Tvardi Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on the development of novel, oral, small molecule therapies targeting STAT3 to treat inflammatory and proliferative diseases, has selected ulcerative colitis (UC) as the initial disease indication for its next generation STAT3 inhibitor – TTI-109.
Tvardi’s decision follows its successful phase 1 healthy volunteer study, in which TTI-109 successfully modulated multiple STAT3-driven immune cell populations, including Th17, T follicular helper (Tfh) and B cells.
These same cell types are known to expand with UC disease severity and infiltrate the inflamed colon.
Further analysis of immune cell populations across the active dose range elucidated:
- Broad suppression of pathogenic Th17-associated immune populations, including up to 76% reduction in subsets associated with mucosal destruction and treatment-refractory UC
- The Tfh immune populations that drive mucosal B cell responses were reduced up to 43% in Tfh subsets associated with disease UC activity
- Suppression extended to B cell (humoral) immunity, including up to 71% decline in subsets associated with colonic inflammation.
STAT3 sits at the centre of the three interconnected processes that drive UC: immune dysregulation, chronic inflammation and the tissue remodelling that leads to fibrosis, positioning it as a single, convergent therapeutic target for a disease with multiple underlying drivers.
These findings are further supported by published clinical studies linking reductions in activated STAT3 with higher rates of clinical remission across multiple UC therapeutic classes.
UC is a large and underserved market. More than 1.25 million patients are diagnosed with UC in the United States, representing an addressable market of approximately $3 billion in the US and $9 billion globally.
Currently approved therapies, including anti-TNF, anti-integrin, anti-IL-12/23, S1P and JAK inhibitors, achieve placebo-adjusted clinical remission rates below 30%, and most are administered parenterally.
Additionally, JAK inhibitors carry a black box warning for major adverse cardiovascular events, mortality, thrombosis, serious infections and malignancy.
By contrast, TTI-109, an oral small molecule, is designed to inhibit STAT3 directly, addressing the inflammation, immune dysregulation and proliferation that single-pathway therapies leave unresolved.
Across more than 400 subjects dosed to date with Tvardi’s STAT3 inhibitors demonstrated a differentiated safety profile from JAK inhibitors. TTI-109 is administered orally without a loading dose, and in preclinical models of UC, achieved more than eight-fold greater drug concentration in target tissue relative to plasma.
