Slide 1: TX2100: A Differentiated Anti-Angiogenic Therapy for HHT and Other Bleeding Disorders
TX2100: A Differentiated Anti-Angiogenic Therapy for HHT and Other Bleeding Disorders FEBRUARY 24, 2026
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: Agenda
3 Agenda Welcome and Introduction Alise Reicin, MD Chief Executive Officer, Director HHT: The Disease and Unmet Need Hanny Al-Samkari, MD Mass. General Hospital, Harvard Medical School TX2100: Discovery and Rationale Peter McNamara, PhD Chief Scientific Officer TX2100: Clinical Update Marcie Ruddy,
Slide 4: Advancing a High-Value Pipeline of GPCR-Targeted Therapies
4 Advancing a High-Value Pipeline of GPCR-Targeted Therapies PROGRAM / • Biologics to target GPCRs DISCOVERY IND-ENABLING PHASE 1 PHASE 2 Clinical-stage INDICATION biotech GROUP 2 PH-HFpEF TX45 TX45 (RXFP1 Agonist) Significant therapeutic • Diseases with high unmet opportunities need and limited opt
Slide 5: TX2100 for Hereditary Hemorrhagic Telangiectasia (HHT)
5 TX2100 for Hereditary Hemorrhagic Telangiectasia (HHT) • HHT is a genetic disorder of dysregulated angiogenesis leading to recurrent bleeding, Blockbuster anemia, arteriovenous malformations (AVMs) and reduced life expectancy with no Potential approved therapies Orphan Indication • Estimated ~75K
Slide 6: Today's Call Features Dr. Hanny Al-Samkari, Joined by Company Management
6 Today’s Call Features Dr. Hanny Al-Samkari, Joined by Company Management Hanny Al-Samkari, MD Dr. Al-Samkari is the Peggy S. Blitz Endowed Chair in Hematology/Oncology at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. He is a classical hematolo
Slide 7: Unmet Need in Hereditary Hemorrhagic Telangiectasia
7 Unmet Need in Hereditary Hemorrhagic Telangiectasia Hanny Al-Samkari, M.D. The Peggy S. Blitz Endowed Chair in Hematology/Oncology Classical Hematologist and Clinical Investigator Co-Director, HHT Center of Excellence Massachusetts General Hospital Associate Professor of Medicine Harvard Medical S
Slide 8: Typical Patient Case
8 Typical Patient Case • 41-year-old man with severe nosebleeds and chronic intestinal bleeding working in the biomedical field • Diagnosed with HHT in his 20s, but not cared for at HHT center; sent for regular nasal and intestinal cautery procedures that each worked for a couple of months but provo
Slide 9: Another Typical Patient Case
9 Another Typical Patient Case • 37-year-old man, father of three children, diagnosed with HHT one month prior to his visit • Came from Maine to HHT Center of Excellence at MGH in Boston • Gushing nosebleeds and chronic intestinal bleeding causing severe anemia, resulting in severe fatigue, reducing
Slide 10: The Spectrum of Inherited Bleeding Disorders
10 The Spectrum of Inherited Bleeding Disorders 3,800
Slide 11: HHT is a Multisystem Hereditary Bleeding Disorder with Numerous Morbid and Potentially Fatal Manifestations
11 HHT is a Multisystem Hereditary Bleeding Disorder with Numerous Morbid and Potentially Fatal Manifestations • Progressive, multisystem bleeding disorder due to abnormal vessel formation – Mucocutaneous telangiectasias → severe recurrent epistaxis and chronic gastrointestinal hemorrhage – Iron def
Slide 12: HHT is the Second-Most-Common Inherited Bleeding Disorder
12 HHT is the Second-Most-Common Inherited Bleeding Disorder • Autosomal dominant inheritance, 1 in 3800 people • Occurs in all sexes equally • Most clinically significant and morbid inherited bleeding disorder of women • Patients with HHT have reduced overall survival compared with healthy controls
Slide 13: HHT is Caused by Mutations in Genes in the BMP9/ALK1 Pathway
13 HHT is Caused by Mutations in Genes in the BMP9/ALK1 Pathway • Genetic Drivers of HHT – HHT arises from loss-of-function mutations in key vascular- signaling genes: – BMP9 (GDF2), Endoglin (ENG), ALK1 (ACVRL1), and SMAD4 (MADH4) – These mutations disrupt BMP9/ALK1 signaling, a pathway required fo
Slide 14: Mouse Models of HHT Replicate Disease, Are Predictive of Clinical Efficacy
14 Mouse Models of HHT Replicate Disease, Are Predictive of Clinical Efficacy • Multiple mouse models of HHT – Anti-BMP9/10 immunoblocked neonatal model – Endoglin (ENG) inducible knockout (iKO) mouse – SMAD4 (MADH4) iKO mouse – ALK1 (ACVRL1) iKO mouse (most severe model with profound GI bleeding) •
Slide 15: Prevalence is Increasing Because More People Are Getting Diagnosed
15 Prevalence is Increasing Because More People Are Getting Diagnosed Increase in Prevalence, 2013-2017 Ferry AM, et al. Am J Rhinol Allergy. 2020.
Slide 16: Mucocutaneous Telangiectasias: Gastrointestinal Tract
16 Mucocutaneous Telangiectasias: Gastrointestinal Tract
Slide 17: Mucocutaneous Telangiectasias: Nasal Cavity
17 Mucocutaneous Telangiectasias: Nasal Cavity
Slide 18: Arteriovenous Malformations (AVMs)
18 Arteriovenous Malformations (AVMs) Liver Lung Brain
Slide 19: What is the MOST FEARED Complication of Any Bleeding Disorder?
19 What is the MOST FEARED Complication of Any Bleeding Disorder?
Slide 20: Incidence of Moderate-to-Severe HHT-Associated Mucosal Bleeding in Centers of Excellence
20 Incidence of Moderate-to-Severe HHT-Associated Mucosal Bleeding in Centers of Excellence Moderate-to-Severe HHT Mucosal Bleeding: Mild (1) ESS>4.00, 24% (2) Systemic medical or surgical intervention for epistaxis and/or GI bleeding, Mod- (3) intravenous iron and/or Severe red cell transfusion to
Slide 21: HHT is an Expensive Disease
21 HHT is an Expensive Disease Al-Samkari et al., American Journal of Hematology 2025
Slide 22: HHT is an Expensive Disease
22 HHT is an Expensive Disease 12% of all diagnosed ~$500M patients are hospitalized per year in one at least once per year sample $21M spent on one patient ~$2B treated outside of an HHT per year Center on huge amounts of a estimated total (wrong) expensive medication U.S. cost to treat bleeding in
Slide 23: Many New and Striking Findings from First CHORUS Report
23 Many New and Striking Findings from First CHORUS Report (Comprehensive HHT Outcomes Registry of the United States) • 3 in 4 people with HHT develop moderate-to-severe mucosal bleeding, including epistaxis, gastrointestinal, and/or heavy menstrual bleeding • 1 in 3 people with HHT develop chronic
Slide 24: Current Treatment Paradigm in HHT is Deeply Inadequate
24 Current Treatment Paradigm in HHT is Deeply Inadequate Al-Samkari H. How I Treat Bleeding in Hereditary Hemorrhagic Telangiectasia. Blood 2024
Slide 25: Limited Tolerability of Currently Used Anti-Angiogenic Drugs
25 Limited Tolerability of Currently Used Anti-Angiogenic Drugs Bevacizumab: Limited by hypertension, proteinuria, thromboembolism risk, waning efficacy Pomalidomide: Limited by neutropenia, rash, neurologic side effects, constipation, thromboembolism risk, waning efficacy No marketed drugs, includi
Slide 26: A Differentiated Anti-Angiogenic Therapy for HHT
26 TX2100 A Differentiated Anti-Angiogenic Therapy for HHT Peter McNamara, Ph.D. Chief Scientific Officer
Slide 27: TX2100: A Potential First-in-Class APJ Antagonist for HHT and Angiogenesis-Driven Bleeding
27 TX2100: A Potential First-in-Class APJ Antagonist for HHT and Angiogenesis-Driven Bleeding Validated approach • Anti-angiogenesis reduces bleeding in HHT and related bleeding disorders, Apelin (Peptide Ligand) but no approved therapies • Toxicity of oncology anti-angiogenic agents are challenging
Slide 28: APJ is a Highly Selective, Highly Specific Anti-Angiogenic Target
28 APJ is a Highly Selective, Highly Specific Anti-Angiogenic Target • APJ is an endothelial-enriched GPCR • Apelin/APJ pathway is upregulated in pathological sprouting angiogenesis • Low baseline apelin/APJ activity during normal vascular homeostasis Upregulated Blocked apelin/APJ signaling apelin/
Slide 29: Three Decades of Progress Lead to Convergence on APJ Antagonism to Treat HHT
29 Three Decades of Progress Lead to Convergence on APJ Antagonism to Treat HHT Angiogenesis emerges as a key driver of HHT 1994 - 1996 2011 2017-2018 2019-2021+ 2025 ENG / ACVRL1 First anti- Real-world Multiple HHT broadly establish angiogenic data: anti- accepted as angiogenic clinical signal anti
Slide 30: Anti-Angiogenesis (VEGF blockade) is Clinically Effective in HHT but On-Target Toxicities Limit Long-Term Use
30 Anti-Angiogenesis (VEGF blockade) is Clinically Effective in HHT but On-Target Toxicities Limit Long-Term Use Anti-VEGF improves hemoglobin Mechanistic proof-of-concept for anti-angiogenesis in severe HHT anemia comes from use of oncology drugs where anti-VEGF therapies show reduced bleeding, inc
Slide 31: APJ Antagonist: A More Selective & Tolerable Anti-Angiogenic Agent
31 APJ Antagonist: A More Selective & Tolerable Anti-Angiogenic Agent VEGFR antagonism: APJ antagonism: Proven efficacy but poor Potential for durable efficacy long-term safety without VEGFR toxicity VEGFR and AKT signaling broadly APJ is endothelial cell enriched Selectivity required across adult t
Slide 32: APJ Expression is Endothelial-Enriched While VEGFR2 Shows Broader Multi-Tissue Expression
32 APJ Expression is Endothelial-Enriched While VEGFR2 Shows Broader Multi-Tissue Expression VEGFR2 appears in more tissues leading to APJ is enriched in endothelial cells for broader on-target biology more selective targeting nCPM nCPM Transcript Level 300 300 Glial 250 Cells Endothelial 250 200 Ba
Slide 33: Apelin is Upregulated in Endothelial Cells in Mouse Models of HHT
33 Apelin is Upregulated in Endothelial Cells in Mouse Models of HHT Potential for local apelin/APJ pathway activation in disease Shared angiogenic gene signature across HHT models Apelin highly upregulated in endothelial cells Apelin expression upregulated in HHT in ALK1 KO mice1 BMP9/10ib model EC
Slide 34: TX2100 is a Highly Potent and Selective Human APJ Antagonist
34 TX2100 is a Highly Potent and Selective Human APJ Antagonist Low-nanomolar potency at human APJ with >1,000-fold selectivity vs. related GPCRs TX2100 TX2100 blocks cAMP signaling with nanomolar potency VHH-Fc fusion • Highly specific, limits off-target toxicities • Long half-life, less frequent d
Slide 35: TX2100 Inhibits AKT and ERK Signaling Through APJ Antagonism, Blocking Pathways Important in Angiogenesis
35 TX2100 Inhibits AKT and ERK Signaling Through APJ Antagonism, Blocking Pathways Important in Angiogenesis AKT inhibition ERK inhibition APJ is primarily expressed in endothelial cells leading to AKT and ERK inhibition selectively in those cells In contrast, VEGF/TKIs/AKT inhibitors are broadly ex
Slide 36: APJ Antagonism Shows Robust and Durable Preclinical Activity in Two Complementary HHT Models
36 APJ Antagonism1 Shows Robust and Durable Preclinical Activity in Two Complementary HHT Models Preclinical result of APJ antagonism Neonatal anti-BMP9/10 • Reduced AVMs Translational model of HHT generated by injection of • Increased hemoglobin anti-BMP9/10 antibodies into • Improved bleeding neon
Slide 37: TX1351 Delivers Robust Disease-Modifying Phenotype in the Anti-BMP9/10 Model
37 TX13511 Delivers Robust Disease-Modifying Phenotype in the Anti-BMP9/10 Model Decreases AVM formation Increases hemoglobin Reduces bleeding (retinal) No Disease Isotype TX1351 No Disease Isotype TX1351 No Disease Isotype TX1351 Ctrl Mice Ctrl Ab Anti-APJ Ctrl Mice Ctrl Ab Anti-APJ Ctrl Mice Ctrl
Slide 38: Anti-VEGFA, AKT Inhibition Provide Less Robust Disease Modification in the Anti-BMP9/10 Model
38 Anti-VEGFA, AKT Inhibition Provide Less Robust Disease Modification in the Anti-BMP9/10 Model AVM formation Hemoglobin Anti-VEGFA Both mechanisms decrease AVM formation Neither improved hemoglobin levels AKT inhibitor No Disease IgG ctrl VEGFA AKT Data represent mean ± SEM; each dot = pups/group.
Slide 39: TX1351 Reduces Anemia & Bleeding in the iALK1-KO Model
39 TX13511 Reduces Anemia & Bleeding in the iALK1-KO Model APJ antagonism maintains durable benefits while VEGFA antagonism effects diminish over time Hemoglobin Levels GI Bleeding WT Littermate Ctrl Isotype Ctrl Ab Anemia threshold TX1351 APJ antagonist (~10 g/dL) G6.31 VEGFA antagonist VEGFA block
Slide 40: TX1351 Significantly Reduces GI Hypervascularization, Hemorrhage, and Vein Dilation in iALK1-KO Mice
40 TX13511 Significantly Reduces GI Hypervascularization, Hemorrhage, and Vein Dilation in iALK1-KO Mice APJ antagonism provides more complete vascular rescue than VEGFA antagonism TX1351 restores vascular architecture toward normal in a severe HHT model Latex dye restricted Venous dye to arterial f
Slide 41: Preclinical Program Did Not Show TX2100 or Target-Related Safety Signals
41 Preclinical Program Did Not Show TX2100 or Target-Related Safety Signals Previously reported physiological effects of apelin1 and APJ antagonism were not • Apelin/APJ pathway has been reproduced in multiple in-house preclinical studied mostly in the context of studies agonist pharmacology • Blood
Slide 42: TX2100 Preclinical Package Supports Phase 1a Clinical Development
42 TX2100 Preclinical Package Supports Phase 1a Clinical Development • Robust preclinical activity across multiple, translatable models of HHT • Clean safety profile in IND-enabling GLP toxicology studies, with no molecule specific or target-related safety signals • Patient-friendly SC formulation i
Slide 43: TX2100 Clinical Update
43 TX2100 Clinical Update Marcella Ruddy, M.D. Chief Medical Officer
Slide 44: Overview of TX2100 Clinical Development Plans
44 Overview of TX2100 Clinical Development Plans Ongoing Phase 1a first-in-human clinical trial in healthy volunteers 2027 • Assess safety, tolerability and PK of single doses of TX2100 • Phase 1a first subject randomized in Feb 2026, expect topline results in Q4’26 Phase 1b clinical trial in patien
Slide 45: Potential Opportunity to Expand TX2100 Patient Population
45 Potential Opportunity to Expand TX2100 Patient Population Anti-angiogenic mechanism of TX2100 offers opportunity to expand into other bleeding disorders caused by dysregulated angiogenesis ‒ Anti-angiogenic agents such as bevacizumab and thalidomide have demonstrated efficacy in treatment of othe
Slide 46: TX2100: A Potential First-in-Class APJ Antagonist to Treat HHT
46 TX2100: A Potential First-in-Class APJ Antagonist to Treat HHT Validated approach • Anti-angiogenesis improves bleeding/anemia in HHT TX2100 VHH • Oncology agents can’t be used chronically Differentiated target / design • APJ is endothelial-enriched + pathology-biased • Built to capture anti-angi
Slide 47: Questions and Answers
47 Questions and Answers