Tvardi Therapeutics, Inc. · NASDAQ:TVRD
Tvardi Therapeutics — Cara Therapeutics — Merger or Acquisition (January 2025)
36 slides from Tvardi Therapeutics's merger presentation, Jan 21, 2025
Slide 1: Tvardi Overview
twa rd I Overview THERAPEUTICS January 2025
Slide 2: Disclaimer and Forward Looking Statements
2 Disclaimer and Forward Looking Statements This presentation and any accompanying oral commentary have been prepared by Tvardi Therapeutics, Inc. (“ Tvardi ”) for informational purposes only and not for any other purpose. All statements contained in this presentation and the accompanying oral comme
Slide 3: Merger of Tvardi and Cara Therapeutics
3 Merger of Tvardi and Cara Therapeutics • Tvardi, a clinical - stage biopharmaceutical company focused on the development of novel, oral, small molecule therapies targeting STAT3 to treat fibrosis - driven diseases with significant unmet need, intends to merge with Cara Therapeutics, Inc. (Nasdaq:
Slide 4: Targeting STAT3: Central Mediator of Fibrosis-Driven Diseases
4 Targeting STAT3: Central Mediator of Fibrosis - Driven Diseases Deep expertise in STAT3 biology Potential to serve as a disease - modifying therapy in IPF 1 Well - positioned to differentiate therapeutic impact in HCC 2 Multiple near - term data catalysts expected • Unlocking highly - validated, y
Slide 5: STAT3's Canonical Function Plays a Central Role in Fibrosis-Driven Diseases
5 Mitochondria STAT3 exists as a monomer in the electron transport chain IL6 Growth Factor Receptors Cytokine Receptors Non - TRKs Extracellular Idiopathic pulmonary fibrosis, Hepatocellular carcinoma, Systemic sclerosis Cytosol Nucleus STAT3’s Canonical Function Plays a Central Role in Fibrosis - D
Slide 6: The Dual Mechanism of Action of STAT3's Function in the Canonical Pathway
6 The Dual Mechanism of Action of STAT3’s Function in the Canonical Pathway EXTRINSICALLY Up - regulates T - cell Activation Immune Activation Degradation Tvardi’s Approach Tvardi’s Impact INTRINSICALLY D own - regulates Proliferation INTRINSIC (Cellular) EXTRINSIC ( Immune) Immune Suppression Pro -
Slide 7: Seasoned Leadership: Deep R&D and Operational Expertise
7 Sujal Shah Chairman Michael Wyzga Director Shaheen Wirk , MD Director Wallace Hall Director Cara Representative Director Seasoned Leadership: Deep R&D and Operational Expertise Dan Conn, JD, MBA CFO John Kauh , MD CMO Imran Alibhai, PhD CEO & Director David Tweardy, MD Founder & Advisor Ron DePinh
Slide 8: Our Pipeline
8 Our Pipeline Anticipated Milestone Phase 3 Phase 2 Phase 1 Discovery & Preclinical Indication Program 2H:2025 Phase 2 data Idiopathic Pulmonary Fibrosis TTI - 101 2H:2025 Phase 1b/2 topline data Hepatocellular Carcinoma TTI - 101 1H:2025 IND submission Fibrosis - driven Disease 1 TTI - 109 Phase 2
Slide 9: in IPF
9 CONFIDENTIAL TTI - 101 in IPF
Slide 10: IPF Unmet Need Represents a Large Commercial Opportunity
10 IPF Unmet Need Represents a Large Commercial Opportunity • IPF is a rare, chronic, interstitial lung disease characterized by inflammation, progressive fibrosis, and lung damage • Patients with IPF have a poor prognosis, poor quality of life, and are at a higher risk of early mortality We believe
Slide 11: STAT3 Activation is a Central Catalyst in the Fibrotic Cascade
11 STAT3 Activation is a Central Catalyst in the Fibrotic Cascade IL6 - / - STAT3 +/ - WT % △ Lung Collagen Denton et al. Ann Rheum Dis. 2018 ; O’Donoghue et al. EMBO Mol Med. 2012 Notch IL6 TGF β NF - KB MAPK Hedgehog PI3K/AKT Wnt Injury Triggers Fibrotic Signaling Pathways Haploinsufficiency of ST
Slide 12: Inhibited Activation of STAT3 and Key Pro-fibrotic Mediators in Sclerosis
12 Pedroza et al. Rheum. 2017 ; Tight skin (Tsk - 1) mice spontaneously develop fibrosis as a result of a duplication in the fibrillin - 1 gene TTI - 101 Inhibited Activation of STAT3 and Key Pro - fibrotic Mediators in Sclerosis TTI - 101 Decreased Hypodermal Fibrosis in Tsk - 1 Mice Control mice +
Slide 13: STAT3 is Activated in Major Compartments of IPF-Affected Lung Tissue
13 STAT3 is Activated in Major Compartments of IPF - Affected Mouse and Human Lung Tissue Pedroza et al. FASEB J. 2016 Activated STAT3 is overexpressed in IPF h uman lung tissue Activated STAT3 is similarly overexpressed in lung tissue of murine IPF pY - STAT3 / GAPDH Fold Induction pY - STAT3 / Act
Slide 14: Reduction of Lung Fibrosis and Improvement of Oxygen Saturation
14 Reduction of Lung Fibrosis and Statistically Significant Improvement of Oxygen Saturation Observed with TTI - 101 * TTI - 101 dosed therapeutically 14 days after bleomycin ( Bleo ) induction of fibrosis, whereas most experimental therapeutics are dosed prophylactically to demonstrate an effect of
Slide 15: Approved and Discontinued Therapies Target Single Mechanisms of IPF
15 Injury Triggers Fibrotic Signaling Pathways Inflammatory Mediators ECM Fibrosis Excess ECM Deposition Macrophage Neutrophil T - cell Platelet Activation Myofibroblast Triggers formation of myofibroblasts Approved and Discontinued Therapies Target Single Mechanisms of IPF Clotting & Coagulation In
Slide 16: Impact on Intrinsic and Extrinsic (Deposition) STAT3 Functions
16 Injury Triggers Fibrotic Signaling Pathways Inflammatory Mediators ECM Fibrosis Excess ECM Deposition Macrophage Neutrophil T - cell Platelet Activation Myofibroblast Triggers formation of myofibroblasts TTI - 101’s Impact on Both Intrinsic (Deposition) and Extrinsic STAT3 Canonical Functions Ass
Slide 17: Impact on Intrinsic and Extrinsic (Degradation) STAT3 Functions
17 TTI - 101’s Impact on Both Intrinsic and Extrinsic (Degradation) STAT3 Canonical Functions Associated with IPF TTI - 101 Demonstrated a Dose - Dependent Increase in the Modulation and Activity of T - cells (Degradation): No Bleomycin Bleomycin + Placebo Bleomycin + 12.5 mg/kg TTI - 101 Bleomycin
Slide 18: Mechanistic Data: Down-regulated Deposition and Up-regulated Degradation
18 Mechanistic Data Revealed TTI - 101 Down - regulated Deposition (Injury) and Up - regulated Degradation (Repair) ↑ Deposition ↑ Clotting & coagulation ↑ Immunomodulation ↑ Fibroblast proliferation ↑ ECM deposition IPF ↓ Degradation ↓ T - cell responses ↓ Deposition x Attenuation of clotting & coa
Slide 19: Dose-Dependent PK Exposure, PD and Improved Lung Function
19 TTI - 101’s Demonstrated Dose - Dependent PK exposure, PD and Improved Lung Function TTI - 101 observed to preferentially accumulate 4x in lung vs plasma Pharmacokinetics TTI - 101 observed to dose dependently inhibit pY - STAT3 Pharmacodynamics TTI - 101 improved lung function (at human equivale
Slide 20: Clinical Proof of Mechanism
20 Clinical Proof of Mechanism – Phase 1 Well - Established Target Preclinical Biological Activity Next Step: IPF Clinical POC x STAT3 is a central mediator in fibrosis x TTI - 101 designed to target the canonical pathway of STAT3 STAT3 correlates with high mortality in IPF patients 1 x Well - toler
Slide 21: REVERT IPF: Double Blind Randomized Phase 2 Study
21 REVERT IPF : Double Blind Randomized Phase 2 Study of TTI - 101 • Oral dosing (BID) • 12 - week d ouble blind, randomized, placebo - controlled study • Alone or in combination with nintedanib • Enrollment of mild and moderate IPF subjects • 1º & 2º Objectives: Safety & PK • Exploratory Objectives
Slide 22: Change in FVC from Baseline in Recent IPF Studies
22 Change in FVC from Baseline at 12 weeks in Recent IPF Studies with Background Anti - fibrotic therapy PLN - 74809 320mg (2023) 3 BMS - 986278 (2023) 2 BI 1015550 (2022) 1 No placebo groups had mean FVC values (including standard error) near or above baseline Certain data on this slide are based o
Slide 23: REVERT IPF: Preliminary Blinded Percent Change in FVC
23 REVERT IPF : Preliminary Blinded Percent Change in FVC from Baseline (N=38) Stable −1% to 1% ~ − 35 to +35ml Decrease < −1% Increase > 1% 34% Increase 26% Stable 39% Decrease ↓ in FVC from baseline ↑ in FVC from baseline Trial Design: 1:1:1 Randomization TTI - 101 800 mg/day (N=25) TTI - 101 400
Slide 24: Cross Trial Comparison of Baseline Characteristics
24 Cross Trial Comparison of Baseline Characteristics Sponsor REVERT IPF NCT05671835 N = 45 INTEGRIS - IPF 3 NCT04396756 N = 112 BMS 2 NCT04308681 N = 276 1305 - 0013 Trial 1 NCT04419506 N=147 Trial TTI - 101 Bexotegrast BMS986278 ( admilparant ) BI 1015550 ( nerandomilast ) Agent ≥25% ≥30% ≥25% ≥25
Slide 25: Key Takeaways: in IPF
25 Driving inhibition of STAT3 activation to address both IPF disease pathologies (downregulating deposition and upregulating degradation) REVERT IPF Phase 2 trial ongoing with clinically relevant endpoints and collection of STAT3 - mediated biomarkers Results from ongoing Phase 2 REVERT IPF trial e
Slide 26: in HCC
26 CONFIDENTIAL TTI - 101 in HCC
Slide 27: Reversed Multiple Pathogenic Steps of Liver Cancer in NASH-induced HCC Model
27 TTI - 101 Reversed Multiple Pathogenic Steps of Liver Cancer in a NASH - induced HCC Model Inflammation Fibrosis/Cirrhosis HCC STAT3 - mediated pathogenesis TTI - 101 STAT3 - inhibition in NASH - induced HCC TTI - 101 Tumor volume Microsteatosis Placebo TTI - 101 TTI - 101 Fibrosis Placebo TTI -
Slide 28: Phase 1 Clinical Trial: Monotherapy Led to Durable Partial Responses
28 Phase 1 Clinical Trial: TTI - 101 Monotherapy Led to Durable Partial Responses in Fibrotic Tumors Baseline Cycle 5, Day 1 Cycle 3, Day 1 Diameter Length in mm (% Change from Baseline) 41mm (0%) 14mm ( - 66%) 21mm ( - 49%) 14mm ( - 70%) 19mm ( - 59%) 46mm (0%) Target Lung Met Target Liver Met Part
Slide 29: Tolerability, PK/PD and Biological Activity
29 Tolerability PK / PD Biological Activity • Well - t olerated BID oral dosing • No DLTs *Most severe AE counted per subject by grade (G1/2=grade 1 or 2, G3=grade 3) **5 subjects started on F2 and transitioned to F3 ***Elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) is the su
Slide 30: Strong Rationale for Combo Therapy with STAT3
30 0 20 40 60 80 100 120 0 90 180 270 360 450 540 Days Sum of Targets Non-Target Lesion Preclinical Model POC Established for STAT3 Inhibition + ICI Phase 1 Trial Responder Overcame ICI Resistance After TTI - 101 Monotherapy → → Ph 2: Danvatirsen (STAT3 ASO) + Durvalumab (ICI) in 2L HNSCC 2 Danvatir
Slide 31: Overview of Current HCC Treatment Landscape
31 Overview of Current Treatment Landscape + Role of TTI - 101 TTI - 101 is Designed to Provide a Distinct and Synergistic Mechanism for Unmet Need in HCC • HCC is 3 rd leading cause of cancer deaths in the world 1 • Annually in the US, >42,000 new cases of HCC and ~32,000 deaths recorded 2 • Incide
Slide 32: REVERT Liver Cancer: Phase 1b/2 Study in HCC
32 REVERT Liver Cancer : Phase 2 Study of TTI - 101 in HCC • Overall Response Rate (ORR) • Duration of Response ( DoR ) • Progression - free survival • Overall survival • Liver stiffness (elastogram) • Biomarkers (IL - 6/AFP) • pY - STAT3 in tumor (21 US Sites) Phase 1b Dose Finding (up to N=54) Pha
Slide 33: REVERT Liver Cancer: Interim Phase 1b/2 Data
33 REVERT Liver Cancer : Interim Phase 1b/2 Data 67% 33% 50% 50% 8% 33% 58% Preliminary radiographic change from baseline RECIST measurements (best response). Data as of Aug 2024. This interim data set wa s not subject to the standard quality control measures typically associated with final clinical
Slide 34: Key Takeaways: in HCC
34 Inhibition of STAT3 activation to have dual therapeutic effect on cancer cells – overcoming tumorigenesis and immune suppression REVERT HCC trial Phase 2 assessing activity in both monotherapy and combination therapy in areas of unmet need Topline results from ongoing Phase 2 REVERT HCC trial exp
Slide 35: Near-Term Anticipated Value-Creating Milestones
35 Near - Term Anticipated Value - Creating Milestones TTI - 101 HCC P2 Topline Readout TTI - 101 IPF P2 Unblinded Readout Transaction Announced TTI - 109 IND Submission Expected Transaction Closes 2H 1H 2H 2025 2024 Pro forma company to be well - capitalized with a frequent cadence of inflection po
Slide 36: Targeting STAT3: Central Mediator of Fibrosis-Driven Diseases
36 Targeting STAT3: Central Mediator of Fibrosis - Driven Diseases Deep expertise in STAT3 biology Potential to serve as a disease - modifying therapy in IPF 1 Well - positioned to differentiate therapeutic impact in HCC 2 Multiple near - term data catalysts expected • Unlocking highly - validated,
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