Slides
Page 1
Interim Data Update of LX2006 for the Treatment of Friedreich Ataxia Cardiomyopathy April 7, 2025 1
Page 2
2 Forward Looking Statements This presentation contains “forward-looking statements” within the meaning of the federal securities laws, including, but not li mited 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, the anticipated benefits of its current product candidates, the timing and likelihood of regulatory approval, and expected cash runway. Words such as “may,” “might,” “will,” “objective,” “intend,” “should,” “could,” “can,” “would,” “expect,” “believe,” “design,” “estimate,” “predict,” “pote ntial,” “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 expecte d 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 year ended December 31, 2024, filed with the SEC on March 24, 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.
Page 3
3 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 leading cause of death for those with FA, often occurring by mid-30s(3)(4) Journey to Diagnosis Life Expectancy Cardiac Dysfunction Diagnosis, Management and Treatment for FA Cardiomyopathy is Critical (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.
Page 4
4 Interim Results Support LX2006 as Potential First-in-Class Treatment for FA Cardiomyopathy; Expect to Initiate Registrational Study By End of 2025 or Early 2026 Cohort 3 cardiac biopsies evaluated via LCMS demonstrated dose response relative to Cohorts 1-2 with increase of 115% on average from baseline frataxin expression (n=4) FDA alignment on key elements of accelerated approval pathway: co-primary endpoints of 10% reduction in LVMI and any increase in frataxin expression above baseline Generally well-tolerated across 16 participants dosed to date, no signs of complement activation or over-expression observed in cardiac tissue Participants with abnormal LVMI at baseline achieved a mean reduction of 25% in LVMI at 12-month timepoint or sooner (n=6) Observed deepening of LVMI reduction over time, supported by improvements in lateral wall thickness and high sensitivity troponin Results to date demonstrate comprehensive improvements in cardiac health in biomarkers associated with mortality in Friedreich ataxia Durable Improvements in Key Cardiac Biomarkers Robust Protein Expression FA, Friedreich Ataxia; FXN, Frataxin; LVMI, Left Ventricular Mass Index; LCMS, Liquid Chromatography Mass Spectrometry. FDA Alignment Safety Profile
Page 5
5 FA is a rare, devastating and progressive multi-system disordercaused 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(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) Cardiac Dysfunction is the Leading Cause of Death in Friedreich Ataxia ~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)
Page 6
LX2006 Has the Potential to Treat the Root Cause of FA Cardiomyopathy: The Significant Decrease in Frataxin in the Heart 6 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. 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
Page 7
LX2006 is Being Evaluated in Parallel Lexeo-Sponsored SUNRISE-FA and Weill Cornell Investigator Initiated Trials 7 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; 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
Page 8
Recent FDA Alignment Guides Future Pivotal Study Inclusion Criteria and Co-Primary Endpoints to Support Accelerated Approval 8 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. Newly Announced Regulatory Alignment Target Increase in Frataxin Expression
Page 9
Baseline Characteristics Consistent with Cardiac Phenotype of FA 9 Cohort 1 (1.8x1011 vg/kg) Cohort 2 (5.6x1011 vg/kg) Cohort 3 (1.2x1012 vg/kg) Participant Characteristic Participant # Participant # Participant # #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #13 #12 #14 #15 #16 Gender F M F F M M F M F F F F M F M F LVMI, g/m2 81 109 53 65 60 86 63 74 57 66 100 110 85 49 72 56 LWT, mm 12 11 8 11 9 9 9 10 7 10 9 13 8 6 7 7 Hs Troponin I, pg/ml 224 148 108 2023 5 22 38 376 820 650 115 2518 25 11 11 42 Follow-up, months 24 24 21 18 18 24 6(2) 6 18 12 9 6 6 <6 <6 <6 Cardiac Biopsy ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Abnormal(1) High-normal(1) (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 and for hs-troponin I abnormal defined as 99th percentile and high-normal defined as level above the threshold to detect individuals at risk of future CV events as referenced in Zeller at al. European Heart Journal (2014) 35, 271–281. Normal LVMI range for males: 39-85 g/m2 and normal LVMI range for females: 30-68 g/m2. (2) Remote 6-month visit, MRI not conducted. • 6 of 16 participants dosed to date have abnormal LVMI at baseline; key inclusion criteria for future pivotal study • Safety data summarized for all 16 participants dosed to date; efficacy data inclusive of 12(2) participants with > 6 months of follow-up Normal(1)
Page 10
Treatment with LX2006 Has Been Generally Well Tolerated to Date 10 • No signs of complement activation or other immunogenicity • No signs of frataxin over-expression observed in cardiac tissue • No participants discontinued from either study • One previously disclosed, possibly treatment-related Grade 2 event of asymptomatic myocarditis observed one year after dosing
Page 11
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 Frataxin Expression Across All Participants Evaluated at 3-Months Post Treatment Utilizing LCMS 11 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:
Page 12
Participants with Abnormal LVMI at Baseline: Improvements in Key Clinical Parameters at Latest Visit, with Latest Visit Average LVMI Reduction of 27% 12 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% 1.3→1.0 -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
Page 13
(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 13 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 (threshold for co-primary endpoint in registrational study) ✓ Low dose responders maintain LVMI response out to 24 months 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 100→70 85→74 81→66 109→95 86→81 110→43
Page 14
Participants with Abnormal LVMI at Baseline: LVMI Reductions Supported by Improvements in Lateral Wall Thickness and High-Sensitivity Troponin I 14 Change from Baseline (mm) Note: Participant 7 remote 6-month follow-up, biomarkers unavailable. Change in LWT for Participants with Abnormal LVMI at Baseline Change in Hs-TnI for Participants with Abnormal LVMI at Baseline -6.0 -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0 BL 6 Mo 9 Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo Change from Baseline (%) (100%) (80%) (60%) (40%) (20%) – 20% 40% BL 6 Mo 9 Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo Cohort 1 (n=3) Cohort 2 (n=2) Cohort 3 (n=1)
Page 15
Participants with Normal LVMI at Baseline Showed Improvement or Stabilization in Key Clinical Parameters at Latest Visit 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 #3 (F) Normal 21 -9.4% 53 → 48 +12.5% 0.8 → 0.9 -34.3% 108 → 71 Participant #4 (F) High normal 18 -9.2% 65 → 59 -9.1% 1.1 → 1.0 -46.5% 2023 → 1083 Participant #5 (M) Normal 18 +5.0% 60 → 63 -11.1% 0.9 → 0.8 -57.1% 7 → 3 Cohort 2 (5.6E11 vg/kg) Participant #8 (M) High normal 6 -9.5% 74 → 67 -10.0% 1.0 → 0.9 -68.6% 376 → 118 Participant #9 (F) Normal 18 +3.5%(1) 57 → 59 -11.0%(1) 0.7 → 0.7 -93.5% 820 → 53 Participant #10 (F)(2) High normal 12 +23.0% 66 → 81 +37.8% 1.0 → 1.3 +1857.2%(3) 650 → 12722 Note: Participant #7 did not complete 6-month cMRI visit and not included on slide. Normal LVMI range for males: 39-85 g/m2 and normal LVMI range for females: 30-68 g/m2. (1) Indicates 12-month timepoint as 18-month cMRI not performed in SUNRISE-FA. (2) Approximately 1 year post treatment Participant #10 experienced-flu like symptoms. Laboratory testing and imaging a few weeks later suggested possible focal myocarditis, biomarkers potentially confounded by myocarditis. (3) Indicates 18-month timepoint. Participants with Normal LVMI at baseline with ≥6 months of follow-up Improved Stabilized Worsened 5 of 6 participants stay within normal LVMI range as of latest visit; Only exception was participant with previously disclosed myocarditis at 12 months2
Page 16
All Participants (n=12): Majority Reach or Remain in the Normal Range for LVMI at Latest Visit 16 Cohort 1 (n=3) Cohort 2 (n=1) Cohort 3 (n=1) 0 20 40 60 80 100 120 BL 6 Mo 9 Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo LVMI (g/m2) for All Male Participants LVMI (g/m2) for All Female Participants LVMI (g/m2) 0 20 40 60 80 100 120 BL 6 Mo 9 Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo Cohort 1 (n=3) Cohort 2 (n=4) Cohort 3 (n=0) LVMI (g/m2) Note: Normal LVMI range for males: 39-85 g/m2 and normal LVMI range for females: 30-68 g/m2. Participant 7 remote 6-month follow-up, biomarkers unavailable. (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. Normal Range Normal Range Participant 10
Page 17
All Participants (n=12): Improvements in Lateral Wall Thickness and High-Sensitivity Troponin I Observed Across Participants Regardless of Baseline LVMI 17 Change from Baseline (mm) Note: Participant 7 remote 6-month follow-up, biomarkers unavailable. *Participant 10 not included in Hs-TNI chart due to scale. Values are +29% at 6M, +45% at 9M, +2,702% at 12M and +1,857% at 18M. Change in Lateral Wall Thickness Change in High-Sensitivity Troponin I* -6.0 -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 BL 6 Mo 9 Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo Change from Baseline (%) (100%) (80%) (60%) (40%) (20%) – 20% 40% BL 6 Mo 9 Mo 12 Mo 15 Mo 18 Mo 21 Mo 24 Mo Cohort 1 (n=6) Cohort 2 (n=5) Cohort 3 (n=1) Cohort 1 (n=6) Cohort 2 (n=4) Cohort 3 (n=1) Participant 10
Page 18
(3) (1) 5 (4) 1 2 (5) (2) (11) (7) (3) (1) -12 -10 -8 -6 -4 -2 0 2 4 6 All Participants (n=12): Evidence of Functional Improvement Observed Across Participants Over Time Regardless of Baseline Status 18 (1) 7 1 9 13 -2 0 2 4 6 8 10 12 14 Change from Baseline (latest visit) Improvement Improvement Modified Friedreich’s Ataxia Rating Scale (mFARS): All Participants Kansas City Cardiomyopathy Questionnaire (KCCQ-12): SUNRISE-FA Participants Change from Baseline (latest visit) Note: Participant 7 remote 6-month follow-up, functional data unavailable. Participant: #8 #12 #13 #11 #10 #4 #5 #9 #3 #1 #2 #6 Month visit: 6 6 6 9 12 18 18 18 21 24 24 24 > 12-month visit Participant: #12 #11 #10 #9 #6 Month visit: 6 9 12 18 24
Page 19
Interim Data Inform Preliminary Pivotal Trial Design: Registrational Single Arm Study with External Comparator 19 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
Page 20
Large Unmet Need Remains in FA-CM Across Individuals with Early Signs of Cardiac Dysfunction to Later Stage Hypertrophy 20 Significant Market Opportunity • Significant commercial opportunity to impact the leading cause of death in FA • While planned pivotal study will focus on severe FA-CM, Phase 1/2 results demonstrate the potential of LX2006 to positively impact cardiac health in those with earlier stages of disease • Heart failure guidelines recommend intervention when individuals present with structural or functional cardiac abnormalities even in the absence of symptomatic heart failure(5) • LX2006 will be studied alongside omaveloxolone, the current standard of care for neurologic symptoms in adults, and may be complementary with other investigational treatment approaches in the future ~25% under 18(1) ~75% Adult(3)(4) 12,000 Individuals with FA-CM globally(2) ~60% Hypertrophy (abnormal LVMI) ~40% signs of cardiac dysfunction ~60% signs of cardiac dysfunction ~40% Hypertrophy (abnormal LVMI) (1) 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. (2) Friedreich’s Ataxia Research Alliance, 2024. (3) Pousset, F. et al. JAMA Neurol, 2015;72(11):1334-1341. (4) Clinical Management Guidelines for Friedreich Ataxia. Chapter 4. The heart and cardiovascular system in Friedreich ataxia. 2022. (5) 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
Page 21
Summary of Results and Next Steps for LX2006 21 • LX2006 (AAVrh10.hFXN) has been generally well tolerated with no signs of complement activation or other immunogenicity to date • All biopsies showed increase in FXN expression at 3 months post treatment; Cohort 3 biopsies achieved mean increase of 115% from baseline • Improvements in key clinical parameters observed as of most recent visit in participants with abnormal LVMI at baseline: ‒ 5 of 6 participants experienced >10% reduction in LVMI at 12-month timepoint or sooner ‒ Reductions in LVMI deepen over time and are supported by improvements in other markers of cardiac structure and health, including lateral wall thickness and high-sensitivity troponin I • FDA alignment on accelerated approval pathway and co-primary endpoints of LVMI reduction and frataxin protein expression supported by results to date • In Q2’25, beginning enrollment for prospective natural history study to serve as concurrent external control arm for future registrational study • Ongoing dialogue with regulators to finalize registrational trial protocol ‒ Expect to initiate registrational study by early 2026
Page 22
Thank you