TTI-101 oral / Tvardi Therap - LARVOL DELTA

Study of TTI-101 in Participants With Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2 | N=100 | Completed | Sponsor: Tvardi Therapeutics, Incorporated | Active, not recruiting ➔ Completed | N=75 ➔ 100

Enrollment change • Trial completion • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Exploring the Role of STAT3 phosphorylation in Mediating Airway Hyperresponsiveness in a Model of Corticosteroid-Resistant Asthma (ERS 2025) - "However, the underlying mechanism remained unknown.The STAT3 inhibitor C188-9 effectively led to a reduction in AHR, decreased neutrophil infiltration, and alleviated airway remodeling in OVA- and ozone-induced mice...STAT3 levels in induced sputum from asthmatic patients exhibited correlation with their large- and small- airway function, neutrophil chemotaxis, and neutrophil levels in induced sputum. STAT3 activation, negatively regulated by SOCS3, plays a key role in corticosteroid-resistant airway neutrophilic inflammation and AHR by influencing the secretion of neutrophil chemokines, the activity of GR, and the levels of HDAC2 in airway epithelial cells."

Asthma • Immunology • Inflammation • Respiratory Diseases • CXCL1 • CXCL8 • HDAC2 • IL13 • IL17A • IL6 • SOCS3

STAT3 Inhibitors Inducing DNA Damage in Multiple Myeloma Cells and Enhancing the Anti-tumor Effects of NK Cells (IMS 2025) - "Using CCK-8 to explore the Half-maximal inhibitory concentration (IC50) of STAT3 inhibitor C188-9 in MM cell lines U266 and RPMI-8266... We found STAT3 inhibitor induces apoptosis and DNA damage in MM cells and STAT3 inhibitor combined with PARP1 inhibitor induced apoptosis and DNA damage in MM cells and mediated the high expression of MICA/B in MM cells. What's more, STAT3 inhibitor combined with PARP1 inhibitor induces DNA damage in MM cells, mediates high expression of MICA/B in MM cells, and activates the anti-tumour effect of NK cells."

Hematological Malignancies • Multiple Myeloma • Oncology • GZMB • MICA • MICB • NKG2D

JAK2/STAT3 Signaling Pathway Modulates Acute Methylmercury Toxicity in the Mouse Astrocyte C8-D1A Cell Line. (PubMed, Neurochem Res) - "Our data demonstrated that pharmacological inhibition of STAT3 using AG490 or C188-9 exacerbated MeHg-induced cell death and compromised antioxidant responses. Furthermore, to fully characterize the role of STAT3 in oxidative stress, we used two different antioxidants, N-acetylcysteine (NAC) and Trolox. Conversely, reactive oxygen species (ROS)-scavenging antioxidants partially ameliorated STAT3 activation, suggesting that MeHg-induced STAT3 activation is mediated, at least in part, by mechanisms independent of ROS. Our findings suggest that STAT3 contributes to neuroprotection against MeHg exposure in astrocytes and is, at least in part, regulated by the increase in ROS levels within these cells."

Journal • Preclinical • CNS Disorders • Inflammation

Phase I/IB Trial of Radiotherapy in Combination With TTI-101 in Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=18 | Recruiting | Sponsor: University of Colorado, Denver | Suspended ➔ Recruiting

Enrollment open • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

INTRINSIC MECHANISMS OF RESISTANCE TO CDK4/6 INHIBITORS IN LUMINAL METASTATIC BREAST CANCER (EACR 2025) - "MTT assays were performed to study cell viability and resistance to CDKi (Palbociclib)...In contrast, inhibited cell models showed reduced phosphorylation levels in STAT3, confirming the inhibitory effect of C188-9... Preliminary data suggest that STAT3 activation induces resistance to CDK inhibitors in HR+/HER2-cells, while its inhibition sensitises these cells to treatment. These findings highlight the potential of STAT3 as a response biomarker and a possible therapeutic target to counteract resistance to CDK inhibitors in this breast cancer subtype."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • IL6

THE MECHANISM OF STAT3 INHIBITORS INDUCING DNA DAMAGE IN MULTIPLE MYELOMA CELLS AND ENHANCING THE ANTI-TUMOR EFFECTS OF NK CELLS (EHA 2025) - "Using CCK-8 to explore the Half-maximal inhibitory concentration (IC50) of STAT3 inhibitor C188-9 in MM cell lines U266 and RPMI-8266... We found STAT3 inhibitor induces apoptosis and DNA damage in MM cells and STAT3 inhibitor combined with PARP1 inhibitor induced apoptosis and DNA damage in MM cells and mediated the high expression of MICA/B in MM cells. What's more, STAT3 inhibitor combined with PARP1 inhibitor induces DNA damage in MM cells, mediates high expression of MICA/B in MM cells, and activates the anti-tumour effect of NK cells."

Hematological Malignancies • Multiple Myeloma • Oncology • GZMB • MICA • MICB • NKG2D

ROS-Responsive Hydrogel for Localized Delivery of Nampt and Stat3 Inhibitors Exhibits Synergistic Antitumor Effects in Colorectal Cancer Through Ferroptosis Induction and Immune Microenvironment Remodeling. (PubMed, Adv Sci (Weinh)) - "Intriguingly, mass cytometry time-of-flight (CyTOF) analysis indicates that the combined treatment with FK866 and C188-9 exerts antitumor effects by increasing the infiltration of CD8+ T cells and neutrophils into the tumor, as well as enhancing the expression of immune-regulatory molecules, including IFN-γ, IL-10, and perforin. Thus, this localized treatment not only minimizes systemic adverse effects, but also markedly amplifies antitumor efficacy through the modulation of both tumor cells and the tumor immune microenvironment, representing a promising antitumor treatment strategy."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CD8 • GPX4 • IFNG • IL10 • NAMPT

Phase I/IB Trial of Radiotherapy in Combination With TTI-101 in Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=18 | Suspended | Sponsor: University of Colorado, Denver | N=35 ➔ 18

Enrollment change • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Tvardi Therapeutics Announces Completion of Enrollment in Phase 2 Clinical Trial of TTI-101 in Idiopathic Pulmonary Fibrosis (Businesswire) - "Tvardi Therapeutics, Inc...today announced that it has completed enrollment for its lead program in a Phase 2 clinical trial of TTI-101 for patients with idiopathic pulmonary fibrosis (IPF). The REVERT IPF Phase 2 clinical trial is a randomized, double-blind, placebo-controlled clinical trial of TTI-101 in patients suffering from IPF....Topline data is expected in Q4 of this year."

Enrollment closed • P2 data • Idiopathic Pulmonary Fibrosis

Study of TTI-101 in Participants With Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2 | N=75 | Active, not recruiting | Sponsor: Tvardi Therapeutics, Incorporated | Recruiting ➔ Active, not recruiting

Enrollment closed • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Randomized Pre-surgical Window-of-Opportunity Trial of TTI-101 in Patients With Stage II-IV Resectable HPV-negative Squamous Cell Carcinoma of the Head and Neck (clinicaltrials.gov) - P1 | N=33 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Feb 2025 ➔ Jun 2028 | Trial primary completion date: Feb 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Tvardi Therapeutics Announces First Quarter 2025 Results and Provides Business Update (Businesswire) - "Upcoming Milestones: Data from the company’s ongoing REVERT IPF Phase 2 clinical trial of TTI-101 anticipated in 2H 2025."

P2 data • Idiopathic Pulmonary Fibrosis

Tvardi Therapeutics Announces First Quarter 2025 Results and Provides Business Update (Businesswire) - "Upcoming Milestones:...Preliminary topline data from the company’s ongoing REVERT Liver Cancer Phase 1b/2 clinical trial of TTI-101 anticipated in 1H 2026."

P1/2 data • Hepatocellular Cancer

Tvardi Therapeutics Announces Presentation at the American Thoracic Society 2025 Annual Conference (Businesswire) - "Tvardi Therapeutics, Inc...announced that an abstract will be presented at the American Thoracic Society 2025 Annual Conference, which is being held May 16-21 in San Francisco...The abstract highlights the role of STAT3 as a master regulator of idiopathic pulmonary fibrosis (IPF). In preclinical studies, TTI-101, Tvardi’s STAT3 inhibitor, suppressed fibrotic markers which are not addressed with currently approved therapies (nintedanib and pirfenidone)....In addition, ex vivo analysis of human lung slices treated with TTI-101, nintedanib or pirfenidone resulted in greater repression of genes within alveolar fibroblast (key effector cells in fibrosis) with TTI-101 vs current approved therapies. Notably, TTI-101 downregulated genes involved in extracellular matrix production, including collagen genes, which were largely unaffected by nintedanib or pirfenidone."

Preclinical • Idiopathic Pulmonary Fibrosis

Targeting STAT3 in combination with epigenetic therapy induces tumor suppressive IL-24 in non-small cell lung cancer (AACR 2025) - "Because persistent STAT3 signaling is associated with poor prognosis and promotes cancer cell survival in multiple cancer types, including NSCLC, we treated a panel of 19 human NSCLC cell lines with the STAT3 inhibitor, C188-9, and epigenetic therapy and identified 12 cell lines demonstrating a synergistic reduction in cancer cell proliferation...To test this hypothesis, we treated NSCLC cells with exogenous IL-24 and confirmed epigenetic therapy-induced sensitization to IL-24. In summary, we define STAT3 as an actionable target that synergizes with epigenetic therapy to diminish the ability of NSCLC cells to proliferate and survive in anchorage-dependent and -independent conditions, associated with significant induction of IL-24."

Combination therapy • IO biomarker • Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • STAT3 • STK11

The role of CD53+ subsets and the JAK/STAT3 pathway in regulating cancer stemness and immune escape in esophageal squamous cell carcinoma (AACR 2025) - "Furthermore, in vivo study showed that JAK inhibitor Ruxolitinib and STAT3 inhibitor C188-9 could efficiently reduce tumor growth and enhance T cell infiltration in CD53+ mouse ESCC cell lines, suggesting a role in tumor proliferation and T cell editing. This study aims to elucidate the biological function of CD53+ subset ESCC cells in tumor progression and verify their role in T cell regulation, offering new therapeutic targets for ESCC treatment."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Hematological Malignancies • Oncology • Solid Tumor • Squamous Cell Carcinoma • CD53 • IL6 • MYC • PD-L1

A Study of TTI-101 as Monotherapy and in Combination in Participants With Locally Advanced or Metastatic, and Unresectable Hepatocellular Carcinoma (clinicaltrials.gov) - P1/2 | N=178 | Recruiting | Sponsor: Tvardi Therapeutics, Incorporated | Trial completion date: Mar 2025 ➔ Jun 2027 | Trial primary completion date: Mar 2025 ➔ Jun 2026

Monotherapy • Trial completion date • Trial primary completion date • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • STAT5

Study of TTI-101 in Participants With Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2 | N=75 | Recruiting | Sponsor: Tvardi Therapeutics, Incorporated | Trial primary completion date: Mar 2025 ➔ Jul 2025

Trial primary completion date • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Oral STAT3 Inhibitor, TTI-101, in Patients with Advanced Cancers (clinicaltrials.gov) - P1 | N=64 | Completed | Sponsor: Tvardi Therapeutics, Incorporated | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Jun 2024 | Trial primary completion date: Dec 2024 ➔ Jun 2024

Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Tvardi Therapeutics Announces Publication of Results from First-in-Human Study of TTI-101 in Patients with Advanced Solid Tumors in the Journal Clinical Cancer Research (GlobeNewswire) - P1 | N=60 | NCT03195699 | Sponsor: Tvardi Therapeutics | "By targeting both intrinsic tumorigenesis and extrinsic immune suppression, TTI-101 showed promising antitumor activity across tumor types, particularly in patients with hepatocellular carcinoma who were refractory to immune checkpoint inhibitors and anti-angiogenic agents....TTI-101 showed dose-linear pharmacokinetics and, at the recommended Phase 2 dose, the trough exposure levels were above the IC90 for STAT3-induced growth. No dose-limiting toxicities or treatment-related adverse events greater than grade 3 were observed. Pharmacodynamic analysis demonstrated TTI-101 decreased levels of phosphotyrosine (pY) STAT3 within paired tumor biopsies."

P1 data • Hepatocellular Cancer • Solid Tumor

REVERT: Phase 1b/2 Study of TTI-101 in Combination for Patients With Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer (clinicaltrials.gov) - P1 | N=6 | Terminated | Sponsor: Tvardi Therapeutics, Incorporated | Phase classification: P1/2 ➔ P1 | Completed ➔ Terminated; The study was terminated prior to Phase 2 due to slow accrual.

Phase classification • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

IL-11 regulates the biosynthesis of PGE2 through JAK1/STAT3 signaling pathway in bovine granulosa cells. (PubMed, Theriogenology) - "Specifically, C188-9 treatment blocked the IL-11-induced STAT3 nuclear translocation, downregulated the mRNA and protein expression levels of PTGS2, and ultimately led to a reduction in PGE2 production induced by 10 ng/mL IL-11. Our findings elucidate the cellular and molecular mechanisms by which IL-11 regulates PGE2 expression through the JAK1/STAT3 signaling pathway in bovine GCs in the presence of LH, contributing to a better understanding of the ovulatory process."

Journal • JAK1 • PACERR • PTGS2

Induction of SUSD2 by STAT3 Activation Is Associated with Tumor Recurrence in HER2-Positive Breast Cancer. (PubMed, Cells) - "In this study, we explored the potential of targeting SUSD2 to overcome trastuzumab (TRZ) resistance in HER2+ breast cancer...Furthermore, we observed that SUSD2 expression was decreased by C188-9, a STAT3-specific inhibitor...Our results showed that SUSD2 expression had a negative correlation with the relapse-free survival of patients with EGFR+ HER2+ breast cancer when compared to EGFR+ breast cancer patients. Collectively, our results demonstrate that SUSD2 expression is mediated by STAT3 and imply the potential of using SUSD2 as a biomarker to stratify HER2+ breast cancer."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGFR • ER • HER-2 • STAT3

Phase 1 Trial of TTI-101, a First-in-Class Oral Inhibitor of STAT3 in Patients with Advanced Solid Tumors. (PubMed, Clin Cancer Res) - P1 | "TTI-101 was well-tolerated. cPRs were observed across tumor types. The anti-tumor activity of TTI-101 monotherapy in patients with advanced, metastatic solid tumors is promising. A phase 2 study of TTI-101 in HCC is currently underway."

Journal • P1 data • Gastric Cancer • Oncology • Ovarian Cancer • Solid Tumor • STAT3