-enabling studies and regulatory engagement expected in 2026 TNNI3 variants compose 3-5% of all HCM cases, causing cardiomyopathy, clinical heart failure and shortened lifespan Non-obstructive phenotype, often with preserved EF; myosin inhibitors not effective ~25K patients in U.S.
Lexeo – a leader in cardiac gene therapy Leader in cardiac genetic medicine addressing high unmet need and clear market opportunity Catalyst rich 2026 with multiple key milestones expected across two clinical stage programs Differentiated AAVrh10 capsid and innovative Sf9 baculovirus manufacturing platform Advancing towards pivotal stage; Phase III trial in FA-CM expected to initiate in 2026 with potential path to accelerated approval Strong financial position with cash runway into 2028 1 2 3 4 5
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