Company: TVRD
Filing Date: 2025-10-20
Form Type: S-1/A
Source: 0001104659-25-100896
Chunk: 179

Company: Tvardi Therapeutics, Inc.
Filing Date: 2025-10-20
Form: S-1/A
Chunk 179
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insically increases myofibroblast proliferation and ECM deposition and extrinsically plays a major role in immune suppression, resulting in the dual cascades associated with IPF. Preclinical studies have shown that TTI-101 not only halts further development of lung fibrosis, but also has the potential to reverse established fibrosis. Through validated functional animal models of fibrosis-driven diseases, TTI-101 has been shown to inhibit STAT3 activation, both intrinsically and extrinsically. We have also demonstrated preclinically that TTI-101 impacts both key components of IPF pathology: downregulation of deposition and upregulation of degradation. In addition, clinically, we have demonstrated oral dosing with TTI-101 lowered levels of pY-STAT3 and was generally well-tolerated. In our Phase 1 clinical trial, eight patients out of ten evaluable patients had elevated baseline pY-STAT3, measured by immunohistochemistry using H-scores, defined as greater than 30 (out of a total score of 300). All eight patients demonstrated a decrease in H-score at the follow-up biopsy (approximately six weeks after initiating treatment), with a median decrease of 55%. Among the three patients who demonstrated a clinical benefit, the median decrease in the H-score was 79%. The Company reported preliminary data from its REVERT IPF Phase 2 clinical trial of TTI-101 in IPF in October 2025 and concluded that the study did not meet its goals. The Company is conducting additional analyses to further understand these results and inform next steps. Preclinical Fibrosis Studies Supporting the Development of TTI-101 for IPF In animal models, TTI-101 downregulated key pro-fibrotic mediators across fibrosis-driven diseases. Specifically, TTI-101 demonstrated dose-dependent decreases in validated targets associated with intrinsic deposition as well as extrinsic degradation. Dr. Tweardy and his collaborators at BCM have evaluated TTI-101 across various established mouse models of fibrosis and observed biologically relevant changes supporting the clinical development of TTI-101.

| Fibrosis-driven 
 Disease         | ​ | ​ | Mouse Models                              | ​ | ​ | Observations of TTI-101 Administration                                                                                                                                                                                                                                                                           | ​ |
| IPF             | ​ | ​ | BLM-induced IPF                           | ​ | ​ | •                                                                                                                                                                                                                                                                                                                
 Observed histologic reduction in lung fibrosis, quantified using Ashcroft score and Masson’s trichrome from murine lung