Slide 1: KOL Event on the Unmet Need in Group 2 PH-HFpEF
KOL Event on the Unmet Need in Group 2 PH-HFpEF (Pulmonary Hypertension due to Heart Failure with Preserved Ejection Fraction(PH-HFpEF) and TX45 as a Potential Treatment Ray Benza Dec ember 12, 2024 Alise Reicin John Teerlink Marcie Ruddy Tony Muslin
Slide 2: Disclaimer
2 DISCLAIMER Statements contained in this presentation regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Words such as "anticipates," "believes," "expects," "intends," “plans,” “pot
Slide 3: Introduction
3 Introduction Alise Reicin, MD CEO, Tectonic Therapeutic, Inc.
Slide 4: Agenda
4 Agenda Time Presenter Agenda Item 01 4:00 PM Alise Reicin Welcome and introductions 02 4:05 PM Raymond Benza Review of Group 2 pulmonary hypertension (PH) Review of relaxin physiology and use as a 03 4:20 PM John Teerlink therapeutic Phase 1b and Phase 2 trial designs for TX45 in Group 04 4:35 PM
Slide 5: KOL Event Expert Physicians in PH-HFpEF
5 KOL Event Expert Physicians in PH-HFpEF Raymond Benza, MD, FACC, FAHA, FACP John Teerlink, MD, FACC, FAHA, FESC, FHFSA Professor of Medicine, Icahn School of Medicine at Mount Sinai Professor of Medicine, University of California, San Francisco Director of Pulmonary Hypertension, Mount Sinai Healt
Slide 6: Pulmonary Hypertension Due to Heart Failure with Preserved Ejection Fraction (PH-HFpEF)
6 Pulmonary Hypertension Due to Heart Failure with Preserved Ejection Fraction (PH-HFpEF) Raymond Benza, MD, FACC, FAHA, FACP
Slide 7: TX45 Initial Indication: Group 2 Pulmonary Hypertension (PH)
TX45 Initial Indication: Group 2 Pulmonary Hypertension (PH) Pulmonary Hypertension Consists of 5 Distinct Diseases Group 2 PH is of Greatest Interest for TX45’s Initial Indication Group 1 Group 2 Group 4 Group 5 Group 3 (“PAH”) Most common (“CTEPH”) (Misc.) • Idiopathic • Due to left heart • Due to
Slide 8: Group 2 PH, the Largest Group of Patients with PH
8 Group 2 Pulmonary Hypertension (PH), the Largest Group of Patients with PH - Single echocardiography lab; Australian community of 165,450; ~7,000 had echos; ~1,000 with PH - Etiology of PH noted on echo (PAH = Group 1; Left heart disease = Group 2; Lung disease = Group 3; CTEPH = Group 4)
Slide 9: Epidemiology of PH in HFrEF & HFpEF
9 Epidemiology of PH in HFrEF & HFpEF • 5 million people in US with HF; 2.7 million people with HFrEF and 2.3 million with HFpEF • 62% of all HFrEF and 52% of all HFpEF patients have PH • ~1.7 million US citizens with HFrEF and ~1.2 million US citizens with HFpEF have Group PH • ↑PH = ↓ survival • A
Slide 10: Key Hemodynamic Endpoints in PH-HFpEF: PCWP, mPAP, PVR
10 Key Hemodynamic Endpoints in PH-HFpEF: PCWP, mPAP, PVR 1. PCWP (pulmonary capillary wedge pressure) - measure of left atrial pressure, the pressure required to fill the left ventricle in diastole, a key marker of LV diastolic function: • Heart failure if PCWP>15 mmHg 2. mPAP (mean pulmonary arter
Slide 11: Subtypes of Group 2 PH: IpcPH and CpcPH
11 Subtypes of Group 2 PH: IpcPh and CpcPH CpcPH is a more severe form of Group 2 PH IpcPH (Isolated, post capillary PH) Heart Increased Left Ventricle Filling Pressures HFpEF Normal HFpEF (Several million pts.)1-3 Increased Pulmonary Venous Pressures Passive Pressure Backflow Group 2 PH Pulmo
Slide 12: 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension
12 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension* Updated hemodynamic definitions of PH Definition Hemodynamic Characteristics PH mPAP≥20 mmHg Isolated post-capillary PH mPAP≥20 mmHg (IpcPH) PCWP>15 mmHg PVR≤2 Wood Units Combined pre- and post- mPAP≥20 mmHg capill
Slide 13: Mortality Rates Within Strata of PVR and PCWP in HFrEF
13 Mortality Rates Within Strata of PVR and PCWP in HFrEF 1: Higher PVR and Higher PCWP are associated with increased mortality risk - In large retrospective cohort study, HF in 58%, PVR>2.2 was associated with increased risk of mortality 2 1Cappola TP et al. Circulation 2002 2Maron BA et al. Lancet
Slide 14: PH-HFpEF: LV Pathology Can Lead to Pulmonary Hypertension
14 PH-HFpEF: LV Pathology Can Lead to Pulmonary Hypertension1 PH-HFpEF 1Modified from Guazzi M. et al. JACC 2020; 76: 1102
Slide 15: Patient Journey in PH-HFpEF
15 Patient Journey in PH-HFpEF Patient presents to caregiver with symptoms: • Shortness of breath (dyspnea) with exercise or at rest • Swelling of legs or abdomen (edema) Caregiver evaluates patient: • Chest X-ray shows mild pulmonary vascular redistribution, perihilar haze Caregiver orders echocard
Slide 16: Management Principles of Group 2 PH
16 Management Principles of Group 2 PH Manage Left Arial Pressure (PCWP) Manage Underlying Substrate Induce Vascular Remodeling Long term phase must emphasize simultaneous management
Slide 17: Relaxin-RXFP1 Signaling in Cardiovascular Physiology
17 Relaxin-RXFP1 Signaling in Cardiovascular Physiology John Teerlink, MD, FACC, FAHA, FESC, FHFSA
Slide 18: Relaxin Hemodynamic and Anti-fibrotic Properties Are Demonstrated by its Role in Pregnancy
18 Relaxin Hemodynamic and Anti-fibrotic Properties Are Demonstrated by its Role in Pregnancy Pharmacology Facilitates Gestation PULMONARY AND SYSTEMIC AGONIST VASODILATOR Increases cardiac output to Natural Ligand of RXFP1 accommodate the increased Receptor demand from developing fetus No RXFP1 int
Slide 19: Beneficial Effects of TX45 in PH-HFpEF
19 Beneficial Effects of TX45 in PH-HFpEF Vasodilation Renal Blood Pulmonary & Systemic TX45 Flow NO Endothelin-1 LV* Relaxation Fibrosis Anti-Inflammatory SERCA2 function MMPs TGFbeta Na+ Excretion Improved LV RV/LV/PA* Reverse Diastolic Function Remodeling RV/LV* Preload RV/LV Afterload Clinical I
Slide 20: Relaxation and Anti-Fibrotic Effects of Relaxin Have Potential for Disease Modification in PH-HFpEF
20 Relaxation and Anti-Fibrotic Effects of Relaxin Have Potential for Disease Modification in PH-HFpEF • Heart, and vascular dysfunction contribute to disease pathology • Renal dysfunction also present in many of these patients CHARACTERISTICS OF PH-HFpEF ANTICIPATED RELAXIN EFFECTS Pulmonary artery
Slide 21: In AHF, Serelaxin Improves LV Function and Lowers Pulmonary Pressures and Resistance
21 In Acute Heart Failure (AHF), Serelaxin Improves LV Function (Lowering PCWP), and Lowers Pulmonary Pressures and Resistance (mPAP, PVR)1 Furosemide given 4h prior to serelaxin infusion, and 8h after initiation of serelaxin PCWP (mmHg) PVR (dyn*s/cm5) mPAP (mmHg) Hours post dose Hours post dose Ho
Slide 22: Serelaxin Reduced Worsening Heart Failure at Day 5 in AHF
TX45 22 Serelaxin Reduced Worsening Heart Failure at Day 5 in AHF1 -Note: trials only included a two-day serelaxin infusion in AHF patients • One of two pivotal studies included in meta-analysis, RELAX-AHF-2, failed to achieve the co-primary endpoints, and we believe that two factors contributed to
Slide 23: Serelaxin Improved Renal Function in AHF
23 Serelaxin Improved Renal Function in AHF: Reduced Creatinine at D2 & D5; Mainly Seen in CKD Patients1 -Note: trials only included a two-day serelaxin infusion in AHF patients 1Teerlink J.R. et al. Eur. J. Heart Fail. 2019; 22: 315-329; CKD = Chronic Kidney Disease
Slide 24: Serelaxin Reduced All-Cause Death in AHF Patients
Serelaxin Reduced All-Cause Death in AHF Patients1 -Note: trials only included a two-day serelaxin infusion in AHF patients 1 Teerlink J.R. et al. Eur. J. Heart Fail. 2019; 22: 315-329
Slide 25: Summary: Pleiotropic Effects of Relaxin Increase Odds of Success in PH-HFpEF
25 Summary: Pleiotropic Effects of Relaxin Increase Odds of Success in PH-HFpEF TX45, a long-acting relaxin-Fc fusion protein, is predicted to have the following effects in PH-HFpEF: • Pulmonary and systemic vasodilator • Directly improves LV diastolic function • Anti-fibrotic activity • Anti-inflam
Slide 26: TX45 Clinical Development Program
26 TX45 Clinical Development Program Marcie Ruddy, MD CMO, Tectonic Therapeutic
Slide 27: What is TX45?
27 What is TX45? • TX45 is a human relaxin-2-Fc fusion protein designed to prolong its half-life • TX-45 has a half life on the order of 2-3 weeks in contrast to serelaxin which had a half-life on the order of hours • TX45 formulation is 150mg/mL, suitable for subcutaneous administration • TX45 is b
Slide 28: TX45 Development Program
28 TX45 Development Program Tectonic Has a Potential Best-In-Class Molecule Completed Q4 2024
Slide 29: Phase 1a Trial In Healthy Volunteers: PK and PD Results
29 Phase 1a Trial In Healthy Volunteers: Pharmacokinetic and Pharmacodynamic (Renal Plasma Flow) Results • TX45 was demonstrated to be well-tolerated with no discontinuations, drug-related SAEs, injection-site reactions or ADA; most common AE of orthostatic tachycardia was transient and not associat
Slide 30: TX45 Phase 1b Trial Design
30 TX45 Phase 1b Trial Design Open Label Safety and Hemodynamics Trial in PH-HFpEF Goal of this study: • Establish single dose safety • Demonstrate relevant acute hemodynamic changes consistent with improvement in both LV function as well as pulmonary vascular dysfunction TX45 IV Cohort A 0.3 mg/kg
Slide 31: APEX Trial: Phase 2 Trial Design
31 APEX Trial = A Phase 2 Efficacy Study of RelaXin Trial Design Double-blind Treatment Period, 24W TX45 300mg Q2W (n=60) Screening Baseline RHC Randomization TX45 300mg Q4W (n=60) End Treatment End of Study Day -45 to -14 Day -21 to -7 Day 1 RHC 6MWD Week 30 Week 24 Placebo (n=60) • 1° Endpoint: Ch
Slide 32: Positive TX45 Phase 1b Trial Expected to Improve Probability of Success
32 Positive TX45 Phase 1b Trial Expected to Improve Probability of Phase 1b trial of Success results TX45 that helpStage in Later predict APEX trial success Development GOAL: Treatment for PH-HFpEF needs to both increase LV function and improve pulmonary vascular component of the disease • Decrease
Slide 33: PCWP has been correlated with 6MWD in HFpEF
33 PCWP has been correlated with 6MWD in HFpEF • At rest, the only hemodynamic parameter that predicts 6MWD in HFpEF patients is PCWP1 • Elevated PCWP is associated with worse outcomes in HFpEF2 • SGLT2 inhibitors lower wedge and increase 6MWD in HFpEF3,4 - Improvement with SGLT2 have demonstrated ~
Slide 34: PCWP and PVR Correlated with 6MWD in PH-HFpEF
34 PCWP and PVR Correlated with 6MWD in PH-HFpEF • Several hemodynamic parameters, including PCWP and PVR, correlated with 6MWD in a PH-HFpEF registry1 - PCWP was highly correlated with 6MWD (P<0.001) - PVR and mPAP were also highly correlated with 6MWD (P<0.001) • 6MWD is also a key predictor of ou
Slide 35: Summary: TX45 is a Potentially Best-in-Class, Long-Acting Relaxin
35 Summary: TX45 is a Potentially Best-in-Class, Long-Acting Relaxin • TX45 is a long-acting relaxin-Fc fusion protein that has optimized biophysical properties • TX45 has demonstrated biologic activity with a significant effect on renal plasma flow (RPF) in healthy volunteers • Phase 1b acute hemod
Slide 36: Q&A All Speakers
TECTONIC Therapeutic All Speakers QTCTONic