Tvardi Therapeutics, Inc. · NASDAQ:TVRD
Tvardi Therapeutics — Cara Therapeutics — Merger or Acquisition (December 2024)
31 slides from Tvardi Therapeutics's merger presentation, Dec 18, 2024
Slide 1: Proposed Merger Overview
1 Proposed Merger Overview December 16, 2024
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”) and Cara Th era peutics, Inc. (“Cara”) for informational purposes only and to assist such parties in making their own evaluation with respec
Slide 3: Chris Posner, CEO, Cara Therapeutics
3 CONFIDENTIAL Chris Posner CEO, Cara Therapeutics
Slide 4: Merger of Tvardi and Cara Therapeutics
4 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 5: Imran Alibhai, PhD, CEO, Tvardi Therapeutics
5 CONFIDENTIAL Imran Alibhai, PhD CEO, Tvardi Therapeutics
Slide 6: Targeting STAT3: Central Mediator of Fibrosis-Driven Diseases
6 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 7: STAT3's Canonical Function Plays a Central Role in Fibrosis-Driven Diseases
7 STAT3’s Canonical Function Plays a Central Role in Fibrosis - Driven Diseases CONFIDENTIAL P 7 IL6 Growth Factor Receptors Cytokine Receptors Non - TRKs Extracellular Intrinsic: Proliferation & Survival Extrinsic: Immune Suppression Idiopathic pulmonary fibrosis, Hepatocellular carcinoma, Systemic
Slide 8: STAT3's Canonical Function Plays a Central Role in Fibrosis-Driven Diseases
8 STAT3’s Canonical Function Plays a Central Role in Fibrosis - Driven Diseases CONFIDENTIAL 8 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, Syste
Slide 9: Dual Mechanism of Action of STAT3's Function in the Canonical Pathway
9 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 10: Seasoned Leadership: Management, Board and Scientific Advisors
10 Sujal Shah Chairman Michael Wyzga Director Shaheen Wirk , MD Director Wallace Hall Director Cara Representative Director Seasoned Leadership: Deep R&D and Operational Expertise & Strong Existing Support Dan Conn, JD, MBA CFO John Kauh , MD CMO Imran Alibhai, PhD CEO & Director David Tweardy, MD F
Slide 11: Our Pipeline
11 Our Pipeline Anticipated Milestone Phase 3 Phase 2 Phase 1 Discovery & Preclinical Indication Program H2:2025 Phase 2 data Idiopathic Pulmonary Fibrosis TTI - 101 H2:2025 Phase 1b/2 topline data Hepatocellular Carcinoma TTI - 101 H1:2025 IND submission Fibrosis - driven Disease 1 TTI - 109 Phase
Slide 12: in IPF
12 CONFIDENTIAL TTI - 101 in IPF
Slide 13: IPF Unmet Need Represents a Large Commercial Opportunity
13 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 14: STAT3 Activation is a Central Catalyst in the Fibrotic Cascade
14 STAT3 Activation is a Central Catalyst in the Fibrotic Cascade IL6 - / - STAT3 +/ - WT % △ Lung Collagen Denton CP Ann Rheum Dis 2018 ; O’Donoghue RJ et al EMBO Mol Med 2012 Notch IL6 TGF β NF - KB MAPK Hedgehog PI3K/AKT Wnt Injury Triggers Fibrotic Signaling Pathways Haploinsufficiency of STAT3
Slide 15: Inhibited Activation of STAT3 and Pro-Fibrotic Mediators in Sclerosis
15 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 + D
Slide 16: STAT3 is Activated in Major Compartments of IPF-Affected Lung Tissue
16 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 / Actin
Slide 17: Reduction of Lung Fibrosis and Improvement of Oxygen Saturation
17 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 o
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: Designed to Address the Unmet Need in IPF
19 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 - tolerated x High blood exposure (PK) x Hits STAT3 target (PD) Reduced pY - STAT3 in humans 3 x No Phase 1 SAD / MAD HV study need
Slide 20: REVERT IPF: Double Blind Randomized Phase 2 Study
20 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 21: Key Takeaways: in IPF
21 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 22: in HCC
22 CONFIDENTIAL TTI - 101 in HCC
Slide 23: Reversed Multiple Pathogenic Steps of Liver Cancer in NASH-induced HCC Model
23 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 24: Phase 1 Clinical Trial: Durable Partial Responses in Fibrotic Tumors
24 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 25: Tolerability, Exposure and pY-STAT3 Reduction
25 • 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 sum of elevated ALT and AST events Tolerabi
Slide 26: Danvatirsen + Durvalumab in HNSCC; POC for STAT3 Inhibition + ICI
26 → → Ph 2: Danvatirsen (STAT3 ASO) + Durvalumab (ICI) in 2L HNSCC 2 % Change from Baseline 0 - 20 - 40 - 60 - 80 - 100 20 40 60 80 100 0 20 40 60 80 100 Weeks Danv . development suspended due to several limitations: • Observed AEs: Thrombocytopenia and transaminitis • Onerous dosing: IV 3x week 1
Slide 27: HCC Treatment Landscape and Role of TTI-101
27 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 28: REVERT HCC: Phase 1b/2 Study in HCC
28 REVERT HCC : 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) Phase 2 Expa
Slide 29: Key Takeaways: in HCC
29 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 30: Near-Term Anticipated Value-Creating Milestones
30 Near - Term Anticipated Value - Creating Milestones TTI - 101 HCC P2 Topline Readout TTI - 101 IPF P2 Unblinded Readout Announce Transaction TTI - 109 IND Submission Transaction Closes 2H 1H 2H 2025 2024 Pro forma company would be well - capitalized with a frequent cadence of inflection points an
Slide 31: Targeting STAT3: Central Mediator of Fibrosis-Driven Diseases
31 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,
Cara Therapeutics — Merger or Acquisition (December 2024) on 6ix