Slide 1: TN-201 MyPEAK-1 Phase 1b Study Initial Cohort 1 Data
TN-201 MyPEAK-1 Phase 1b Study Initial Cohort 1 Data December 17, 2024
Slide 2: Today's speakers
Today’s speakers Milind Desai, M.D., Director at the Cleveland Clinical Faraz Ali, MBA HCM Center; Vice Chair of Heart Chief Executive Officer Vascular Thoracic Institute and MyPEAK-1 investigator Michelle Corral Whit Tingley, M.D., PhD Vice President, Corporate Chief Medical Officer Communications
Slide 3: Forward-looking statement
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 availabl
Slide 4: Introductory comments
Introductory comments Faraz Ali, Chief Executive Officer
Slide 5: Initial MyPEAK-1 Cohort data derisks safety; reaffirms AAV9 as capsid of choice
Initial MyPEAK-1 Cohort 1 data derisks safety; reaffirms AAV9 as capsid of choice 1 Safety: TN-201 well tolerated; safety profile is consistent with other gene therapies • No cardiotoxicities • Liver enzyme elevations manageable and reversible • DSMB endorsed dose escalation 2 Biopsy: TN-201 reaches
Slide 6: MYBPC3-associated HCM is estimated to affect 120,000 people in the U.S. alone
MYBPC3-associated HCM is estimated to affect 120,000 people in the U.S. alone(1) A severe and progressive autosomal dominant condition affecting adults, teens, children and infants H C M H E A R T ~57%of identified genetic variants underlying familial HCM are MYBPC3 mutations1 Thickened left ventric
Slide 7: TN-201 is the first gene therapy being developed for MYBPC3-associated HCM
TN-201 is the first gene therapy being developed for MYBPC3-associated HCM Underlying Problem Tenaya Approach • Mutations of the MYBPC3 gene lead to lower levels of • Target the underlying genetic cause of disease myosin-binding protein C (MyBP-C) • Deliver a working MYBPC3 gene utilizing AAV9 capsi
Slide 8: MyPEAK-1 Phase 1b/2 clinical trial
MyPEAK-1 Phase 1b/2 clinical trial Open-label, multi-center dose escalation and expansion trial Study objectives DSMB endorsed dose escalation and broadening of eligibility criteria based on acceptable safety profile at 3E13 vg/kg • Safety, tolerability • Dose-finding ✓ ✓ ✓ • Pharmacodynamics Cohort
Slide 9: MyPEAK-1 Phase 1b/2 clinical trial endpoints
MyPEAK-1 Phase 1b/2 clinical trial endpoints Seeking directional consistency across multiple parameters over time Study Endpoints Over Time Post-Gene Therapy Safety and tolerability Pharmacokinetics (PK) Guidance Cardiac biopsy (Transgene, mRNA & protein) Pharmacodynamics (PD) 2024 Plasma biomarkers
Slide 10: Baseline characteristics and emerging safety profile
Baseline characteristics and emerging safety profile Dr. Milind Desai Haslam Family Endowed Chair in Cardiovascular Medicine, Vice Chair, Heart Vascular Thoracic Institute, and Director of the Hypertrophic Cardiomyopathy Center at the Cleveland Clinic MyPEAK-1 investigator
Slide 11: MyPEAK-1 patients younger and more severe than average HCM patient
MyPEAK-1 patients younger and more severe across multiple parameters compared to average HCM patient Very Typical Abnormal abnormal for HCM for HCM for HCM Average HCM Patient Patient 1 Patient 2 Patient 3 Length of Follow-Up—12 months 9 months 3 months Gender Male (63%)1 Female Female Male Current
Slide 12: TN-201 was generally well tolerated
TN-201 was generally well tolerated Reported AEs are consistent with other AAV gene therapies and known effects of immunosuppression TN-201 related-events Grade 3 AE at Week 15 Patient 1 Mitigated for subsequent patients by Reversible elevated liver enzymes occurred in all increased monitoring throu
Slide 13: Biopsy Findings
Biopsy Findings Dr. Whit Tingley, Chief Medical Officer
Slide 14: TN-201 mechanism of action occurs in stages within cardiomyocytes
TN-201 mechanism of action occurs in 3 stages within cardiomyocytes TN-201 Mechanism of Action TN-201 1 2 3 DELIVERY: EXPRESSION: EXPRESSION: Upon Infusion Transduction (DNA) Transcription (RNA) Translation (Protein) TN-201 enters cardiomyocytes. TN-201’s healthy copy of TN-201 mRNA is then Healthy
Slide 15: Cardiac biopsies are collected to quantify leading indicators of TN-201 efficacy
Cardiac biopsies are collected to quantify these leading indicators of TN-201 efficacy Measurement assays Anticipated result over time • Total VCN initially decreases as TN-201 DNA TN-201 TN-201 DNA is measured by ddPCR is cleared from non-CM cells Quantifies the number of TN-201 vector • TN-201 DNA
Slide 16: Overview of initial biopsy findings
Overview of initial biopsy findings TN-201 has been delivered to the heart with evidence of expression in Patients 1 & 2 1 2 3 DELIVERY EXPRESSION RESTORATION Is TN-201 DNA getting Is TN-201 DNA getting Is TN-201 RNA Objective of Biopsy into the heart? expressed in the heart? translating into protei
Slide 17: TN-201 demonstrates robust and durable cardiac transduction at 3E13 vg/kg
TN-201 demonstrates robust and durable levels of cardiac transduction at 3E13 vg/kg dose Vector copy number (VCN) exceeds preclinical expectations TN-201 Cardiac Transduction Cohort 1 results to date 2.5 • Consistently high VCN >2.0 vg/dg at Patient 1 efficacy Patient 2 Week 8 for P1 and P2 2.0 • Ex
Slide 18: TN-201 cardiac transduction compares favorably with other cardiac gene therapies
TN-201 cardiac transduction compares favorably with clinical data from other cardiac gene therapies TN-201 VCN and published results from peer cardiac GTx program1* 6.0 Patient 1 (3E13 vg/kg) • Higher VCN achieved at a 4.8 Patient 2 (3E13 vg/kg) 5.0 higher dose AAV9 Peer (6.7E13 vg/kg) 4.0 AAV9 Peer
Slide 19: TN-201 RNA expression in cardiomyocytes confirmed
TN-201 RNA expression in cardiomyocytes confirmed TN-201 RNA expression increases over time; performs similarly to other sponsors’ data TN-201 RNA Expression Cohort 1 results to date • RT-qPCR assay is TN-201 specific • P1 and P2 clearly show expression at Week 8 • P1 expression increased +75% from
Slide 20: MyBP-C protein levels vary between healthy and MYBPC3+HCM populations
MyBP-C protein levels vary between healthy and MYBPC3+HCM populations and between individuals Range of MyBP-C protein levels in 1 MyBP-C protein in MYBPC3-associated HCM MYBPC3-associated HCM and healthy controls Max = 109% • MYBPC3-associated HCM patients exhibit 100% Mean = 100% ~40% lower MyBP-C
Slide 21: Increase in MyBP-C protein levels observed in Patient 1
Increase in MyBP-C protein levels observed in Patient 1 Changes in both mRNA and protein levels suggest TN-201 is being transcribed and expressed MyBP-C Protein Levels in Patients 1 & 2 and MYBPC3+ HCM and Healthy Controls Protein levels over time 80% • 3% increase may not 79% 78% represent total ch
Slide 22: Biomarkers and clinical impressions
Biomarkers and clinical impressions Dr. Milind Desai, Director at the Cleveland Clinical HCM Center and MyPEAK-1 investigator
Slide 23: Circulating biomarker levels overall stable at this early time point
Circulating biomarker levels overall stable at this early time point NT-proBNP Levels Cardiac Troponin I Levels 3000 100 52 40 5240 Baseline Week Baseline Week Baseline TBD L) 80 Baseline Week Baseline Week Baseline TBD 2000 (pg/mL) (ng/m 60 cTnI 40 1000 proBNP 20 ULN—ULN NT 0 0 Patient Patient Pati
Slide 24: Encouraging early clinical signals
Encouraging early clinical signals More follow-up, more patients, and data from higher-dose cohort needed Clinical Snapshot Patient 1 Patient 2 Domain at Week 52 at Week 40 • Initial improvement and/or NT-proBNP stabilization observed across Biomarker several domains Troponin I • Seeking directional
Slide 25: Closing remarks and Q&A
Closing remarks and Q&A Faraz Ali, Chief Executive Officer
Slide 26: Summary
Summary • Safety: TN-201’s emerging safety profile is consistent with other AAV gene therapies and known effects of immunosuppressives o Immunosuppressive regimen has been successful in preventing and managing immunologic reactions to TN-201 o No cardiac AEs, including myocarditis or arrhythmia o Ej
Slide 27: Study status and next steps
Study status and next steps • Cohort 1 readout anticipated in 1H 2025 o Continued focus on safety o Biopsy data - Patient 2 at one year and Patient 3 at baseline and post dose • Cohort 2 enrollment ongoing o Initial readout anticipated in 2025 27
Slide 28: Thank you
Thank you