AVROBIO(AVRO) - 2025 Q2 - Quarterly Results

Disclaimer Forward-Looking Statements This section outlines forward-looking statements concerning product candidates (TX45, TX2100) clinical trials, regulatory approvals, market potential, and future development, subject to significant risks and no update obligation - Forward-looking statements cover clinical trial design, initiation, timing, progress, and results for product candidates (TX45, TX2100), as well as regulatory approvals, market potential, cash flow, and future product development[2] - Actual results may differ significantly from expectations due to early development stages, clinical trial success rates, regulatory changes, macroeconomic conditions, and litigation[3] - The company assumes no obligation to update any forward-looking statements unless required by law[3] Company Overview Tectonic Tx: GPCR-Targeted Therapies for High-Value Opportunities Tectonic Tx, founded in 2019, focuses on GPCR-targeted biologics to address unmet medical needs, with core product TX45 in Phase II for PH-HFpEF and TX2100 for HHT - Tectonic Tx, founded in 2019, focuses on the discovery and development of GPCR-targeted biologics to address significant unmet medical needs[5] - TX45 is the core product, in Phase II clinical trials, with Phase I results supporting its best-in-class potential, primarily targeting PH-HFpEF, a market with 1.4 million+ patients in the US and no approved therapies, offering multi-billion dollar peak revenue potential[5] - TX45 is expected to expand to PH-HFrEF (adding approximately 1.1 million patients) and PH-ILD (adding $1.8 billion+ indication)[5] - The second pipeline product, TX2100, targets the rare bleeding disorder HHT, with Phase I clinical trials expected to start in Q1 2026, affecting approximately 75,000 patients in the US with no approved therapies[5] Company Financial Status | Metric | Amount (million USD) | | :--- | :--- | | Cash and Cash Equivalents (as of June 30, 2025) | 287.4 | | Cash Runway until | Q4 2028 | This Accomplished Team Has Delivered for Patients and Investors Tectonic Tx boasts an experienced executive team with a track record of 20 "first-in-class" drug approvals and leadership from award-winning GPCR experts - The executive team has extensive experience in the pharmaceutical industry, having achieved 20 "first-in-class" drug approvals[5] - Co-founders Tim Springer and Andrew Kruse are GPCR experts, having received multiple awards, including the 2022 Lasker Award[7] Biologics Offer Advantages Over Small Molecules in Targeting GPCRs Biologics offer significant advantages over small molecules in targeting GPCRs, enabling complex ligand/receptor binding, minimizing off-target effects, and allowing for tissue-specific targeting - Biologics can capture the complexity of ligand/receptor binding and minimize off-target binding to improve safety and tolerability[9] - Biologics can be engineered to target or exclude specific tissues/compartments and support bispecific approaches for multi-modal action[9] - Only three antibodies among approved GPCR-targeted drugs indicate a large untapped market for biologics in the GPCR field[8][9] Pipeline Overview Unique Pipeline of GPCR-Targeted Biologics Underpinned By TX Tectonic Tx's unique pipeline focuses on GPCR-targeted biologics, primarily including TX45 for Group 2 PH and TX2100 for HHT - The company's pipeline primarily includes TX45 (long-acting relaxin for Group 2 pulmonary hypertension) and TX2100 (for hereditary hemorrhagic telangiectasia)[12] TX45 Program TX45: Long-acting relaxin to address large, unmet need in Group 2 PH TX45 is a long-acting relaxin, an RXFP1 agonist with differentiated properties, designed to address the significant unmet medical need in Group 2 pulmonary hypertension - TX45 is an RXFP1 agonist with differentiated properties, designed to address the significant unmet need in Group 2 pulmonary hypertension[15] TX45: Potential Best-in-class Treatment for Group 2 PH-HFpEF TX45 is a potential best-in-class treatment for Group 2 PH-HFpEF, a disease with no approved therapies, high mortality, and a large patient population, offering multi-modal benefits and simplified clinical strategy - PH-HFpEF currently has no approved therapies, affects over 1 million patients in the US, and has a high 5-year mortality rate, representing a significant unmet need[16] - TX45 addresses PH-HFpEF pathology through pulmonary and systemic vasodilation, improved cardiac diastole, fibrosis reversal, and anti-inflammatory effects[16] - Optimized protein engineering extends TX45's half-life to support monthly dosing, with Phase I clinical data showing improved left heart function and pulmonary hemodynamics in PH-HFpEF[16] - The simplified clinical strategy anticipates using the 6-minute walk test as a Phase III endpoint, potentially allowing for earlier market entry and premium pricing[16] - TX45 has the potential to expand to Group 2 PH-HFrEF, PH-ILD, and other PH groups[16] TX45 Initial Indication: Group 2 Pulmonary Hypertension (PH) Group 2 PH is the largest and chronically progressive category of pulmonary hypertension, primarily caused by left heart failure or valvular heart disease, leading to elevated pulmonary artery pressure and right heart failure, with no approved therapies - Group 2 pulmonary hypertension is the largest and chronically progressive category of PH, primarily caused by left heart failure or valvular heart disease[17][18] - The disease leads to elevated pulmonary artery pressure, vascular narrowing, and ultimately right heart failure and death[19] - Currently, there are no approved therapies[19] Initial Focus on Group 2 PH due to Heart Failure with Preserved EF (PH-HFpEF), Enriched for CpcPH Patients TX45's clinical program focuses on PH-HFpEF, specifically enriching for CpcPH patients due to their greatest unmet need, with a large patient population and potential for expansion to PH-HFrEF - The clinical program design aims to evaluate TX45's efficacy in PH-HFpEF patients, enriching for CpcPH patients due to their greatest unmet need[20][21] - PH-HFpEF affects approximately 1.4 million patients in the US, with CpcPH patients accounting for about 400,000 to 700,000[21] - Expansion to PH-HFrEF could add approximately 1.1 million additional patients[21] Group 2 PH vs. PAH (Group 1) Group 2 PH presents a larger market opportunity than PAH, with significantly more patients in the US and no approved therapies, despite similar 5-year survival rates - Group 2 PH has a significantly larger patient population in the US, approximately 1.4 million, compared to PAH with over 25,000 patients[23][24] - Group 2 PH currently has no approved therapies, whereas PAH has multiple approved drugs and mechanisms[23] - The 5-year survival rate for Group 2 PH is similar to PAH, approximately 50%[23] - The Group 2 PH market has multi-billion dollar potential[23] Hemodynamic and Anti-fibrotic Properties of Relaxin Demonstrated by its Role in Pregnancy Relaxin plays a crucial role in pregnancy as a natural RXFP1 receptor ligand, exhibiting potent hemodynamic and anti-fibrotic properties that support chronic treatment without receptor desensitization - Relaxin is a natural ligand for the RXFP1 receptor, exhibiting pulmonary and systemic vasodilation, and increasing cardiac output[26] - Relaxin possesses anti-fibrotic properties and prepares musculoskeletal tissues for pregnancy[26] - RXFP1 agonism does not lead to receptor internalization and desensitization, supporting chronic treatment[26] - Relaxin is upregulated during pregnancy and parturition, further confirming its physiological importance[27] Relaxin Addresses Multiple Organ System Pathologies in PH-HFpEF Relaxin, as an RXFP1 agonist, addresses multi-organ system pathologies in PH-HFpEF through vasodilation, reduced cardiac afterload, improved left ventricular diastolic function, and anti-fibrotic/anti-inflammatory effects - Relaxin addresses PH-HFpEF pathology through vasodilation, reducing ventricular afterload, and improving left ventricular diastolic function[29] - It exhibits anti-fibrotic and anti-inflammatory effects, promoting reverse remodeling of ventricles and pulmonary arteries[29] - Relaxin also improves renal function, increasing renal blood flow and sodium excretion, and reducing ventricular preload[29] Relaxation and Anti-Fibrotic Effects of Relaxin Have Potential for Disease Modification in PH-HFpEF Relaxin's relaxing and anti-fibrotic effects hold disease-modifying potential in PH-HFpEF by simultaneously reducing pulmonary artery pressure and increasing cardiac function through vasodilation, anti-inflammatory action, and improved cardiac/renal function - PH-HFpEF is characterized by pulmonary artery narrowing, thickening, stiffness, and fibrotic remodeling, along with left ventricular thickening and stiffness, often accompanied by impaired renal function[30][31] - Relaxin, through pulmonary vasodilation, anti-inflammatory, and anti-fibrotic effects, improves cardiac relaxation and left ventricular remodeling, as well as renal function, potentially reducing pulmonary pressure and increasing cardiac function simultaneously[30] TX45 is Engineered to Solve a Critical PK Problem Observed With Other Relaxin Molecules TX45 is engineered to overcome critical pharmacokinetic issues of other relaxin molecules, specifically by reducing net positive charge to prevent rapid clearance and achieve a significantly extended half-life - Natural relaxin has an extremely short half-life in vivo, while other Fc-fusion relaxins experience rapid clearance due to high pI values causing glycocalyx binding[33] - TX45 is engineered to reduce net positive charge (and pI value), effectively preventing rapid clearance and demonstrating superior pharmacokinetic properties[33] TX45 Group 2 PH Development Program Overview The TX45 Group 2 PH development program plans key data announcements in 2025 and 2026, with Phase Ia completed, Phase Ib ongoing, and Phase II for PH-HFpEF (enriched CpcPH) expected to start in 2026 - The TX45 Group 2 PH development program plans to announce key data in 2025 and 2026[35] - Phase Ia study in healthy volunteers is complete, and Phase Ib study in PH-HFpEF patients (RHC study, establishing hemodynamic proof-of-concept) is ongoing[35] - A Phase II randomized, 6-month study for PH-HFpEF (enriched CpcPH) is expected to start in 2026[35] Phase 1a Clinical Study Complete The Phase Ia clinical study for TX45 is complete, showing positive results that support further development, with a robust design assessing safety, tolerability, and PK/PD across various doses - The Phase Ia clinical study used a robust single ascending dose (SAD) design, evaluating the safety, tolerability, and PK/PD of various TX45 doses[37][39] - The study results are positive, supporting the continued development of TX45[36] TX45 Shows Favorable Safety Profile TX45 demonstrated a favorable safety profile in the Phase Ia clinical study, with no serious adverse events, injection site reactions, or immunogenicity, and only transient, mild-to-moderate adverse events - No discontinuations or treatment-related serious adverse events occurred, with no injection site reactions, immunogenicity, or anti-drug antibodies observed[41] - The most common adverse event was transient orthostatic tachycardia (17% placebo vs 23% TX45), unrelated to blood pressure decrease[41] - No clinically significant changes in vital signs or laboratory tests were observed[41] TX45 Single Dose Demonstrates Extended Half-Life in Subjects TX45 single-dose administration demonstrated a potentially best-in-class terminal elimination half-life of 14-20 days in subjects, with dose-proportional pharmacokinetics and approximately 50% subcutaneous bioavailability - TX45 single-dose administration showed a terminal elimination half-life of 14-20 days, with best-in-class potential[45] - Pharmacokinetics were dose-proportional, with subcutaneous bioavailability of approximately 50%[45] TX45 Steady-State Accumulation Prediction | Dosing Regimen | Steady-State Accumulation Factor | | :--- | :--- | | 300 mg SC every 4 weeks | 1.5X | | 300 mg SC every 2 weeks | 2X | Preclinical PK/PD from Acute Renal Blood Flow (RBF) Model Informs Target Plasma Concentration Levels at Trough for Maximum Therapeutic Effect Preclinical PK/PD data from RBF and MCT models informed the target plasma trough concentration for TX45's maximum therapeutic effect, predicting 2 µg/ml in humans due to higher potency for human RXFP1 - The RBF model evaluated TX45's acute vasodilatory effects, while the MCT model assessed anti-inflammatory/anti-proliferative efficacy[46][49] - Preclinical studies predict a trough concentration of 2 µg/ml is required for maximum therapeutic effect in humans[49] - The human-required concentration is 3 times lower than in rats because TX45 is 3 times more potent for human RXFP1[49] Robust Human-Exposure Model Allows for Phase 2 Dose Selection A robust human-exposure model, based on Phase Ia renal plasma flow data, guided TX45's Phase II dose selection, predicting optimal trough concentrations for efficacy with monthly or bi-weekly dosing - Phase Ia RPF data showed an increase in renal plasma flow of up to 42% in the average dose cohort, with an Emax of 33% (p<0.0001)[51][53] - A steady-state trough concentration of 2.6 µg/ml (EC80) is achieved with 300 mg SC monthly dosing, slightly above the preclinical prediction for maximum therapeutic effect (2 µg/ml)[53] - 300 mg SC bi-weekly dosing (steady-state trough concentration of 8.7 µg/ml) will also be evaluated to explore if higher exposure leads to greater efficacy[53] TX45 Group 2 PH Development Program Overview (Updated) The updated TX45 Group 2 PH development program plans key data announcements in 2025 and 2026, with Phase Ib PH-HFpEF data released in January 2025, PH-HFrEF data expected in Q4 2025, and Phase II PH-HFpEF (enriched CpcPH) starting in 2026 - Preliminary topline data for the Phase Ib study (PH-HFpEF part) was announced in January 2025[55] - Topline data for the Phase Ib study (PH-HFrEF part) is expected in early Q4 2025[55] - The Phase II PH-HFpEF (enriched CpcPH) study is expected to start in 2026, primarily evaluating PVR, PCWP, and 6MWD[55] Phase 1b Clinical Trial Design The TX45 Phase Ib clinical trial is an open-label, single-dose acute hemodynamic study in IpcPH and CpcPH subjects, with Part A completed in HFpEF and Part B enrolled in HFrEF, achieving effective exposure ranges via right heart catheterization - The Phase Ib clinical trial is a single-dose, open-label acute hemodynamic study conducted in IpcPH and CpcPH subjects[56] - Part A has been completed in HFpEF subjects, and Part B has completed enrollment in HFrEF subjects[56] - All intravenous doses achieved the predicted effective exposure range (trough concentration above 2 µg/ml) within the 8-hour evaluation period[58] Key Hemodynamic Measures Assessed in Phase 1b Trial Key hemodynamic measures assessed in the Phase Ib trial aim to simultaneously improve left ventricular function and pulmonary vascular disease, including PCWP, PVR, TPR, CO, and SV - Treating PH-HFpEF requires simultaneous improvement in left ventricular function and pulmonary vascular disease[59] Phase 1b Trial Key Hemodynamic Measures | Metric | Definition | Significance | | :--- | :--- | :--- | | PCWP (Pulmonary Capillary Wedge Pressure) | Left atrial pressure measurement | Key indicator of left ventricular function | | PVR (Pulmonary Vascular Resistance) | Measurement of blood flow resistance in pulmonary vessels | Pulmonary vascular health status | | TPR (Total Pulmonary Resistance) | Measurement of right ventricular afterload | Right ventricular workload | | CO (Cardiac Output) | Volume of blood pumped by the heart | Overall cardiac function | | SV (Stroke Volume) | Volume of blood ejected by the ventricle per beat | Cardiac pumping efficiency | Phase 1b PH-HFpEF (Part A): Baseline Characteristics and Medications are Consistent with Target Population Baseline characteristics and concomitant medications in the Phase Ib PH-HFpEF (Part A) study were consistent with the target patient population, showing an average age of 65.1 years, 36.8% female, and common comorbidities like hypertension and atrial fibrillation Phase 1b PH-HFpEF (Part A) Baseline Characteristics (N=19) | Characteristic | Value (Mean, SD) | | :--- | :--- | | Age | 65.1 (8.7) | | Female Ratio | 36.8% | | BMI | 28.9 (3.6) | | Hypertension | 84.2% | | Atrial Fibrillation | 63.2% | | Coronary Artery Disease | 63.2% | | NYHA Class II | 63.2% | | NYHA Class III | 36.8% | Phase 1b PH-HFpEF (Part A) Key Concomitant Medications (N=19) | Medication | Percentage (%) | | :--- | :--- | | ACEi/ARB | 52.6% | | MRA | 84.2% | | SGLT2i | 42.1% | | Loop Diuretics | 68.4% | | Beta-blockers | 78.9% | Phase 1b PH-HFpEF (Part A): Baseline Hemodynamics Are Consistent with Target Population Baseline hemodynamic parameters in the Phase Ib PH-HFpEF (Part A) study were consistent with the target patient population, showing average heart rate of 68.9 bpm, mean pulmonary artery pressure of 27.0 mmHg, and a significant proportion of CpcPH patients Phase 1b PH-HFpEF (Part A) Baseline Hemodynamics (N=19) | Parameter | Baseline Value (Mean, SD) | | :--- | :--- | | Heart Rate (bpm) | 68.9 (11.4) | | Systolic Blood Pressure (mm Hg) | 127.8 (11.5) | | Mean Pulmonary Artery Pressure (mm Hg) | 27.0 (4.4) | | Pulmonary Capillary Wedge Pressure (mm Hg) | 17.2 (3.6) | | Pulmonary Vascular Resistance (Wood Units) | 2.33 (1.06) | | Cardiac Output (L/min) | 4.48 (1.06) | - Based on PVR definition, 9 patients were CpcPH (PVR≥2 WU) and 5 patients were CpcPH (PVR≥3 WU), consistent with the strategy of enriching for CpcPH patients[62] Phase 1b (Part A) Results - TX45 Improved Cardiac and Pulmonary Hemodynamics in PH-HFpEF Patients Phase Ib (Part A) results demonstrated that TX45 significantly improved cardiac and pulmonary hemodynamics in PH-HFpEF patients, with notable reductions in PCWP, PVR, TPR, and SVR, alongside increased cardiac output Phase 1b (Part A) Impact of TX45 on Hemodynamics (N=19) | Metric | Absolute Change (Mean [95% CI]) | Percentage Change (Mean [95% CI]) | | :--- | :--- | :--- | | Mean ΔPCWP (all participants) | -3.2 [-4.3 to -2.1] mm Hg | -19.0% [-26.1% to -11.9%] | | Mean ΔPVR (CpcPH, PVR ≥ 2 WU, n=9) | -1.06 [-1.34 to -0.78] WU | -32.0% [-35.9% to -28.1%] | | Mean ΔCardiac Output (all participants) | +0.73 [0.39 to 1.08] L/min | +18.5% [10.2% to 26.9%] | | Mean ΔTPR (all participants) | -1.89 [-2.42 to -1.36] WU | -28.7% [-34.1% to -22.1%] | | Mean ΔSVR (all participants) | -3.95 [-5.82 to -2.08] mmHg | -16.6% [-24.4% to -8.8%] | Phase 1b (Part A) Results - TX45 Consistently Reduced PCWP in IpcPH and CpcPH patients and Improved PVR in CpcPH Patient Phase Ib (Part A) results showed TX45 consistently reduced PCWP in all PH-HFpEF patients and significantly improved PVR in CpcPH patients with baseline PVR≥2 WU, while increasing cardiac output across all patients - TX45 consistently reduced PCWP in all PH-HFpEF patients, with an average reduction of 3.2 mmHg (-19.0%)[65][67] - In CpcPH patients with baseline PVR≥2 WU, TX45 significantly improved PVR, with an average reduction of 1.06 WU (-32.0%)[65][67] - PVR remained unchanged in IpcPH patients with baseline PVR<2 WU[65] - TX45 increased cardiac output in all patients, with an average increase of 0.73 L/min (+18.5%)[67] Phase 1b (Part A) Results - Echo Results Suggest Sustained Improvement in Hemodynamic Effects with TX45 Phase Ib (Part A) echocardiography results suggest sustained improvement in hemodynamic effects with TX45, indicated by increases in TAPSE/SPAP and RVFAC, implying ongoing benefits for right heart function and pulmonary vascular resistance - After TX45 administration, both TAPSE/SPAP (a surrogate for PVR) and RVFAC (a right heart function indicator) increased[68][70] - These results suggest that TX45 has sustained improvement in hemodynamic effects[68] Phase 1b (Part A) - TX45 was Well-tolerated TX45 was well-tolerated in the Phase Ib (Part A) study, with only mild-to-moderate, self-limiting treatment-emergent adverse events, no serious events, and transient, asymptomatic blood pressure effects that resolved by follow-up - A total of 10 treatment-emergent adverse events (TEAEs) occurred in 8 patients, all mild/moderate and self-limiting[72] - No serious or severe adverse events, discontinuations, infusion reactions, or drug-related adverse events occurred[72] - No clinically significant changes in vital signs, ECG, or safety laboratory values were observed[72] - Transient, asymptomatic blood pressure effects were observed, with a mild acute systemic blood pressure decrease (5-11 mmHg) on Day 1, but blood pressure returned to baseline by Day 8 follow-up[72] Combined Decrease in PCWP and PVR Appears to Enhance Improvement in Exercise Capacity A combined decrease in PCWP and PVR appears to significantly enhance improvement in exercise capacity, with individual reductions in PCWP and PVR correlating with clinically significant improvements in 6-minute walk distance - A decrease in PCWP alone has been shown to improve exercise capacity in HFpEF and Group 2 PH patients[75] - In PAH, a 20% reduction in PVR is associated with a clinically significant improvement in 6-minute walk distance (6MWD)[75] - In CpcPH patients, a combined decrease in PCWP and PVR is associated with an increase in 6MWD, for example, a 69-meter increase after pulmonary artery denervation with 19% and 32% reductions in PCWP and PVR, respectively[75] TX45 Phase 1b Part A Results in PH-HFpEF Met/Exceeded Expectations, Expected to Increase Phase 2 Probability of Success TX45 Phase Ib Part A results in PH-HFpEF met or exceeded expectations, significantly increasing the probability of success for the APEX Phase II trial by demonstrating good tolerability, improved cardiac and pulmonary hemodynamics, and sustained effects - TX45 was well-tolerated, with transient asymptomatic blood pressure decreases observed within 24 hours after a single intravenous dose[77] - TX45 was observed to improve left heart function and pulmonary hemodynamics, unlike PAH drugs that failed in PH-HFpEF[77] - Echocardiography analysis suggested sustained improvement in hemodynamics after a single TX45 dose[77] - These data support PH-HFpEF as the initial indication for TX45 and enriching for CpcPH patients in Phase II trials, expected to increase Phase II success probability[76][77] APEX Phase 2 Efficacy Clinical Trial Design for TX45 The APEX Phase II efficacy clinical trial for TX45 is a global, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate TX45's efficacy in PH-HFpEF patients with enriched CpcPH, with PVR change as the primary endpoint - The APEX Phase II trial is a global, multicenter, double-blind, randomized, placebo-controlled proof-of-concept study evaluating TX45's efficacy in PH-HFpEF patients with an enriched CpcPH subgroup[78][79] - The trial will last 24 weeks, with patients randomized to receive TX45 300mg bi-weekly (Q2W), TX45 300mg every four weeks (Q4W), or placebo[79] APEX Phase 2 Trial Primary and Secondary Endpoints | Endpoint Type | Metric | | :--- | :--- | | Primary Endpoint | Change in PVR from baseline | | Secondary Endpoints | Change in PCWP, 6MWD, KCCQ from baseline | Pharma Has Interest In The Relaxin MoA and Group 2 PH Patient The pharmaceutical industry shows strong interest in the relaxin mechanism of action and Group 2 PH patient population, with Tectonic Tx's TX45 and other companies developing pipeline products for this unmet need - The pharmaceutical industry shows strong interest in the relaxin mechanism of action and Group 2 PH patient population[80] Competitive Landscape: Relaxin MoA and Group 2 PH Pipeline | Company | Format | Route of Administration | Half-Life (NHV) | Dosing Frequency | Patient Population | Phase 2 Endpoint | Status | | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | | TECTONIC (TX45) | Fc-Relaxin Fusion | Subcutaneous | 14-20 days | Every 4 weeks | Group 2 PH / HFpEF (Enriched CpcPH) | ΔPVR | Phase II | | AstraZeneca (AZD3427) | Fc-Relaxin Fusion | Subcutaneous | 7-9 days | Every 2 weeks | Group 2 PH / HFpEF and HFrEF | ΔPVR | Phase II | | AstraZeneca (AZD5462) | Small Molecule Relaxin | Oral | 3-6 hours | Daily | CHF | ΔEcho Parameters | Phase I | | MERCK (ACE-011) | ActRIIA-Fc | Subcutaneous | N/A | Every 3 weeks | Group 2 PH (CpcPH) / HFpEF | VLAK | Phase II | | TENAX (TNX-103) | Levosimendan | Oral | N/A | 2/3 times daily | Group 2 PH / HFpEF | Δ6MWD | Phase II | TX45 PH-ILD Program The TX45 PH-ILD program aims to provide differentiated treatment for PH-ILD (WHO Group III PH), a disease with significant unmet medical need, leveraging TX45's anti-inflammatory, anti-fibrotic, and vascular remodeling effects - The TX45 PH-ILD program aims to provide differentiated treatment for interstitial lung disease-associated pulmonary hypertension (PH-ILD, WHO Group III PH)[82] - PH-ILD affects over 60,000 patients, with a 3-year mortality rate of 60%-77%, and currently only inhaled treprostinil is approved, which has side effects like cough/bronchospasm, indicating a significant unmet need[83] - TX45's preclinical anti-inflammatory, anti-fibrotic, and vascular remodeling data, along with observed hemodynamic improvements in Group 2 PH, support its application in PH-ILD[83] - The company plans to initiate a Phase II PH-ILD clinical trial for TX45 in 2026[83] Strong Rationale for TX45 in PH-ILD TX45 has a strong rationale for PH-ILD, with its pulmonary vasodilation, anti-inflammatory, and anti-fibrotic effects expected to improve exercise capacity and offer disease modification by reversing vascular remodeling and preserving lung function - PH-ILD is characterized by pulmonary vasoconstriction and PAH-like vascular remodeling, leading to elevated mPAP and PVR, ultimately causing right ventricular dysfunction[84] - Relaxin, by activating the nitric oxide (NO) pathway and antagonizing the endothelin-1 (ET-1) pathway, achieves pulmonary vasodilation, improving mPAP, PVR, and exercise capacity[84] - Its anti-inflammatory and TGFβ pathway inhibitory effects are expected to reverse vascular remodeling, improve pulmonary hemodynamics and ventricular function, and potentially reduce lung inflammation and fibrosis, preserving lung function[84] TX45 Demonstrates Clinical Hemodynamic Changes and Preclinical Effects on Histopathology Important for PH-ILD TX45 demonstrates clinical hemodynamic changes and important preclinical histopathological effects relevant for PH-ILD, including improved hemodynamics in PH-HFpEF patients and reduced fibrosis and muscularization in PH animal models TX45 Impact on Hemodynamics in PH-HFpEF Patients (N=9-19) | Hemodynamic Endpoint | Absolute Change (Mean [95% CI]) | Percentage Change (Mean [95% CI]) | | :--- | :--- | :--- | | Mean ΔPVR (CpcPH, PVR ≥ 2 WU, n=9) | -1.06 [-1.34 to -0.78] WU | -32.0% [-35.9% to -28.1%] | | Mean ΔPVR (CpcPH, PVR ≥ 3 WU, n=5) | -1.35 [-1.55 to -1.15] WU | -35.5% [-38.6% to -32.5%] | | Mean ΔCardiac Output (all participants, N=19) | +0.73 [0.39 to 1.08] L/min | +18.5% [10.2% to 26.9%] | | Mean ΔmPAP (all participants, N=19) | -4.63 [-5.77 to -3.48] mmHg | -16.8% [-20.8% to -12.8%] | | Mean ΔSVR (all participants, N=19) | -3.95 [-5.82 to -2.08] mmHg | -16.6% [-24.4% to -8.8%] | - In PH animal models, Fc-relaxin significantly reduced fibrosis and pulmonary arteriolar muscularization, remodeling effects relevant to PH-ILD[85] Why Have Inhaled Therapies Succeeded in PH-ILD And Systemic Pulmonary Vasodilatory Compounds Have Failed? Inhaled therapies have succeeded in PH-ILD by targeting pulmonary hemodynamics while avoiding systemic side effects, unlike systemic pulmonary vasodilators which failed due to various factors beyond just worsening hypoxemia - Inhaled treprostinil achieves targeted pulmonary hemodynamic effects, reducing PVR and mPAP, while avoiding significant systemic blood pressure effects or worsening hypoxemia due to ventilation/perfusion (VQ) mismatch[87] - Systemic PAH therapies failed due to multiple reasons, including patient selection, specific mechanism toxicities, and study design, not solely worsening hypoxemia[87] - TX45 is expected to improve pulmonary hemodynamics without causing systemic hypotension or worsening hypoxemia[87] TX45 Phase 2 PH-ILD Study: Overview of Design and Rationale The TX45 Phase II PH-ILD study is an open-label, 16-week, repeated-dose trial for approximately 20 PH-ILD patients, with PVR change as the primary efficacy endpoint, aiming to assess efficacy improvement and sustained effects on fibrosis/vascular remodeling - The TX45 Phase II PH-ILD study is an open-label, repeated-dose, 16-week trial, planning to enroll approximately 20 PH-ILD patients[88][89] - The dosing regimen is 300mg subcutaneous injection every two weeks[89] TX45 Phase 2 PH-ILD Study Endpoints | Endpoint Type | Metric | | :--- | :--- | | Safety | Oxygenation and systolic blood pressure (sBP) | | Primary Efficacy | Change in PVR from baseline | | Secondary and Exploratory | Change in mPAP, CO, 6MWD, QoL from baseline | - The study aims to assess efficacy improvement within 16 weeks through an open-label trial, replicate placebo-controlled trial results, and provide sufficient treatment duration to evaluate improvements in fibrosis/vascular remodeling and effect maintenance[88][89] TX45: A Differentiated Therapy for PH-ILD TX45 is poised to be a differentiated therapy for PH-ILD, offering potential efficacy, safety, and convenience as an Fc-relaxin fusion protein administered subcutaneously every 2 or 4 weeks, with PVR change as its primary endpoint - TX45, an Fc-relaxin fusion protein, is administered subcutaneously every 2 or 4 weeks, with a relaxin mechanism of action[90] - Its primary endpoint is change in PVR at 16 weeks, with Phase II clinical trials planned for 2026[90] - Compared to approved inhaled treprostinil (multiple times daily) and other inhaled or oral drugs in clinical stages, TX45's administration method and mechanism of action may offer differentiated advantages[90] Summary: Strong Rationale for TX45 to Bring a Differentiated Treatment Approach to Address Unmet Needs in PH-ILD TX45 presents a strong rationale for a differentiated treatment approach in PH-ILD, addressing high morbidity and mortality with limited existing options, leveraging its preclinical and clinical hemodynamic data, and expanding its program to a significant market opportunity - PH-ILD is characterized by high morbidity and mortality, with insufficient existing treatment options[91] - TX45's preclinical PH data and clinical hemodynamic data from PH-HFpEF indicate its strong suitability for treating PH-ILD[91] - TX45 offers a potential systemic relaxin therapy, expected to expand the TX45 program to another significant market opportunity[91] - Tectonic Tx plans to initiate a Phase II study in 2026 to explore the safety and efficacy of 16 weeks of TX45 treatment in PH-ILD patients[91] TX2100 HHT Program TX2100 HHT program The TX2100 HHT program aims to provide a potential first-in-class and first-in-indication therapy for Hereditary Hemorrhagic Telangiectasia (HHT), a second most common genetic bleeding disorder with no approved treatments - The TX2100 HHT program aims to provide a potential first-in-class and first-in-indication therapy for hereditary hemorrhagic telangiectasia (HHT)[93] - HHT is the second most common genetic bleeding disorder, with no approved therapies currently available[93] Hereditary Hemorrhagic Telangiectasia (HHT) HHT is a rare autosomal dominant genetic disorder affecting approximately 75,000 patients in the US, caused by BMP9/10 pathway mutations leading to vascular malformations and telangiectasias, with no approved therapies - HHT is a rare autosomal dominant genetic disorder, affecting approximately 75,000 patients in the US, caused by BMP9/10 pathway mutations[95] - The disease leads to vascular malformations (AVMs) and telangiectasias, with high phenotypic variability, 15-20% severe cases, increasing mortality risk[95] - Primary symptoms include recurrent epistaxis (>95%) and cutaneous telangiectasias (>90%), potentially affecting lungs, liver, GI tract, and brain, leading to severe complications[95] - Currently, there are no approved therapies[95] Anti-VEGF: Mouse HHT Model Predictive of Efficacy in Patients Anti-VEGF therapy in mouse HHT models shows potential to inhibit AVM formation and visceral bleeding, and improve epistaxis severity and hematological parameters in patients, despite challenges with clinical studies and patent expiration - Anti-VEGF monoclonal antibodies can inhibit AVM formation and visceral bleeding in mouse HHT models[97] - Anti-VEGF therapy can reduce the severity of epistaxis and improve hemoglobin levels in patients[97] - Lack of rigorous clinical studies and patent expiration reduces investment incentives, while dosage, dosing interval, and side effects remain concerns[97] A GPCR3 Antagonist Significantly Reduces AVM Formation and Bleeding in Animal Model of HHT A GPCR3 antagonist monoclonal antibody significantly reduced AVM formation and bleeding in an HHT mouse model, providing strong preclinical evidence for TX2100 as a GPCR3 antagonist for HHT treatment - A GPCR3 antagonist monoclonal antibody significantly reduced AVM formation and bleeding in an HHT mouse model[98][99] - Both AVM formation and retinal bleeding were significantly reduced in the treatment group, with improved hemoglobin levels[99] TX2100 Development Program Overview The TX2100 development program plans to advance from DC selection in November 2024 to Phase I clinical trials in Q1 2026 for healthy volunteers, followed by a Phase II study in HHT patients in early 2027 - Development Candidate (DC) was identified in November 2024, with IND-enabling studies and CMC work ongoing[102] - Phase I clinical trials in healthy volunteers, evaluating safety and tolerability, are expected to start in Q1 2026[102] - A Phase II randomized, 3-month study in HHT patients is planned for early 2027, primarily evaluating hematocrit and epistaxis scores, and monitoring transfusions[102] Platform Technology Platform Tectonic Tx possesses a proprietary platform enabling reproducible discovery and optimization of GPCR-targeted biologics, designed to address key challenges in this field - The company possesses a proprietary platform capable of reproducible discovery and optimization of GPCR-targeted biologics[105] Solving Key Challenges in GPCR Targeted Biologics Discovery Tectonic Tx's GEODe™ platform addresses critical challenges in GPCR-targeted biologic discovery by providing native conformation receptor reagents, optimizing antibody discovery through yeast display, and engineering antigens for agonist/antagonist identification - The GEODe™ platform aims to solve key challenges in GPCR-targeted biologic discovery, including preserving endogenous GPCR structure, purifying sufficient target quantities, inducing immune responses to human GPCRs, and stabilizing receptors in active conformations[106] - The platform provides large quantities of native conformation receptor reagents through receptor engineering and purification technologies[106] - It optimizes high-diversity Fab and VHH libraries through in vitro yeast display antibody discovery[106] - It utilizes protein engineering to optimize pharmacology and engineer antigen formats for discovering agonists and antagonists[106] Company Outlook Tectonic Tx: Positioned to Deliver on Value-Creating Milestones Tectonic Tx is well-positioned to achieve value-creating milestones in 2025 and 2026 with its two pipeline candidates, TX45 and TX2100, supported by an experienced team and strong financial backing - The company has two pipeline candidates targeting large untapped markets with significant market potential[108] - TX45, supported by Phase Ib trial results, has best-in-class potential, targeting over 1 million PH-HFpEF patients, with potential expansion to PH-HFrEF and PH-ILD[108] - TX2100 targets HHT, a rare bleeding disorder with no approved therapies[108] - A series of key data announcements are expected in 2025 and 2026: TX45 Phase Ib Part B results (early Q4 2025), TX2100 Phase I initiation (Q1 2026), PH-ILD Phase II initiation (2026), and TX45 APEX Phase II topline results (2026)[108] - The company has an experienced leadership team and strong financial backing, with cash and cash equivalents of $287.4 million as of June 30, 2025, expected to provide runway until Q4 2028[108] Thank You