Tvardi Therapeutics, Inc. · NASDAQ:TVRD
Tvardi Therapeutics — Cara Therapeutics — Merger or Acquisition (December 2024)
31 slides from Tvardi Therapeutics's merger presentation, Dec 20, 2024
Slide 1: Proposed Merger Overview
1 Proposed Merger Overview December 18, 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 Therapeutics, Inc. (“Cara”) for informational purposes only and to assist such parties in making their own evaluation with respect to
Slide 3: Chris Posner, CEO, Cara Therapeutics
3 C O N F I D E N T I A L 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: CARA
Slide 5: Imran Alibhai, PhD, CEO, Tvardi Therapeutics
5 C O N F I D E N T I A L 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 IPF1 Well-positioned to differentiate therapeutic impact in HCC2 Multiple near-term data catalysts expected • Unlocking highly-validated, yet historica
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 7 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
Slide 8: The Dual Mechanism of Action of STAT3’s Function in the Canonical Pathway
8 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 Down-regulates Proliferation INTRINSIC (Cellular) EXTRINSIC (Immune) Immune Suppression Pro-prolifera
Slide 9: Seasoned Leadership: Deep R&D and Operational Expertise
9 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 Imran Alibhai, PhD CEO & Director Dan Conn, JD, MBA CFO John Kauh, MD CMO David Tweardy, MD Foun
Slide 10: Our Pipeline
10 Our Pipeline Program Indication Discovery & Preclinical Phase 1 Phase 2 Phase 3 Anticipated Milestone TTI-101 Idiopathic Pulmonary Fibrosis H2:2025 Phase 2 data TTI-101 Hepatocellular Carcinoma H2:2025 Phase 1b/2 topline data TTI-109 Fibrosis-driven Disease1 H1:2025 IND submission Phase 2 Phase 1
Slide 11: TTI-101 in IPF
11 CONFIDENTIAL TTI-101 in IPF
Slide 12: IPF Unmet Need Represents a Large Commercial Opportunity
12 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 13: STAT3 Activation is a Central Catalyst in the Fibrotic Cascade
13 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 TGFβ NF-KB MAPK Hedgehog PI3K/AKT Wnt Injury Triggers Fibrotic Signaling Pathways Haploinsufficiency of STAT3 (STAT3+/-
Slide 14: TTI-101 Inhibited Activation of STAT3 and Key Pro-fibrotic Mediators
14 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 + DMSO Tsk-1 mic
Slide 15: STAT3 is Activated in Major Compartments of IPF-Affected Lung Tissue
15 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 human lung tissue Activated STAT3 is similarly overexpressed in lung tissue of murine IPF pY-STAT3 / GAPDH Fold Induction pY-STAT3 / Actin Fold I
Slide 16: STAT3 Correlates with High Mortality in IPF Patients
16 IPF Transplant-free survival over the course of 3.5 years post-diagnosis in a cohort of patients (n=55) based on STAT3 expression. Activated STAT3 (pSTAT3) induces the expression of STAT3 transcript. Celada et al Sci Transl Med 2018 STAT3 Correlates with High Mortality in IPF Patients
Slide 17: Reduction of Lung Fibrosis and Improvement of Oxygen Saturation with TTI-101
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 of fibr
Slide 18: TTI-101 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 ✓Attenuation of clotting & coagulation
Slide 19: TTI-101 is Designed to Address the Unmet Need in IPF
19 Well-Established Target Preclinical Biological Activity Clinical Proof of Mechanism – Phase 1 Next Step: IPF Clinical POC ✓ STAT3 is a central mediator in fibrosis ✓ TTI-101 designed to target the canonical pathway of STAT3 STAT3 correlates with high mortality in IPF patients1 ✓ Well-tolerated ✓
Slide 20: REVERTIPF: Double Blind Randomized Phase 2 Study of TTI-101
20 REVERTIPF: Double Blind Randomized Phase 2 Study of TTI-101 • Oral dosing (BID) • 12-week double 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: • Phase
Slide 21: Key Takeaways: TTI-101 in IPF
21 Driving inhibition of STAT3 activation to address both IPF disease pathologies (downregulating deposition and upregulating degradation) REVERTIPF Phase 2 trial ongoing with clinically relevant endpoints and collection of STAT3-mediated biomarkers Results from ongoing Phase 2 REVERTIPF trial expec
Slide 22: TTI-101 in HCC
22 CONFIDENTIAL TTI-101 in HCC
Slide 23: TTI-101 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 Microsteatosis Tumor volume Placebo TTI-101 TTI-101 Fibrosis Placebo TTI-101 After formation
Slide 24: Phase 1 Trial: TTI-101 Monotherapy Led to Durable Partial Responses
24 Phase 1 Clinical Trial: TTI-101 Monotherapy Led to Durable Partial Responses in Fibrotic Tumors Baseline Cycle 3, Day 1 Cycle 5, Day 1 Diameter Length in mm (% Change from Baseline) 41mm (0%) 21mm (-49%) 14mm (-66%) 46mm (0%) 19mm (-59%) 14mm (-70%) Target Lung Met Target Liver Met Partial Respon
Slide 25: Tolerability, Pharmacokinetics and Pharmacodynamics of TTI-101
25 • Well-tolerated 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 Tolerabilit
Slide 26: Strong Rationale for Combo Therapy with STAT3
26 → → Ph 2: Danvatirsen (STAT3 ASO) + Durvalumab (ICI) in 2L HNSCC2 % 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 then Q
Slide 27: Overview of Current 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 3rd leading cause of cancer deaths in the world1 • Annually in the US, >42,000 new cases of HCC and ~32,000 deaths recorded2 • Incidence has
Slide 28: REVERTHCC: Phase 1b/2 Study of TTI-101 in HCC
28 REVERTHCC: 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 Expansion (N=100
Slide 29: Key Takeaways: TTI-101 in HCC
29 Inhibition of STAT3 activation to have dual therapeutic effect on cancer cells – overcoming tumorigenesis and immune suppression REVERTHCC trial Phase 2 assessing activity in both monotherapy and combination therapy in areas of unmet need Topline results from ongoing Phase 2 REVERTHCC trial expec
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 2024 2025 Pro forma company would be well-capitalized with a frequent cadence of inflection points and have runwa
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 IPF1 Well-positioned to differentiate therapeutic impact in HCC2 Multiple near-term data catalysts expected • Unlocking highly-validated, yet historic
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