Company: TVRD
Filing Date: 2025-02-14
Form Type: 424B3
Source: 0001104659-25-014310
Chunk: 470

Company: Tvardi Therapeutics, Inc.
Filing Date: 2025-02-14
Form: 424B3
Chunk 470
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, et al .

The canonical STAT3 pathway associated with fibrosis-driven diseases can be broadly defined by a dual mechanism of action: intrinsic activity (within proliferative cells and the ECM) and extrinsic activity (within the immune system). Intrinsically (within proliferative cells and the ECM), pY-STAT3 increases cell proliferation and survival and promotes the deposition of ECM proteins, while extrinsically (within the immune system), pY-STAT3 contributes to immune suppression. Increased levels of extrinsic and intrinsic pY-STAT3 signaling result in fibrosis-driven diseases, including but not limited to IPF, HCC and systemic sclerosis (SSc).

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<div align='center'>**The Dual Mechanism of Action of STAT3’s Function in the Canonical Pathway**</div>

Critical and well-established signaling regulators of fibrosis, such as IL-6 and TGF-β, have been shown to induce pY-STAT3-dependent fibrotic conditions. pY-STAT3 is known to act both independently and in conjunction with other signaling networks that contribute to fibrosis. pY-STAT3 drives the development and progression of fibrosis through clotting and coagulation, inflammatory cell migration and fibroblast proliferation, ultimately leading to ECM deposition. STAT3’s role as the central mediator in the pathogenesis of fibrosis has been validated in third-party preclinical haploinsufficiency models, where one of two alleles of STAT3 were knocked out. In these preclinical studies, haploinsufficient STAT3 mice did not develop lung fibrosis despite injury, whereas the knockout of IL-6 or TGF-β receptor (TGF-βR), still resulted in fibrosis. These preclinical studies suggest that targeting individual signaling pathways is insufficient to block the development of fibrosis, however inhibiting STAT3 activation can potentially prevent the initiation of fibrosis.

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<div align='center'>**STAT3 Activation is a Central Catalyst in the Fibrotic Cascade**</div>

#### Tvardi’s Approach to Targeting STAT3
STAT3, like many transcription factors, has historically been deemed undruggable due largely to its intracellular location and the failure to identify residues within its Src-homology (SH) 2 domain critical for its activation. Though STAT3 has been a recognized and interrogated target for drug development, there is yet to be an