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November 10, 2025 Scaling new heights in the fight against heart disease
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2 Forward-looking statement This presentation contains forward-looking statements within the meaning of Section 27A of the Securities Act and Section 21E of the Securities Exchange Act of 1934, as amended, that are based on our management’s beliefs and assumptions and on information currently available to our management. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. All statements other than statements of historical facts contained in this presentation, including statements regarding business strategy, plans and strategic priorities; the clinical, therapeutic and market potential of and expectations regarding our product candidates, platforms and proprietary capabilities; development plans for Tenaya’s product candidates;availability and content of data from MyPEAKTM-1 and RIDGETM-1; expectations regarding the impact of the FDA’s clinical hold on data milestones and development timelines targeted populations for clinical trials and treatments; anticipated 2025-26 milestones; the sufficiency of Tenaya’s cash runway to fund operations, as well as statements regarding industry trends, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “purpose,” “focus,” “plan,” “potential,” “may,” “future,” “anticipated,” “objective,” or the negative of these terms or other similar expressions. We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. These forward-looking statements are subject to time, risks, uncertainties and assumptions described in our filings with the SEC, including, but not limited to the section titled “Risk Factors” in our Form 10-Q for quarter ended September 30, 2025, and other documents we have filed, or will file with the SEC. These filings, once filed, are or will be available on the SEC website at www.sec.gov. Such risks include, among other things: the availability of data at the referenced times; the timing of the initiation, progress, completion and potential results of our clinical trials and preclinical studies; our ability to advance product candidates into, and successfully complete, clinical trials and preclinical studies; the potential for clinical trials of our product candidates to differ from preclinical, preliminary, interim or expected results; the potential for the FDA or other regulatory agencies to conclude at any time that our product candidates may not have an appropriate risk/benefit profile; the timing or likelihood of regulatory filings and approvals; our estimates of the number of patients who suffer from the diseases we are targeting and the number of patients thatmay enroll in our clinical trials; our ability to successfully manufacture and supply our product candidates for preclinical studies, clinical trials and for commercial use, if approved; our ability to commercialize our product candidates, if approved; future strategic arrangements and/or collaborations and the potential benefits of such arrangements and/or collaborations; our estimates regarding expenses, capital requirements and needs for financing, and our ability to obtain capital; our ability to retain the continued service of our key personnel and to identify, hire and retain additional qualified professionals; our ability to obtain and maintain intellectual property protection for our platforms, programs and product candidates; our ability to contract with third-party suppliers and manufacturers and their ability to perform adequately; the pricing, coverage and reimbursement of our product candidates, if approved; and developments relating to our competitors and our industry, including competing product candidates and therapies; general economic and market conditions; and other risks. These risks are not exhaustive. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements. In light of the significant uncertainties in these forward-looking statements, you should not regard these statements as a representation or warranty by us or any other person that we will achieve our objectives and plans in any specified time frame or at all. The forward-looking statements made in this presentation relate only to events as of the date on which such statements are made. Except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions, and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. This presentation discusses product candidates that are under clinical study and have not yet been approved for marketing by the U.S. Food and Drug Administration. No presentation is made as to the safety or efficacy of these product candidates for the use for which such product candidates are being studied. This presentation contains trademarks, service marks, trade names and copyrights of Tenaya Therapeutics, Inc. and other companies which are the property of their respective owners.
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3 Faraz Ali, MBA Chief Executive Officer • Opening Remarks – Faraz Ali • TN-201 Program Overview – Whit Tingley • MyPEAK-1 Interim Data – Whit Tingley • Conclusions and next steps – Faraz Ali • Q&AWhit Tingley, M.D., PhD Chief Medical Officer Agenda & speakers
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4 https://doi.org/10.1093/cvr/cvaf200 Late-breaker presentation at AHA.25 with simultaneous publication in Cardiovascular Research
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5 Interim Cohort 1 and Cohort 2 data highlights • TN-201 was well tolerated at BOTH the 3E13 vg/kg dose and 6E13 vg/kg doses • Optimized IS resulted in reduced steroid use in Cohort 2SAFETY • MyBP-C protein levels increased over time (N=4), incl. 2 with baseline biopsies • >2x higher transduction and MyBP-C expression observed in first evaluable Cohort 2 patient BIOPSY • Deeper, consistent and durable responses in Cohort 1, with multiple parameters (biomarkers, hypertrophy, heart failure symptoms) improving meaningfully • Hypertrophy reductions compare favorably to data from other studies CLINICAL RESPONSE PVC = Premature ventricular contractions • Continued follow-up of Cohort 1 and Cohort 2 patients • Dosing patients following implementation of FDA-requested changes • Seek regulatory feedback in 2026 on late-stage development plans NEXT STEPS Vg/kg = vector genome/kilogram IS = immunosuppression MyBP-C = myosin binding protein C • All patients have objectively severe nonobstructive HCM, with levels of hypertrophy significantly above average, despite standard-of-care treatment DISEASE BURDEN
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6 Clinical hold status • U.S. Food and Drug Administration (FDA) placed hold on MyPEAK -1 Phase 1b/2a clinical trial with request for certain protocol amendments o Primary aim: standardize patient monitoring and management of immunosuppressive regimen o Revised protocol has been submitted for review • Requests followed proactive correspondence with the FDA related to future plans for the TN-201 program • No meaningful treatment-related safety events have occurred since the most recent DSMB reviews • No anticipated impact to data milestones or development timelines DSMB = Data Safety Monitoring Board
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7 SAFETY Taking a comprehensive approach to safety DOSE MONITORING CAPSID IMMUNOSUPPRESSION • Temporary prophylactic sirolimus and prednisone • Complement inhibitor available (not used to date) • In-hospital monitoring for one week after infusion • Frequent lab assessments enable safe & personalized withdrawal of immunosuppressives • Close oversight by DSMB of experts in cardiology, hepatology, immunology, and AAV therapy • AAV9 is the most widely used serotype worldwide >5000 patients dosed • Preclinical studies indicate higher expression vs. other serotypes • Ful-length copy of human gene • Promoters and regulatory elements enable preferential expression in the heart • Low-to-mid 1013 vg/kg purposefully chosen to optimize for safety and efficacy CASSETTE AAV = Adeno-associated virus
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TN-201 for MYBPC3-associated HCM
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9 A severe and progressive autosomal dominant condition affecting adults, teens, children and infants GABE | AGE 10 Living with MYBPC3+ HCM 1. Sedaghat-Hemedani, et al., Clin Res Cardiol 2018 2. Ho, et al, Circulation 2018 3. Marston, et al, Eur Heart Jrnl 2021 MYBPC3-associated HCM is estimated to affect 120,000 people in the U.S. alone(1) HCM HEART • Significant functional impairment • Social and psychological impacts • Symptoms include shortness of breath, fainting, chest pain, fatigue, palpitations, arrhythmias • Elevated risk of sudden cardiac death and heart failure Thickened left ventricle ~57% of identified genetic variants underlying familial HCM are MYBPC3 mutations (2) of genetic variants underlying childhood- onset HCM are MYBPC3 mutations (3) >30%
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10 TN-201 is the first gene therapy being developed for MYBPC3-associated HCM(1) MyBP-C = Myosin-binding protein C MyBP-C protein present in sarcomere TN-201 Mechanism of Action MYBPC3 Pathophysiology Heterozygous mutations in the MYBPC3 gene lead to significantly lower levels of MyBP-C protein and dysregulated cardiac contractility1 TN-201 delivers a full-length, functional copy of the MYBPC3 gene to cardiomyocytes using the most widely dosed capsid, AAV92 Expression of the MYBPC3 gene increases MyBP-C protein levels and is expected to restore sarcomeric function, reduce hypertrophy, and halt disease progression3 1O'Leary, et al., J Mol Cell Cardiol 2019 2Byrne, et al., Mol Ther 2025 3Greer-Short, et al., Nat Commun 2025
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11 Design • Open-label, multi-center, dose-escalation and dose-expansion • 52-week trial period with four-year safety and efficacy follow-up • Cardiac biopsies at baseline, post-dose and ~52 weeks (effective with Cohort 1, patient 3) DSMB = Data Safety Monitoring Board Study Objectives • Safety, tolerability • Dose-finding • Pharmacodynamics MyPEAK-1 Phase 1b/2 clinical trial design Endpoints • Safety and tolerability • Transgene uptake and expression • Plasma biomarkers • Structural/hemodynamic changes • Functional changes • Symptom improvement Seeking directional consistency across multiple parameters over time with the goal of halting or even reversing steady disease progression We are here
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Interim MyPEAK-1 Data for Cohorts 1 & 2
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13 MyPEAK-1: Patients in both cohorts have more severe disease burden vs. average HCM patient 1Ho, et al; Circulation 2018 2Rowin, et al; Circ Arrhytm EP 2020 3Olivotto, et al; JACC 2008 4Maron, et al; JACC Heart Fail 2018 5Maurizi, et al; Circulation 2024 6Cui, et al; JACC 2019 7Neubauer, et al; JACC 2019 8Okamoto, et al; Int Heart J 2013 Average / % of HCM Cohort 1 Cohort 2 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Gender Male (63%)1 Female Female Male Female Female Female Phenotype nHCM (72%)1 nHCM nHCM nHCM nHCM nHCM nHCM Age at Dose 50y1 27 43 47 60 48 63 LVMI (g/m2) F: 89 | M: 1043 174 105 178 110 143 138 Myectomy 18%5 Yes Yes Yes - Yes - ICD 21%1 Yes Yes Yes Yes Yes Yes NT proBNP 563 pg/mL7 1884 351 913 337 1013 465 Troponin I 27 ng/L8 46 34 53 10 27 8 NYHA Class 50% ≥ II4 II III II II II II Baseline Characteristics • Substantial hypertrophy • All high-risk with ICD • Majority with history of myectomy • All symptomatic • Anti-AAV9 neutralizing antibody titers ≤1:40 LEGEND Typical for HCM Abnormal for HCM Very abnormal for HCM nHCM = nonobstructive HCM LVMI = left ventricular mass index ICD = implantable cardiac defibrillator NT proBNP = N‐terminal pro‐B‐type natriuretic peptide NYHA = New York Heart Association
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14 MyPEAK-1: Cohort 1 follow up ≥52 weeks and most Cohort 2 ≥ 26 weeks • All patients other than Patient 5 have completed every visit and remain in study • Subsequent results come from a July 2025 data cut Week 12 Week 26 Week 40 Week 52 Week 78 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Lost-to-follow-up Week 4 Cohort 1 (3E13 vg/kg) Cohort 2 (6E13 vg/kg) Amount of Follow-Up
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15 MyPEAK-1 safety: TN-201 has been well tolerated at both doses • Majority of treatment-emergent adverse events were mild, transient and/or reversible • Nausea (n=5) was the most common treatment-emergent adverse event • Two treatment-related serious adverse events (SAEs) occurred • One SAE of moderate (Grade 2) transaminase elevations, treated with IV steroid in hospital • One SAE of mild (Grade 1) complement elevation monitored in hospital • Majority of patients (n=4) experienced reversible elevations in liver enzymes • Elevations normalized after additional steroid treatment • All transaminase elevations asymptomatic, with no change in bilirubin or liver synthetic function • Two patients in Cohort 2 experienced laboratory abnormalities, including complement elevation, related to innate immune response within 1 week of dosing • Abnormalities resolved in days without additional treatment or organ involvement • All 6 patients have tapered off prophylactic immunosuppression with prednisone and sirolimus • No signs of cardiotoxicity, including no declines in left ventricular ejection fraction (LVEF)
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16 MyPEAK-1: Optimized immunosuppression successfully reduced steroid requirements in Cohort 2 AST = aspartate aminotransferase ALT = alanine aminotransferase IS Adjustments During Cohort 1 • Reduced maximum starting dose of prednisone dose from 80mg to 60mg • Sirolimus initiated earlier (Day -7) • Weekly monitoring during taper Cohort 2 Results • Despite higher dose of TN-201, Cohort 2 had fewer, lower elevations in AST/ALT • Prednisone taper shorter for Cohort 2 (82±23 days) vs. Cohort 1 (262±98 days) IV methylprednisolone Liver Enzyme Levels & Prednisone Dose Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
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17 MyPEAK-1: TN-201 DNA and RNA levels across doses and over time 2.1 0.8 2.1 0.8 1.4 4.7 0.0 1.0 2.0 3.0 4.0 5.0 Patient 1 (Week 8) Patient 1 (Week 52) Patient 2 (Week 8) Patient 2 (Week 52) Patient 3 (Week 26) Patient 6 (Week 12) TN-201 DNA in Cardiac Biopsy* *Patients 4 and 5 had not yet provided post-dose biopsy at time of data cut 3E13 vg/kg Cohort 6E13 vg/kg Cohort* TN-201 DNA & RNA Levels • Assays specific for TN-201 DNA & TN-201 mRNA • Patient 6 had a >2x increase in TN-201 DNA levels following 2x increase in dose • Levels across both cohorts exceed threshold necessary for efficacy in preclinical studies • TN-201 mRNA expression clearly detected at first post-dose biopsy and increases over time; initial Cohort 2 mRNA level higher than Cohort 1 • Increasing TN-201 mRNA expression consistent with simultaneous increase in MyBP-C protein levels TN-201 DNA copies/genome
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18 MyPEAK-1: Higher dose resulted in greater increase in MyBP-C protein levels Interim MyBP-C Protein Levels • Quantitative assay sensitive, but need baseline to quantify full amount of TN-201-derived MyBP-C protein • Cohort 1 MyBP-C protein levels increased simultaneous with increase in RNA • First patient from Cohort 2 shows dramatic increase only 12 weeks post-dose • DNA and RNA similarly follow dose response in Cohort 2 Change in MyBP-C Protein Levels Over Time 5% 2% 5% 14% 0% 5% 10% 15% 20% Patient 1 (Weeks 8 to 52) Patient 2 (Weeks 8 to 52) Patient 3 (Baseline to Week 52) Patient 6 (Baseline to Week 12) 3E13 vg/kg Cohort 6E13 vg/kg Cohort* Relative Increase in MyBP-C Protein Over Time *Patients 4 and 5 had not yet provided post-dose biopsy at time of data cut
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19 MyPEAK-1: Cardiac biomarkers improved or remained stable 52-78 weeks after dosing 46 24 (-48%) 34 15 (-56%) 53 14 (-74%) 10 18 (+80%) 0 20 40 60 80 0 26 52 78 Patient 1 Patient 2 Patient 3 Patient 4 Cardiac Troponin I (ng/L) ULN 1,884 1,550 (-18%) 351 149 (-58%) 913 1,524 (+67%) 337 300 (-11%) 0 1,000 2,000 3,000 0 26 52 78 Patient 1 Patient 2 Patient 3 Patient 4 NT-proBNP (pg/mL) ULN Cardiac Troponin I Levels Over Time (Change) N-terminal Pro Brain Natriuretic Peptide (Change) Week Week • Cardiac troponin declined 48-74% to normal or near-normal levels at most recent visit in all patients with abnormal levels at baseline • NT-proBNP increased with IS, but declined from or returned to baseline after IS in 2 of 3 patients from Cohort 1 Male Female
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20 MyPEAK-1: Reductions in hypertrophy have emerged after 6 months 174 203 (+17%) 105 92 (-12%) 178 139 (-22%) 110 118 (+7%) 60 85 110 135 160 185 210 0 26 52 Patient 1 Patient 2 Patient 3 Patient 4 1.26 1.00 (-21%)1.07 0.65 (-39%) 1.63 1.24 (-24%) 0.78 0.71 (-9%) 0.50 0.70 0.90 1.10 1.30 1.50 1.70 1.90 0 26 52 Patient 1 Patient 2 Patient 3 Patient 4 Left Ventricular Posterior Wall Thickness Over Time Left Ventricular Mass Index Over Time LV Posterior Wall Thickness (cm) ULN (M) ULN (F) Baseline Week 26 Week 52 LV Mass Index (g/m2) Baseline Week 26 Week 52 Male Female • Measures of diastolic function have remained stable in patients ULN (M) ULN (F)
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21 MyPEAK-1: Patients’ heart failure symptoms similarly improved over time 3 3 2 3 11 Baseline (n=4) Week 26 (n=4) Week 52 (n=3) Week 78 (n=2) Class III Class II Class I NYHA Classification NYHA Classification Over Time NYHA Classification • Investigator-reported evaluation of heart failure symptoms • All patients were symptomatic at baseline • All patients—across multiple sites—saw improvement in NYHA Class by Week 26 • All patients with follow-up through Week 52 were free of heart failure symptoms and remain asymptomatic • Changes in NYHA class coincide with positive changes in cardiac biomarkers and measures of hypertrophy
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22 MyPEAK-1: Interim data are promising and support continued development of TN-201 Potential first-in-class gene therapy for HCM remains well tolerated at both 3E13 vg/kg and 6E13 vg/kg doses Robust transduction and durable expression at both 3E13 vg/kg and 6E13 vg/kg doses Directional improvements noted in biomarkers and markers of cardiac structure and function Data support continued dosing of patients in the future and potential expansion into other populations beyond adults, including pediatrics WELL TOLERATED MECHANISM WORKS INDICATORS OF REMODELING MOVE DEVELOPMENT FORWARD
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23 • MyPEAK-1 patients and their families • Drs. Milind Desai, Sherif Nagueh, and John Giudicessi and fellow MyPEAK-1 investigators • Cleveland Clinic site staff and colleagues • Members of the DSMB: Dr. Barry Greenberg, Dr. Gary Lipshutz, Ena Bromley, and Dr. James Lewis • Michael Previs, PhD, and the Previs Lab at University of Vermont for MyBP-C protein level quantification • Drs. Scott Solomon and Jon Cunningham and the team at the Cardiovascular Imaging Core Lab at Brigham • Team Tenaya MyPEAK-1: Acknowledgements
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Putting TN-201 Program and MyPEAK-1 Data Into Perspective
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25 Potential to address larger patient populations compared to most peer gene therapy programs 1Belter, et al., JAMA Peds 2024 2Parent Project Muscular Dystrophy 3UniQure presentation, Sep 2025 4Lexeo presentation, Oct 2025 5Rocket Pharma presentation, Sep 2025 6Rocket Pharma presentation, Sep 2025 0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 ZOLGENSMA SMA* ELEVIDYS DMD AMT-130 Huntington's Disease LX-2006 Friedreich's Ataxia RP-A501 Danon Disease RP-A701 BAG3+ DCM TN-401 PKP2+ ARVC TN-201 MYBPC3+ HCM Addressable Patients in US *ZOLGENSMA population represents 10y cumulative incidence Addressable Populations for Peer Gene Therapy Programs1-6 Significantly Higher Prevalence vs. Cardiac Gene Therapy Peers
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26 MyPEAK-1: Cohort 1 patients have significantly higher cardiac hypertrophy compared to peer trials oHCM = obstructive HCM nHCM = nonobstructive HCM • Biggest hearts: our 1st cohort has most hypertrophied hearts across recent interventional trials • Despite standard-of-care, still severe: all having had surgery, remain hypertrophic and symptomatic • Puts our changes in hypertrophy into context: compared to other therapies, amount of change is more dramatic, given starting point 1Greenberg, et al., NEJM 2024 2Lexeo Apr&Oct’25 Corp Updates 3Hegde, et al., JACC 2021 4Desai, et al., JACC 2025 5Hegde, et al., JACC 2024 152 123 74 112 122 130 0 50 100 150 200 250 300 TN-201 Cohort 1 Rocket in Danon Lexeo in Friedreich's Mavacamten in oHCM Mavacamten in nHCM Aficamten in oHCM Range Mean Average and Range of Baseline LVMI Values of Relevant HCM Trials AAV Cardiac Gene Therapy1,2 HCM Therapy (CMI)3-5 LV Mass Index (g/m2) Upper Limit of Normal
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27 MyPEAK-1: Despite level of severity, reductions in hypertrophy compare favorably to peers -7% -12% -14% -7% -5% -4% -16% -14% -12% -10% -8% -6% -4% -2% 0% TN-201 RP-A501 LX2006 CAMZYOS (oHCM) CAMZYOS (nHCM) Aficamten -28% -23% -9% -6% -10% -2% -30% -25% -20% -15% -10% -5% 0% TN-201 RP-A501 LX2006 CAMZYOS (oHCM) CAMZYOS (nHCM) Aficamten Change in LVMI from Baseline to 12 Months/MRV*1-5 Change in LVPWT from Baseline to 12 Months/MRV*1-5 *Rocket and Lexeo most proximal visit to 12mo. BMS oHCM & nHCM 30 and 48wk, respectively. Cytokinetics oHCM at 24wk 1Greenberg, et al., NEJM 2024 2Lexeo Apr&Oct’25 Corp Updates 3Hegde, et al., JACC 2021 4Desai, et al., JACC 2025 5Hegde, et al., JACC 2024 6Sun, et al. JACC 2022 oHCM nHCM oHCM oHCMoHCM nHCM (Max wall) (-0.2 mm)(-2.1 mm)(-0.6 mm)(-0.9 mm)(-6.4 mm)(-3.6 mm)Absolute Decline(-5 g/m2)(-6 g/m2)(-7 g/m2)(-11 g/m2)(-17 g/m2)(-8 g/m2)Absolute Decline MRV = most recent visit LVMI = left ventricular mass index LVPWT = left ventricular posterior wall thickness 2 of 3 had reductions of 12%-22% 3 of 3 with reductions of >20%; all under threshold assoc. risk of death6 *Lexeo most proximal visit to 12mo. Rocket most recent vist. BMS oHCM & nHCM 30 and 48wk, respectively. Cytokinetics oHCM at 24wk Comparison with peer programs is not intended to indicate likelihood of TN-201 clinical benefit.
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Q&A and Closing Remarks
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29 Anticipated 2025-26 milestones Cash and equivalents sufficient to fund operations into 2H’26 – beyond planned longer-term data readouts for MyPEAK-1 and RIDGE-1 trials Based on $56.3M cash, cash equivalents and investments as of 9/30/25 *Tenaya has not drawn on the SVB credit facility put in place in Q3’24 1H’25 2H’25 2026+ TN-201 MyPEAK-1 Present additional Cohort 1 data Complete Cohort 2 enrollment Provide Cohort 1 data update & present initial Cohort 2 data • 1H’26: Present two-year Cohort 1 and one-year Cohort 2 data • Pursue regulatory alignment on pivotal studies • Initiate pediatric pivotal study MyClimb Presented data at ESC Congress TN-401 RIDGE-1 Complete Cohort 1 enrollment Ex-US expansion • Cohort 1 initial data Cohort 2 and/or expansion cohort enrollment • 1H’26: Present one-year Cohort 1 data and early Cohort 2 data • Pursue regulatory alignment on pivotal study RIDGE Presented data at Heart Rhythm Society
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30 Our purpose: To transform and extend lives through the discovery, development and delivery of potentially curative therapies that target the underlying causes of heart disease.
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31 Thank you