TTI-101 oral / Tvardi Therap - LARVOL DELTA

STAT3 Inhibitors Inducing DNA Damage in Multiple Myeloma Cells and Enhancing the Anti-Tumor Effects of NK Cells (IMS 2026) - "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

Targeting STAT3 Phosphorylation Attenuates Corticosteroid Resistance and Airway Hyperresponsiveness in Asthma with Eosinophilic and Neutrophilic inflammation (ERS 2026) - "Given marked STAT3 upregulation in EOS+NEU+ patients, we established a murine EOS+NEU+ asthma model via ovalbumin plus ozone, treating mice with dexamethasone, STAT3 inhibitor C188-9, or both. STAT3 inhibition or SOCS3 upregulation restored pGR and HDAC2 levels while suppressing cytokine release. C188-9 also attenuated IL-13-induced ASMC hypercontractility.In vitro and in vivo inhibition of pSTAT3 reduces AHR, mitigates ASMC hypercontractility, and restores steroid sensitivity, highlighting its potential as a therapeutic target and biomarker."

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

Farnesoid X receptor activates STAT3 to promote fatty acid oxidation and suppress inflammatory macrophage responses in cholestasis. (PubMed, J Biol Chem) - "Conversely, co-administration of the STAT3 inhibitor C-188-9 partially reversed GW4064-mediated suppression of inflammatory and fibrogenic gene programs and reduced induction of FAO genes...STAT3 siRNA knockdown in hepatocyte and macrophage cell systems also blunted FXR agonist-induced transcriptional responses. These findings identify a novel FXR agonist-driven STAT3 immunometabolic axis that integrates bile acid signaling, FAO, and macrophage reprogramming to regulate inflammation during cholestatic liver injury."

Journal • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • STAT3 • TGFB1

Development of thiazole-hydrazone hybrids for targeted therapy of non-small cell lung cancer. (PubMed, Bioorg Chem) - "Among these compounds, compound 2b exhibited the highest cytotoxic activity against A549 cells (IC50= 6.10 µM), followed by compounds 2g, 2k, 2r, 2f, 2o, 2e, 2s, and 2h, all of which were more potent than erlotinib (IC50 = 77.35 μM). Compound 2r was identified as the most potent STAT3 inhibitor, exerting 10.8-fold higher activity than C188-9. These findings highlight the potential of thiazolyl hydrazones as targeted therapeutic agents, warranting further investigations for NSCLC treatment."

Journal • Embryonal Tumor • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

THE MECHANISM OF STAT3 INHIBITORS INDUCING DNA DAMAGE IN MULTIPLE MYELOMA CELLS AND ENHANCING THE ANTI-TUMOR EFFECTS OF NK CELLS (EHA 2026) - "Using CCK-8 to explore the Half- maximal inhibitory concentration (IC50) of STAT3 inhibitor C188-9 in MM cell lines U266 and RPMI-8266...Summary/Conclusion 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

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=193 | Recruiting | Sponsor: Tvardi Therapeutics, Incorporated | Trial completion date: Jun 2027 ➔ Mar 2027 | Trial primary completion date: Jun 2026 ➔ Feb 2027

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

STAT3 inhibitor TTI-101 effectively intercepts bladder cancer in a carcinogen-induced rat bladder tumor model (AACR 2026) - "In the present study, we determined pharmacodynamic pSTAT3 inhibitory effect of STAT3 inhibiting small molecules (GLG-302, SH5-07, TTI-101) in-vitro BC cells and in-vivo rat tumors...(Project funded in whole with Federal funds from the NCI-NIH, DHHS, under Contract No. 75N91019D00020-75N91020F00005)."

Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

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

RNA-Seq Analysis of Ruminal Methane Emissions in Beef-on-Dairy Cattle: Evidence for Immune, Nervous, and Endocrine Pathway Involvement. (PubMed, Animals (Basel)) - "The analysis identified eleven differentially expressed genes (DEGs), including six downregulated (KIAA1211L, LOC107131224, OSCP1, IL12B, LOC618859, FREM1) and five upregulated (DSCAML1, OSBP2, ACAN, PRSS16, CD1B) genes (Padj < 0.05) with one gene exhibiting potential biomarker characteristics. Gene and cell enrichment, as well as pathway analysis, suggested that nervous, immune, and endocrine systems may be involved in ruminal methane production by beef-on-dairy cattle. These findings highlight the potential of transcriptomic biomarkers to guide genetic selection strategies, offering a sustainable pathway to reduce methane emissions and enhance both environmental and agricultural efficiency."

Journal • ACAN • DSCAM • FREM1 • IL12B • PRSS16

Tvardi Therapeutics Announces Further Phase 2 REVERT IPF Data, Expanding Clinical Insights (The Manila Times) - "Fibrosis: Fibrosis decline was greater in patients treated with TTI-101 compared to placebo, -9.4% vs -2.4%, respectively, in baseline-weighted high resolution CT lung fibrosis score (centrally read, blinded and independently assessed); Inflammation: A greater IL-6 decline was observed among TTI-101-treated patients vs placebo. In addition, greater reduction in IL-6 was observed among patients with higher baseline IL-6 in the TTI-101-treated patients. IL-6 is a key pro-inflammatory cytokine that signals through STAT3...63% of pooled patients treated with TTI-101 demonstrated an increase in FVC at 12 weeks, compared to 46% of the placebo group."

P2 data • Idiopathic Pulmonary Fibrosis

Ferroptosis escape in AML stem cells uncovered by single-cell profiling and reversed by STAT3/NRF2 inhibition (ASH 2025) - "These cells were treated with STAT3 inhibitor C188-9 or STAT3-NRF2dual inhibitor (Brusatol) and the effect on cell proliferation was determined using CCK-8 assay, geneexpression by qPCR, flow cytometry was used for the detection of lipid ROS levels by Bodipy dye andintracellular iron estimation were performed...Moreover, acombination of NRF2-STAT3 inhibitor potentiated the effect of ferroptosis inducers RSL3 and Erastin andenhanced the cytotoxicity in LSCs.Our scRNAseq analysis of enriched AML LSCs revealed and dissected the mechanistic differencesbetween LSCs and non-LSCs...Our findings suggest that promoting ferroptosis is indeed apromising strategy to combat chemoresistance in AML. Therefore, dual targeting of NRF2-STAT3 alongwith ferroptosis inducers hold potential as adjuvant therapy by promoting ferroptosis-mediated celldeath in AML LSCs."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD34 • FTH1 • GPX4 • KIT • STAT3

Galectin-7 as a biomarker for aggressiveness and poor prognosis in thymic epithelial tumors. (PubMed, Transl Oncol) - "Galectin-7 is a potential biomarker for aggressive TETs, with expression levels associated with features of poor prognosis. These findings provide insight into TET biology and support further exploration of Galectin-7 in tumor stratification and therapeutic research."

Biomarker • Journal • Oncology • Solid Tumor • Thymic Carcinoma • Thymic Epithelial Tumor • Thymus Cancer

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=0 | Withdrawn | Sponsor: M.D. Anderson Cancer Center | N=33 ➔ 0 | Trial completion date: Jun 2028 ➔ Nov 2025 | Active, not recruiting ➔ Withdrawn | Trial primary completion date: Jun 2026 ➔ Nov 2025

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

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 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Active, not recruiting

Enrollment closed • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

E3 Ubiquitin Ligase TRIM21 Enhances Macrophage-Mediated Bortezomib Resistance By Inducing M2 Polarization in Multiple Myeloma (ASH 2023) - "QPCR and WB results showed that the macrophage polarization effect induced by TRIM21 overexpression was reversed after treatment with the STAT3 inhibitor C188-9. Our study shows that TRIM21 is overexpressed in macrophages in patients with relapsed and refractory MM. In addition, TRIM21 induces M2 polarization by activating the JAK-STAT3 pathway, thereby enhancing the protective effect of macrophage on MM cells. These findings provide a new insight into the role of TRIM21 in MM drug resistance and lay an important theoretical foundation for targeting macrophages in MM."

Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • TRIM21

E3 Ubiquitin Ligase TRIM21 Enhances Macrophage-Mediated Bortezomib Resistance By Inducing M2 Polarization in Multiple Myeloma (ASH 2024) - "Pre-treatment of macrophages with the JAK-STAT pathway inhibitor C188-9 reversed TRIM21-mediated regulation of macrophage polarization and notably reduced its protective effect on MM cells. Immunoprecipitation and ubiquitination experiments confirmed that TRIM21 interacts with SOCS3, and TRIM21 significantly increases its ubiquitination, thereby reducing SOCS3 protein levels.In summary, our research confirms that TRIM21 induces M2 polarization in macrophages by targeting SOCS3 to activate the JAK-STAT pathway, thereby enhancing its protective effect on MM cells. Targeting TRIM21 could potentially be a strategy to improve MM treatment efficacy."

Bone Marrow Transplantation • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CSF2 • SOCS3 • TRIM21

Tvardi Therapeutics Provides Update on Preliminary Data from Phase 2 REVERT Trial in Idiopathic Pulmonary Fibrosis (Tvardi Press Release) - "After reviewing the preliminary safety data and exploratory efficacy results, including changes in Forced Vital Capacity (FVC), the Company concluded that the study did not meet its goals...Preliminary data demonstrated patients’ baseline characteristics were similar across treatment arms, with the exception of percent predicted FVC, which was lower in the placebo-treated patients (70.1%) compared to the TTI-101-treated arms (74.1% and 81.1%, respectively)...Preliminary analysis of exploratory efficacy showed no statistically significant differences between placebo and treatment arms."

P2 data • Trial status • Idiopathic Pulmonary Fibrosis

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