Company: TVRD
Filing Date: 2025-01-27
Form Type: S-4/A
Source: 0001104659-25-006050
Chunk: 467

Company: Tvardi Therapeutics, Inc.
Filing Date: 2025-01-27
Form: S-4/A
Chunk 467
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 associated with increased degradation downstream of extrinsic STAT3 signaling. Specifically, Tvardi demonstrated significant increases in biomarkers associated with T-cell activation (STAT1 and IFN γ), interferon responses (GBP3 and XAF1), cytotoxic T- and NK cells (NK GP7 and Perforin) and apoptosis-inducing factors (Granzyme A and B) with increased doses of TTI-101 (p<0.05 for trend). TTI-101’s Impact on Both Extrinsic and Intrinsic STAT3 Canonical Functions Associated with IPF These findings translated into a dose-dependent relationship between TTI-101 dose and observed effects:

| ● | Pharmacokinetics — Tvardi observed TTI-101 concentration in mouse lungs accumulated in the lung four times as much as compared to its accumulation in the plasma as measured by LC/MS/MS (50mg/kg: 8868 vs 1672; 25mg/kg: 8927 vs 2348; 12.5mg/kg: 7407 vs 1995). Administration of TTI-101 in a non-disease mouse model did not accumulate in the lung. |

| ● | Pharmacodynamics — Dose-dependent decrease of pY-STAT3 observed: the higher the dose of TTI-101 administered, the lower the levels of activated STAT3. |

| ● | Biological activity — At the higher two doses of 25 mg/kg and 50 mg/kg, TTI-101 demonstrated statistically significant improvement in lung function as compared to treatment with placebo (50mg/kg: 91.3; 25mg/kg: 92.7; 12.5mg/kg: 87.9 versus 94.9) (p<0.05) or with BLM alone (86.1) (p<0.05) as measured by SO2, where mice continued to experience loss of lung function. |

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<div align='center'>TTI-101’s Demonstrated Dose-Dependent PK exposure, PD and Improved Lung Function</div>

Tvardi believes its findings further support TTI-101 as a therapeutic product candidate for IPF as it was able to impact multiple mechanisms associated with the critical components of deposition and degradation in the pathogenesis of IPF.

Clinical Development of TTI-101 for IPF

Phase 1 TTI-101 Healthy Volunteer Drug-Drug Interaction Clinical Trial

Prior to the initiation of Tvardi’s ongoing Phase 2 clinical trial of T