Company: TVRD
Filing Date: 2025-10-20
Form Type: S-1/A
Source: 0001104659-25-100896
Chunk: 175

Company: Tvardi Therapeutics, Inc.
Filing Date: 2025-10-20
Form: S-1/A
Chunk 175
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STAT3. TTI-101 binds tightly to the SH2 domain of STAT3, which specifically blocks its ability to bind to signaling complexes that contain tyrosine kinases. This is designed to prevent STAT3 from being phosphorylated at tyrosine (Y) 705 and further prevent STAT3 dimerization and nuclear translocation. The selective binding of TTI-101 to the SH2 domain thus inhibits STAT3’s canonical nuclear function, while preserving its essential non-canonical functions associated with cellular respiration within the mitochondria.

Preclinical studies in fibrotic conditions and cancers indicate inhibition of STAT3 using TTI-101 can disrupt the STAT3 canonical pathway to address fibrosis-driven diseases. Specifically, preclinical IPF models using TTI-101 have demonstrated that STAT3 inhibition resulted in (1) an observed histologic reduction in lung fibrosis, quantified using Ashcroft score and Masson’s trichrome from murine lung tissues, and (2) increase in lung function as measured by percent pulse oxygen saturation (“SO2”). Preclinical nonalcoholic steatohepatitis (“NASH”), models demonstrated that treatment with TTI-101 reduced (1) elevated hepatic enzymes and microsteatosis, or abnormal liver fat accumulation, (2) hepatic fibrosis, measured by Masson’s trichrome staining and (3) tumor growth as evidenced by reduction in average tumor volume determined by MRI. In SSc preclinical models, TTI-101 demonstrated an observed reduction in dermal fibrosis, measured by histological examination of skin sections stained with H&E and Masson’s trichome.

In a broad range of cancer models, TTI-101 demonstrated the capability to intrinsically induce apoptosis, or cell death, of tumor cells as evidenced by reduction in tumor weight or tumor volume and extrinsically overcome immune suppression in the tumor microenvironment as monotherapy and in combination with immune checkpoint inhibitors, as measured by immunohistochemical staining. We believe this preclinical data supports the development of TTI-101 across fibrosis-driven diseases. We also completed Phase 1 clinical trials of TTI-101 in advanced cancers and in healthy volunteers and are currently conducting a Phase 2 clinical trial of TTI-101 in HCC.

#### Our TTI-109 Product Candidate
Our second product candidate, TTI-109, is an oral, small-molecule, prodrug of, and mechanistically identical to, TTI-101. TTI-109 itself does