Slides
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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 D e c e m b e r 1 2 , 2024 Alise Reicin Marcie Ruddy Tony Muslin Ray Benza John Teerlink
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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,” “potential,” "projects,” “would” and "future" or similar expressions are intended to identify forward-looking statements. Each of these forward-looking statements involves substantial risks and uncertainties that could cause actual results to differ significantly from those expressed or implied by such forward- looking statements. Forward-looking statements contained in this presentation include, but are not limited to, statements regarding: the design, objectives, initiation, timing, progress and results of current and future preclinical studies and clinical trials of our product candidates, including the ongoing Phase 1b and Phase 2 clinical trial for TX45, in Group 2 Pulmonary Hypertension; the expected timing of program updat es and data disclosures; the timing of filing INDs and other regulatory documents; the timing and likelihood of seeking regulatory approv al for our product candidates including TX45; the competitive landscape for our product candidates; and our ability to identify and develop additional product candidates. These forward-looking statements reflect our current beliefs and expectations. Many factors may cause differences between current expectations and actual results, including the early stage of our development efforts; success in preclinical testing and earlier clinical trials does not ensure that later clinical trials will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of a product candidates; clinical site activation rates or clinical trial enrollment rates that are lower than expected; changes in expected or existing competition; changes in the regulatory environment; the uncertainties and timing of the regulatory approval process; the impact of macroeconomic conditions, including the conflict in Ukraine and the conflict in the Middle East, heightened inflation and uncertain credit and financia l markets, on our business, clinical trials and financial position; and unexpected litigation or other disputes. These and other risks are described more fully in our filings with the Securities and Exchange Commission (“SEC”), including the risks detailed in our Quarterly Report on Form 10-Q filed with the SEC on November 12, 2024, and other documents we subsequently filed with or furnished to the SEC. All forward-looking statements contained in this presentation speak only as of the date on which they were made. Except as required by law, we assume no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. 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. Neither we nor any other person makes any representation as to the accuracy or completeness of such data or undertakes any obligation to update such data after the date of this presentation. In addition, projections, assumptions and estimates of our future pe rformance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. DISCLAIMER 2
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Introduction Alise Reicin, MD CEO, Tectonic Therapeutic, Inc. 3
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4 Agenda Time Presenter Agenda Item 4:00 PM Alise Reicin Welcome and introductions 4:05 PM Raymond Benza Review of Group 2 pulmonary hypertension (PH) 4:20 PM John Teerlink Review of relaxin physiology and use as a therapeutic 4:35 PM Marcella Ruddy Phase 1b and Phase 2 trial designs for TX45 in Group 2 PH 4:45 PM Marcella Ruddy Results of Phase 1b that may inform the outcome of Phase 2 4:50 PM All Q&A 01 02 03 04 05 06
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5 KOL Event Expert Physicians in PH-HFpEF Raymond Benza, MD, FACC, FAHA, FACP Professor of Medicine, Icahn School of Medicine at Mount Sinai Director of Pulmonary Hypertension, Mount Sinai Health System John Teerlink, MD, FACC, FAHA, FESC, FHFSA Professor of Medicine, University of California, San Francisco
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Pulmonary Hypertension Due to Heart Failure with Preserved Ejection Fraction (PH-HFpEF) Raymond Benza, MD, FACC, FAHA, FACP 6
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Group 4 (“CTEPH”) Group 2 Most common Group 5 (Misc.)Group 3Group 1 (“PAH”) Group 2 PH is of Greatest Interest for TX45’s Initial Indication TX45 Initial Indication: Group 2 Pulmonary Hypertension (PH) Pulmonary Hypertension Consists of 5 Distinct Diseases • Chronic thrombo- embolic pulmonary hypertension –i.e., as a consequence of blood clots • Due to left heart disease (HFpEF, HFrEF) or valvular heart disease • CAD, HTN, T2DM1, high cholesterol are risk factors • Two Subtypes: CpcPH / IpcPH • Miscellaneous group with causes unclear or multiple underlying factors • Due to lung disease or hypoxia • May be due to COPD, interstitial lung disease (i.e., IPF) or obstructive sleep apnea • Idiopathic • Hereditary • Connective tissue disease-associated • Congenital heart disease-associated • Drug-induced 1. CAD: Coronary Artery Disease, HTN: Hypertension, T2DM: Type 2 Diabetes Mellitus Nat. Pul. Hypertension Unit, Ireland
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Group 2 Pulmonary Hypertension (PH), the Largest Group of Patients with PH 8 - 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)
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Epidemiology of PH in HFrEF & HFpEF 9 1. Khush KK Am heart Journal. 2009;157:1026-34.; 2. Shalaby A JACC 2008;101(2):238-41.; 3. Ghio S JACC. 2001;37:183-8.; 4. Grigioni F JHLT 2006;25:1241-6.; 5. Leung CC JACC 2010; 106:284-6.; 6. Gerges M AJRCCM 2015;192:1234-46; 7. Gerges M J Card Fail. 2020; 26: 43-51. • 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 significant number of patients with HF have an even higher risk of dying beyond that, related to their PH
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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 artery pressure) – mean of systolic and diastolic pulmonary artery pressures: • Pulmonary hypertension if mPAP≥20 mmHg 3. PVR (pulmonary vascular resistance) - measure of resistance to blood flow in pulmonary arteries and arterioles: • PVR = (mPAP – PCWP)/CO • Combined pre- and post-capillary PH (CpcPH) if PVR>3 Wood Units (>2 new definition) 4. TPR (Total pulmonary resistance) = mPAP/CO; useful for following IpcPH. Provides an assessment for the combined IpcPH and CpcPH patients on their right ventricular afterload. Key Hemodynamic Endpoints in PH-HFpEF: PCWP, mPAP, PVR 10
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CpcPH is a more severe form of Group 2 PH Subtypes of Group 2 PH: IpcPh and CpcPH Group 2 PH HFpEF (Several million pts.)1-3 IpcPH CpcPH Normal HFpEF Heart IpcPH (Isolated, post capillary PH) 1. US prevalence numbers. Estimates based on data from 2. Kapelios, C. et al. Cardiac Failure Review 2023;9:e14 3. Sera F. et al. Heart 2023;109:626–633 CpcPH (Combined, pre- and post capillary PH) Normal PAH-like Pulmonary VasculatureChronic PH and/or Other Drivers Permanent Vascular Changes, e.g. Pulmonary Artery Remodeling Increased Vascular Resistance Right Heart Failure Increased Left Ventricle Filling Pressures Increased Pulmonary Venous Pressures Passive Pressure Backflow Pulmonary Hypertension 11
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2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension* 12 *Some physicians still consider PVR>3 to be the definition of CpcPH Updated hemodynamic definitions of PH Definition Hemodynamic Characteristics PH mPAP≥20 mmHg Isolated post-capillary PH (IpcPH) mPAP≥20 mmHg PCWP>15 mmHg PVR≤2 Wood Units Combined pre- and post- capillary PH (CpcPH) mPAP≥20 mmHg PCWP>15 mmHg PVR>2 Wood Units
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Mortality Rates Within Strata of PVR and PCWP in HFrEF 1: Higher PVR and Higher PCWP are associated with increased mortality risk 13 1Cappola TP et al. Circulation 2002 2Maron BA et al. Lancet Respir. 2020 - In large retrospective cohort study, HF in 58%, PVR>2.2 was associated with increased risk of mortality2
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PH-HFpEF: LV Pathology Can Lead to Pulmonary Hypertension 1 1Modified from Guazzi M. et al. JACC 2020; 76: 1102 14 PH-HFpEF
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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 • Elevated NTproBNP • Diagnosis: possible heart failure, recommend echo Caregiver orders echocardiogram: • LV ejection fraction ≥50% • Thickened LV • Left atrial enlargement • Systolic pulmonary artery pressure high • Diagnosis: possible PH -HFpEF, recommend RHC Right heart catheterization: • Cardiac output mildly reduced • mPAP high (≥20 mmHg) • PCWP high (>15 mmHg) • PVR high (>3 WU) • Diagnosis: CpcPH due to HFpEF Initiate Rx for HFpEF (none for PH): • SGLT2 inhibitor • Mineralocorticoid receptor antagonist • Consider ARNI, diuretics Patient Journey in PH-HFpEF 15
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16 Management Principles of Group 2 PH Long term phase must emphasize simultaneous management Induce Vascular Remodeling Manage Underlying Substrate Manage Left Arial Pressure (PCWP)
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Relaxin-RXFP1 Signaling in Cardiovascular Physiology John Teerlink, MD, FACC, FAHA, FESC, FHFSA 17
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Pharmacology AGONIST Natural Ligand of RXFP1 Receptor No RXFP1 internalization from relaxin agonism → no desensitizationwith chronic therapy Relaxin upregulatedin pregnancy Relaxin Hemodynamic and Anti-fibrotic Properties Are Demonstrated by its Role in Pregnancy Facilitates Gestation PULMONARY AND SYSTEMIC VASODILATOR Increasescardiac output to accommodatethe increased demand from developingfetus ANTIFIBROTIC Prepares musculoskeletal tissues for pregnancy and childbirth ORGAN PROTECTION Protects heart, liver and kidney in pregnancy 18
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Beneficial Effects of TX45 in PH-HFpEF TX45 LV* Relaxation SERCA2 function Renal Blood Flow Na+ Excretion RV/LV* Preload Clinical Improvement Improved LV Diastolic Function *RV: right ventricle; LV: left ventricle; PA, pulmonary arteries Vasodilation Pulmonary & Systemic NO Endothelin-1 RV/LV Afterload Fibrosis Anti-Inflammatory MMPs TGFbeta RV/LV/PA* Reverse Remodeling 19
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• Heart, and vascular dysfunction contribute to disease pathology • Renal dysfunction also present in many of these patients Relaxation and Anti-Fibrotic Effects of Relaxin Have Potential for Disease Modification in PH-HFpEF CHARACTERISTICS OF PH-HFpEF ANTICIPATED RELAXIN EFFECTS Pulmonary artery narrowing, thickening, stiffening, fibrotic remodeling Pulmonary Vasodilation Anti-inflammatory, anti-fibrotic Thickening and stiffening of Left Ventricle Peripheral vasodilation, improved cardiac relaxation, left ventricular remodeling Compromised kidney function Improvement in kidney function, natriuresis Combined Decrease in Pulmonary Pressure and Increased Cardiac Function Are Expected to be Needed for Efficacy in PH-HFpEF 20
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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 Hours post dose Hours post doseHours post dose PCWP (mmHg) mPAP (mmHg) PVR (dyn*s/cm5) 21 1Ponikowski P. et al. Eur. Heart J. 2014
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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 contributedto this outcome – Operationalchallengesand site selection 1Teerlink J.R. et al. Eur. J. Heart Fail. 2019; 22: 315-329 TX45 22
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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 23
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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
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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-inflammatory activity TX45 could also be evaluated in: • PH-HFrEF • HFpEF • HFrEF • Chronic Kidney Disease (glomerular protection) 25
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TX45 Clinical Development Program Marcie Ruddy, MD CMO, Tectonic Therapeutic 26
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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 being developed by Tectonic Therapeutic for the treatment of PH-HFpEF 27
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28 Completed Q4 2024 TX45 Development Program Tectonic Has a Potential Best-In-Class Molecule
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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 associated with change in BP • TX45 terminal half-life of 2-3 weeks • TX45 increased renal plasma flow consistent with relaxin mechanism, Emax=33% increase in RPF (p=0.0001) • Phase 2 dose selection based on exposure-response relationship: 300 mg Q4W SC achieves EC80 at trough, 300 mg Q2W SC achieves >EC90 at trough: preclinical data suggest maximal efficacy at exposures > EC70 RPF
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TX45 Phase 1b Trial Design Open Label Safety and Hemodynamics Trial in PH -HFpEF 30 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 Screening Day -28 to -2 Admit to Unit Day -1 TX45 IV Cohort A 0.3 mg/kg Cohort B 1 mg/kg Cohort C 3 mg/kg Follow up visits Days 2, 15, 29 *HD = Hemodynamics Monitor Hemodynamics 8h Day 1 RHC Baseline HD* Day 1
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31 APEX Trial = A Phase 2 Efficacy Study of RelaXin Trial Design Randomization Day 1 Screening Day -45 to -14 Baseline RHC Day -21 to -7 Double-blind Treatment Period, 24W TX45 300mg Q2W (n=60) TX45 300mg Q4W (n=60) Placebo (n=60) End of Study Week 30 • 1° Endpoint: Change from baseline in PVR • 2° Endpoints: Change from baseline in PCWP, 6MWD, KCCQ End Treatment RHC 6MWD Week 24
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Phase 1b trial results that help predict APEX trial success GOAL: Treatment for PH-HFpEF needs to both increase LV function and improve pulmonary vascular component of the disease • Decrease in pulmonary capillary wedge pressure (PCWP) (~15-20%) − PCWP provides insight into left ventricular function and correlates with exercise capacity in HFpEF and HFrEF1 • Decrease in pulmonary vascular resistance (PVR) in patients with CpcPH (~15-20%) − PVR is normal in IpcPH, so a floor effect is likely in this subgroup − In PAH, a lowering of PVR is associated with improvement in 6MWD 2 • Reduction in total pulmonary resistance (TPR) in the overall patient population 32 Positive TX45 Phase 1b Trial Expected to Improve Probability of Success of TX45 in Later Stage Development 1 Wolsk E et al. Eur. J. Heart Fail. 2018 2www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209279Orig1s000MedR.pdf
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• 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 ~20m increase in 6MWD with ~20% decrease in PCWP 1Wolsk E et al. Eur. J. Heart Fail. 2018 2Mascherbauer J et al., J. Am. Coll. Cardiol. H.F. 2017 3Borlaug BA et al. Circulation 2023 4Nassif ME et al. Nat. Med. 2021 33 PCWP has been correlated with 6MWD in HFpEF
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• 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 outcomes in PH-HFpEF1 - Outcomes included CV death and HF hospitalization - Most significant factor in predicting outcomes for PH -HFpEF was 6MWD • Concomitant decreases in both PCWP and PVR were associated with marked improvement in 6MWD in CpcPH patients undergoing surgical Pulmonary Artery Denervation (PADN)2 1Zotter-Tufaro C et al. J. Am. Coll. Cardiol. H.F. 2015 2Zhang H et al. JACC Cardiovasc. Interv. 2019 34 PCWP and PVR Correlated with 6MWD in PH -HFpEF
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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 hemodynamic data expected in late 1Q’25 / early 2Q’25 o Data demonstrating a reduction in PCWP and PVR (in CpcPH patients) should improve the likelihood of success in later stage development • Phase 2 APEX study is ongoing; aiming to deliver data in 2026
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Q&A 36 All Speakers