Tvardi Therapeutics, Inc. · NASDAQ:TVRD
Tvardi Therapeutics — Cara Therapeutics — Merger or Acquisition (April 2025)
37 slides from Tvardi Therapeutics's merger presentation, Apr 11, 2025
Slide 1: Overview April 2025
Overview April 2025
Slide 2: Forward-looking statements disclaimer
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 commentary, other than statements of historical fac
Slide 3: Merger of Tvardi and Cara Therapeutics
SEC Effective S-4 Filed 24 Jan 2025; SEC 8-K Filed 1 Apr 2025 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, intends to merge with Car
Slide 4: Targeting STAT3: Central Mediator of Fibrosis-Driven Diseases
1. Idiopathic pulmonary fibrosis. 2. Hepatocellular carcinoma. 3. Investigational new drug. 4 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
Slide 5: STAT3's Canonical Function Plays a Central Role in Fibrosis-Driven Diseases
5 STAT3’s Canonical Function Plays a Central Role in Fibrosis-Driven Diseases IL6 Growth Factor Receptors Cytokine Receptors Non-TRKs Extracellular Intrinsic: Proliferation & Survival Extrinsic: Immune Suppression Idiopathic pulmonary fibrosis, Hepatocellular carcinoma, Systemic sclerosis Cytosol Nu
Slide 6: STAT3's Dual Mechanism of Action in Fibrosis-Driven Diseases
6 STAT3’s Dual Mechanism of Action in Fibrosis-Driven Diseases 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-proliferative cells Ac
Slide 7: Seasoned Leadership: Deep R&D and Operational Expertise
7 Seasoned Leadership: Deep R&D and Operational Expertise Sujal Shah Chairman Michael Wyzga Director Cynthia Smith Director Susan Shiff, PhD Director Shaheen Wirk, MD Director Wallace Hall Director Imran Alibhai, PhD CEO & Director Dan Conn, JD, MBA CFO John Kauh, MD CMO David Tweardy, MD Founder &
Slide 8: Our Pipeline
1. We plan to commence clinical trials in fibrosis and/or oncology pending IND submission and FDA feedback. 8 Our Pipeline Program Indication Discovery & Preclinical Phase 1 Phase 2 Phase 3 Anticipated Milestone TTI-101 Idiopathic Pulmonary Fibrosis 2H:2025 Phase 2 data TTI-101 Hepatocellular Carcin
Slide 9: TTI-101 in IPF
THERAPEUTIC TTI-101 in IPF
Slide 10: IPF Unmet Need Represents a Large Commercial Opportunity
1. Raghu, G et al. Am J Respir Crit Care Med. 2006. 2. Du, K. et al. Respir Res. 2022. 3. Based on $3.8B in sales of Ofev and $1.1B in sales of Esbriet from Boehringer Ingelheim and Genentech (Roche) filings. 4. Dempsey, T. M. et al. Ann Am Thorac Soc. 2021 10 IPF Unmet Need Represents a Large Comme
Slide 11: STAT3 Activation is a Central Catalyst in the Fibrotic Cascade
Denton CP. et al. Ann Rheum Dis. 2018; O’Donoghue RJ. et al. EMBO Mol Med. 2012 11 STAT3 Activation is a Central Catalyst in the Fibrotic Cascade IL6-/- STAT3 WT +/- % △ Notch Lung Collagen IL6 TGFβ NF-KB MAPK Hedgehog PI3K/AKT Wnt Injury Triggers Fibrotic Signaling Pathways Haploinsufficiency of ST
Slide 12: TTI-101 Inhibited Activation of STAT3 and Key Pro-fibrotic Mediators in Sclerosis
Pedroza et al. Rheum. 2017; Tight skin (Tsk-1) mice spontaneously develop fibrosis as a result of a duplication in the fibrillin-1 gene 12 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 m
Slide 13: STAT3 is Activated in Major Compartments of IPF-Affected Lung Tissue
Pedroza et al. FASEB J. 2016 13 STAT3 is Activated in Major Compartments of IPF-Affected Mouse and Human Lung Tissue 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
Slide 14: Reduction of Lung Fibrosis and Improvement of Oxygen Saturation with TTI-101
Pedroza et al. FASEB J. 2016 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 d
Slide 15: Approved and Discontinued Therapies Target Single Mechanisms of IPF
Adapted from Wynn J. Exp Med. 2011; Libra et al. Int. J. Mol. Sci. 2024 15 Approved and Discontinued Therapies Target Single Mechanisms of IPF Injury Triggers Fibrotic Signaling Pathways Inflammatory Mediators ECM Fibrosis Excess ECM Deposition Macrophage Neutrophil T-cell Platelet Activation Myofib
Slide 16: TTI-101's Impact on Intrinsic and Extrinsic STAT3 Functions (Deposition)
Kauh et al. CHEST. 2024 - Bleomycin-induced IPF mouse model: therapeutically treated with TTI-101 9 days after induction of fibrosis using bleomycin. 16 TTI-101’s Impact on Both Intrinsic (Deposition) and Extrinsic STAT3 Canonical Functions Associated with IPF Injury Triggers Fibrotic Signaling Path
Slide 17: TTI-101's Impact on Intrinsic and Extrinsic STAT3 Functions (Degradation)
Kauh et al. CHEST. 2024 - Bleomycin-induced IPF mouse model: therapeutically treated with TTI-101 9 days after induction of fibrosis using bleomycin. 17 TTI-101’s Impact on Both Intrinsic and Extrinsic (Degradation) STAT3 Canonical Functions Associated with IPF TTI-101 Demonstrated a Dose-Dependent
Slide 18: TTI-101 Down-regulated Deposition and Up-regulated Degradation
Kauh et al. CHEST. 2024 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
Slide 19: TTI-101 Demonstrated Dose-Dependent PK, PD and Improved Lung Function
Kauh et al. CHEST. 2024 - Bleomycin-induced IPF mouse model: therapeutically treated with TTI-101 9 days after induction of fibrosis using bleomycin. 19 TTI-101’s Demonstrated Dose-Dependent PK, PD and Improved Lung Function TTI-101 exposure observed to preferentially accumulate 4x in lung vs plasma
Slide 20: Clinical Proof of Mechanism – Phase 1
1. Celada et al. Sci Transl Med. 2018. 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 (pY-STAT3) induces the expression of STAT3 transcript. 2. Pedroza et al. FASEB J. 2016. 3. Tsimberidou et al Clin
Slide 21: REVERTIPF: Double Blind Randomized Phase 2 Study of TTI-101
1. NCT05671835: On July 17, 2024, the independent Safety Monitoring Committee (SMC) conducted a benefit-risk analysis of the preliminary unblinded data from the Phase 2 IPF clinical trial data across all doses and recommended continuation of the 400 mg/day and 800 mg/day dose and discontinuation of
Slide 22: Change in FVC from Baseline at 12 Weeks in Recent IPF Studies
Certain data on this slide are based on cross-study comparisons and are not based on any head-to-head clinical trials. Cross-study comparisons are inherently limited and may suggest misleading similarities and differences. The values shown in the cross-study comparisons are directional and may not b
Slide 23: Preliminary Blinded FVC Data from REVERTIPF
*Trial is blinded to Sponsor, investigators and patients; unknown exposure to 400mg/day of TTI-101, 800mg/day of TTI-101 or placebo. Data as of September 2024. Preliminary data for efficacy-evaluable patients defined as: patients with acceptable baseline and at least one on-treatment pulmonary funct
Slide 24: Cross Trial Comparison of Baseline Characteristics
Certain data on this slide are based on cross-study comparisons and are not based on any head-to-head clinical trials. Cross-study comparisons are inherently limited and may suggest misleading similarities and differences. 1. Richeldi et al. NEJM 2022 2. Corte et al. Am J Respir Cri Care Med. 2023 3
Slide 25: Key Takeaways: TTI-101 in IPF
25 Key Takeaways: TTI-101 in IPF Driving inhibition of STAT3 activation to address both IPF disease pathologies (downregulating deposition and upregulating degradation) Ongoing Phase 2 trial → preliminary blinded data demonstrated ~50% of participants near or above baseline FVC Results from ongoing
Slide 26: TTI-101 in HCC
THERAPEUTIC TTI-101 in HCC
Slide 27: TTI-101 Reversed Multiple Pathogenic Steps of Liver Cancer in NASH-induced HCC Model
Jung KH et al. Clin Cancer Res. 2017 – Genetically engineered HepPTEN- murine model which replicates nonalcoholic steatohepatitis (NASH) induced hepatocellular carcinoma (HCC) 27 TTI-101 Reversed Multiple Pathogenic Steps of Liver Cancer in a NASH-induced HCC Model Inflammation Fibrosis/Cirrhosis HC
Slide 28: TTI-101 Monotherapy Led to Durable Partial Responses in Fibrotic Tumors
Tsimberidou et al. Clin Cancer Res. 2025 28 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
Slide 29: Phase 1: TTI-101 Monotherapy Clinical Trial Summary
Tsimberidou et al. Clin Cancer Res. 2025; SD: Stable Disease; TREAE: Treatment related adverse events; F1-3: Formulation 1-3 29 Phase 1: TTI-101 Monotherapy Clinical Trial Summary PK / PD Tolerability Biological Activity • Well-tolerated BID oral dosing • No DLTs *Most severe AE counted per subject
Slide 30: Strong Rationale for TTI-101 and ICI Combination Therapy
1. Adapted from Zhao, Y et al. Hepatology. 2021 2. Cohen et al. Ann Oncol. 2018 3. Siu et al. JAMA Oncol. 2019. ICI: Immune Checkpoint Inhibition; Bev: Bevacizumab. Certain data on this slide are based on cross-study comparisons and are not based on any head-to-head clinical trials. Cross-study comp
Slide 31: TTI-101 Designed to Provide Distinct Mechanism for Unmet Need in HCC
1. World Health Organization (WHO) 2. WHO US Statistics 3. American Cancer Society 4. Represents range of ORRs from previous studies (MORPHEUS, Tempest, IMBrave150). 5. Listed 2nd line ORR expected to be <5% as 2nd line therapies inhibit VEGF/angiogenesis as common mechanism with bevacizumab and pem
Slide 32: REVERTLiver Cancer: Phase 2 Study of TTI-101 in HCC
NCT05440708; Dayyani et al. JCO. 2024; Data as of April 2025 32 REVERTLiver 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
Slide 33: REVERTLiver Cancer: Interim Phase 1b/2 Data
Preliminary radiographic change from baseline RECIST measurements (best response). Data as of Aug 2024. This interim data set was not subject to the standard quality control measures typically associated with final clinical trial results. 1. Tempest press release 23 Apr 2023 of Phase 2 Study. Tempes
Slide 34: Key Takeaways: TTI-101 in HCC
34 Key Takeaways: TTI-101 in HCC Inhibition of STAT3 activation to have dual therapeutic effect on cancer cells – overcoming tumorigenesis and immune suppression Clinically meaningful activity in both monotherapy and combination therapy in areas of unmet need Topline results from ongoing Phase 2 REV
Slide 35: TTI-109
THERAPEUTIC TTI-109
Slide 36: TTI-109: Prodrug of TTI-101 and Next Generation STAT3 Inhibitor
36 TTI-109: Prodrug of TTI-101 and Next Generation STAT3 Inhibitor TTI-109 ✓ Prodrug with mechanism of action of TTI-101 preserved ✓ No new toxicity observed in IND-enabling studies or unexpected results compared to TTI-101 ✓ Improved drug delivery increasing bioavailability and simplifying CMC TTI-
Slide 37: Targeting STAT3: Central Mediator of Fibrosis-Driven Diseases
1. Idiopathic pulmonary fibrosis. 2. Hepatocellular carcinoma. 3. Investigational new drug. 37 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 i
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