Slide 1: TTI-109 in Ulcerative Colitis
TTI-109 in Ulcerative Colitis Randy Longman, MD, PhD Associate Professor, Weill Cornell Medicine Imran Alibhai, PhD CEO, Tvardi Therapeutics August 19, 2026
Slide 2: Disclaimer and Forward-Looking Statements
Disclaimer and Forward-Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements about our expectations regarding the poten
Slide 3: Webinar Objectives
Webinar Objectives 1. KOL review of ulcerative colitis: the evolving treatment landscape and the case for targeting STAT3 2. TTI-109: an oral prodrug of TTI-101 and the rationale for UC as its initial indication 3. Proposed TTI-109 proof-of-concept trial design 4. KOL perspective on the potential cl
Slide 4: The Evolving Ulcerative Colitis Treatment Landscape
The Evolving Ulcerative Colitis Treatment Landscape Randy Longman, MD, PhD Director, Jill Roberts Center for IBD Jill Roberts Institute for Research in IBD Associate Director, Tri-Institutional MD-PhD program Program Director, GI T32 training program Associate Professor of Medicine Division of Gastr
Slide 5: Ulcerative Colitis: Overview
Ulcerative Colitis: Overview • Chronic, continuous mucosal inflammation of the large intestine • Pathogenesis: interplay of multiple factors • Clinical Features • Location: begins in rectum, extends proximally • Symptoms: bloody diarrhea, urgency, cramping, weight loss, fever • Diagnosis: history, l
Slide 6: Ulcerative Colitis: Disease Biology and Pathogenesis
Ulcerative Colitis: Disease Biology and Pathogenesis PATHOPHYSIOLOGICAL FEATURES 1 Disease phenotype 2 Immune dysregulation 3 Genetic & environmental Chronic, relapsing-remitting Aberrant Th1, Th17, and Complex genetic predisposition inflammation limited to colon humoral responses; dysbiosis- + envi
Slide 7: Ulcerative Colitis Treatment Pathway
Ulcerative Colitis Treatment Pathway Induction and maintenance of remission by disease severity Proctitis Inadequate response MAINTENANCE MILD TO Rectal 5-ASA; add MODERATE Immunosuppressants, then oral systemic Oral 5-ASA; No topical steroid if no steroids steroids response Confirmed UC Corticoster
Slide 8: Therapeutic Classes: Mechanism and Clinical Evidence
Therapeutic Classes: Mechanism and Clinical Evidence Three broad therapeutic classes — with different mechanisms, efficacy profiles and practical tradeoffs Therapeutic class Mechanism and clinical considerations CONVENTIONAL THERAPIES 5-ASAs Topical anti-inflammatory; uncertain mechanism in oral for
Slide 9: Persistent Unmet Needs Despite Therapeutic Advances
Persistent Unmet Needs Despite Therapeutic Advances Placebo-Adjusted Remission (%) 100 90 THERAPEUTIC 80 CEILING 1 Secondary loss of response 70 ~30% 60 response / remission Heterogeneity of disease 50 ~70% 2 40 remain unmet biology 30 20 10 3 Safety and tolerability 0 Anti-TNF Anti-Integrin Anti-IL
Slide 10: Disease Complexity: Rationale for Multi-Driver Targeting
Disease Complexity: Rationale for Multi-Driver Targeting Interconnected pathogenic drivers of UC 1 Immune dysregulation Th17, Th1, follicular helper T cells, pathogenic B cells; abnormal IL-6, IL-23, TNFα signaling Rather than targeting individual pSTAT3 upstream pathways, 2 Inflammation CONVERGENT
Slide 11: Potential Role of STAT3 in the IBD Landscape
Potential Role of STAT3 in the IBD Landscape FRONT-LINE UC (ADVANCED- BIOLOGIC-EXPOSED / CROHN’S DISEASE THERAPY NAÏVE) REFRACTORY UC Current standard: Switch Current standard: TNFα, Current standard: IL-23 to alternate pathway IL-23 inhibitors; JAK if and TNFα inhibitors (TL1A, JAK, S1P) refractory
Slide 12: TTI-109 in Ulcerative Colitis
TTI-109 in Ulcerative Colitis Imran Alibhai, PhD CEO, Tvardi Therapeutics
Slide 13: Targeting STAT3: a Convergence Point of Inflammatory and Proliferative Disease
Targeting STAT3: a Convergence Point of Inflammatory and Proliferative Disease Diverse Disease Signaling Pathways Converge on STAT3 HGF IL-23 IL-6 IL-21 IL-1β TNF-α IL-17A/F IL-12 TGF-β Extracellular P direct STAT3 activation indirect STAT3 activation Cytosol Nucleus Immune dysregulation Inflammatio
Slide 14: Targeting STAT3: a Convergence Point of Inflammatory and Proliferative Disease
Targeting STAT3: a Convergence Point of Inflammatory and Proliferative Disease Current Therapies Target Individual Pathways HGF IL-23 IL-6 IL-21 IL-1β TNF-α IL-17A/F IL-12 TGF-β Extracellular P direct STAT3 activation indirect STAT3 activation Cytosol Nucleus Immune dysregulation Inflammation Prolif
Slide 15: Targeting STAT3: a Convergence Point of Inflammatory and Proliferative Disease
Targeting STAT3: a Convergence Point of Inflammatory and Proliferative Disease Diverse Disease Signaling Pathways Converge on STAT3 HGF IL-23 IL-6 IL-21 IL-1β TNF-α IL-17A/F IL-12 TGF-β Extracellular direct STAT3 activation Tvardi’s oral small …With no impact on indirect STAT3 activation molecules i
Slide 16: TTI-101 Clinical Foundation for Development of TTI-109
TTI-101 Clinical Foundation for Development of TTI-109 pY-STAT3 Target Engagement IL-6 & Fibrosis Reduction Overall TTI-101 Safety Oncology Phase 11 REVERT IPF Phase 22 Decline in pY-STAT3 Decline in IL-6 0 In over 300 subjects 0% -0.25 treated with TTI-101: pY-STAT3 H-score Change from Baseline -0.
Slide 17: TTI-109 Advances TTI-101's Clinical Profile Across PK, GI Tolerability and Immune Modulation
We Believe TTI-109 Advances TTI-101's Clinical Profile Across PK, GI Tolerability and Immune Modulation TTI-109 is designed to enhance delivery & improve tolerability while preserving P mechanism of action TTI-101 Clinical Observations1,2 TTI-109 Clinical Observations ✓ Target Engagement ✓ PK Rapid
Slide 18: TTI-109 Selectively Reduced Immune Cell Populations Driven by STAT3 in Phase 1 MAD
TTI-109 Selectively Reduced Immune Cell Populations Driven by STAT3 in Phase 1 MAD Cohort MAD 80% Th17 At active doses, downregulation of STAT3- T follicular helper cells driven immune populations observed: % Change from baseline normalized to placebo 60% B cells 40% ✓ Effects sustained across activ
Slide 19: TTI-109 Reduced Th17 Cells Implicated in UC Pathology
TTI-109 Reduced Th17 Cells Implicated in UC Pathology MAD Cell Type %Δ UC Rationale Central pathogenic effectors in UC Th17 cells (core) -54% and drive mucosal inflammation.1 CD4 T cells CCR6+ -47% Enriched in active UC biopsies.2 Drive IL-21-mediated B cell activation CD4 T helpers -51% and pathoge
Slide 20: TTI-109 Reduced T Follicular Cells Implicated in UC Pathology
TTI-109 Reduced T Follicular Cells Implicated in UC Pathology MAD Cell Type %Δ UC Rationale Drive UC through humoral autoantibody production and direct T follicular helper cells (Tfh) -34% cellular Bcl6-dependent mucosal inflammation.1,2 Track with UC disease activity and CD4 T cells CXCR5+ -38% pro
Slide 21: TTI-109 Reduced B Cells Implicated in UC Pathology
TTI-109 Reduced B Cells Implicated in UC Pathology MAD Cell Type %Δ UC Rationale Mucosal B-cell and plasma cell expansion is a hallmark of active UC, contributing B cells -20% directly to colonic inflammation and tissue injury.1 Track serum Ig levels and humoral activity in Memory B cells -46% activ
Slide 22: One Target, Three Mechanisms: pY-STAT3 Drives the Shared Biology of UC
One Target, Three Mechanisms: pY-STAT3 Drives the Shared Biology of UC Chronic immune activation and Persistent inflammation, tissue injury and Chronic remodeling, fibrosis and increased perpetuation of intestinal inflammation ulceration dysplasia risk Epithelial Aberrant Crypt Epithelial Injury Reg
Slide 23: pY-STAT3 Reduction Demonstrated in Preclinical Models and Clinical Biopsies
pY-STAT3 Reduction Demonstrated in Preclinical Models Activated STAT3 and Clinical Biopsies pY-STAT3 is associated with pY-STAT3 levels restored to baseline Clinical PoC: UC clinical activity after TVRD STAT3 inhibitor treatment Reduced pY-STAT3 Tissue pY-STAT3 increases with UC activity1 GI model d
Slide 24: STAT3 Inhibition Normalized Preclinical and Clinical Immune Dysregulation
STAT3 Inhibition Normalized Preclinical and Clinical Immune dysregulation Pathogenic Immune Cell Populations Cellular (Th17) and Humoral (B cell) Th17 restored to homeostatic levels Clinical PoC: dysregulation in UC patients after TVRD STAT3 inhibitor Reduced key immune cell populations Th17 cell fr
Slide 25: STAT3 Inhibition Reduced IL-6 and Inflammation Preclinically and in Patients
STAT3 Inhibition Reduced IL-6 and Inflammation Preclinically Inflammation and in Patients Inflammatory cytokine IL-6 correlates Colonic inflammation significantly Clinical PoC: with UC severity attenuated with TVRD STAT3 inhibitor Reduced IL-6 Increases in serum levels of inflammatory GI model drive
Slide 26: STAT3 Inhibition Reduced Proliferative Signaling and Fibrosis
STAT3 Inhibition Reduced Proliferative Signaling and Fibrosis Proliferation Preclinically and in Patients Proliferation and fibrosis correlate Preserved tissue integrity and colon Clinical PoC: with UC severity length with TVRD STAT3 inhibitor Reduced fibrosis Disease severity indices integrate hist
Slide 27: Proposed Clinical Trial Designed to Address Key Challenges in UC
Proposed Clinical Trial Designed to Address Key Challenges in UC Study Design Key inclusion Treatment Period Maintenance Period Endpoints criteria: (Induction 12 weeks) (12 weeks) • Primary: Safety • Moderate to Dose 1 (QD) • Secondary: Efficacy severe UC Dose 2 (QD) • Clinical remission at 12 weeks
Slide 28: Overcoming Persistent Disease Biology
Overcoming Persistent Disease Biology HGF IL-23 IL-6 IL-21 IL-1β TNF-α IL-17A/F IL-12 TGF-β Single-pathway inhibition fails to suppress STAT3 direct STAT3 activation due to redundant indirect STAT3 activation signaling cascades Immune dysregulation Inflammation Proliferation UC Murine Models ↓ Patho
Slide 29: A Differentiated Oral Therapy with Targeted Exposure
A Differentiated Oral Therapy with Targeted Exposure Differentiated safety Tissue-targeted Rapid and durable Safety concerns biologic effect profile exposure • Class-related safety risks with JAK inhibitors1 and S1P2,3 modulators: • MACE, venous thromboembolism, 83% malignancy, ~400 objective respon
Slide 30: Enabling Precision Medicine
Enabling Precision Medicine pY-STAT3 associated with STAT3-associated genetic & Limited Molecular Insight clinical activity1,2 immune signatures Elevated UC risk3,4 • Broad, unselected patient Reduced Clinical populations pY-STAT3 response STAT3 polymorphisms pY-STAT3 rs744166 | rs2293152 • Unpredic
Slide 31: Our STAT3 Inhibitors are Designed to Address the Unmet Need in Inflammatory and Proliferative Diseases
Our STAT3 Inhibitors are Designed to Address the Unmet Need in Inflammatory and Proliferative Diseases STAT3: Highly Validated Translational TTI-109 Validation in P1 TTI-109 Convergent Node Proof-of-Concept Healthy Volunteers Lead Indication IL17 IL6 IL23 Preclinical ↓ pY-STAT3 ↓ immune dysregulatio
Slide 32: Our Pipeline
Our Pipeline Program Indication Preclinical Phase 1 Phase 2 Phase 3 Anticipated Milestones Ulcerative Colitis TTI-109 IND submission expected 2027* • Study initiation expected 2027* (UC) Hepatocellular • Phase 1b/2 topline data TTI-101 Carcinoma Phase 1b/2 4Q:2026 (HCC) *Tvardi’s ability to initiate
Slide 33: Perspective: The Potential Clinical Role of STAT3 Inhibition
Perspective: The Potential Clinical Role of STAT3 Inhibition Randy Longman, MD, PhD Director, Jill Roberts Center for IBD Jill Roberts Institute for Research in IBD Associate Director, Tri-Institutional MD-PhD program Program Director, GI T32 training program Associate Professor of Medicine Division
Slide 34: Appendix A. Preclinical Support
Appendix A. Preclinical Support
Slide 35: TVRD STAT3 Inhibition Demonstrated Activity Across Multiple Validated IBD Immune Axes
TVRD STAT3 Inhibition Demonstrated Activity Across Multiple Validated IBD Immune Axes Model Systems and Select Therapies Approved or Developed for IBD TVRD Anti- Anti-TNFα Anti-TL1A Anti-IL-6 JAK1i JAK2/3i TyK2i S1P1m STAT3i IL12/23 Model Immune Axis / Key Cytokines DSS • Innate → Th1/Th17 ✓ ✓ ✓ ✓ (
Slide 36: TVRD STAT3 Inhibitors in the DSS-UC Model
TVRD STAT3 Inhibitors in the DSS-UC Model 5% DSS UC Model with TTI-1011 Colon Morphology and Length pY-STAT3 8 Vehicle 7 * 140 Colon Length (cm) pY-STAT3 / total protein 6 120 5 100 4 80 5% DSS 3 60 * 2 40 1 20 5% DSS + TTI-101 0 0 0% DSS (naïve) 5% DSS + Vehicle 5% DSS + TTI-101 0% DSS + Vehicle 5%
Slide 37: TVRD STAT3 Inhibitors in the TNBS-CD Model
TVRD STAT3 Inhibitors in the TNBS-CD Model TNBS CD Model with TTI-1011 Colon Morphology and Length pY-STAT3 80 Sham 70 * 120 pY-STAT3 (relative units, 60 Colon length (mm) norm. to total protein) 100 50 TNBS + vehicle 80 40 60 30 40 TNBS + TTI-101 20 * 10 20 0 0 Sham TNBS + vehicle TNBS + TTI-101 Sh
Slide 38: TVRD STAT3 Inhibitors in the OXA-UC Model
TVRD STAT3 Inhibitors in the OXA-UC Model OXA UC Model with TTI-1091 Colon Morphology and Length 10 Vehicle 9 8 * Colon Length (cm) 7 6 OXA 5 pY-STAT3 4 3 40 2 35 OXA + TTI-109 1 0 30 pY-STAT3 H-Score 2 Sham 3 OXA+Vehicle 4 OXA+TTI-109 25 Colonic inflammation Diarrhea 20 4.0 4 15 10 * 3.5 3.5 Diseas