Announcement • Jul 31
Tvardi Therapeutics Selects Ulcerative Colitis as Initial Indication for TTI-109 Tvardi Therapeutics, Inc. 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 center of the three interconnected processes that drive UC: immune dysregulation, chronic inflammation and the tissue remodeling 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 1,250,000 patients are diagnosed with UC in the United States, representing an addressable market of approximately $3 billion in the U.S. 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. Tvardi plans to initiate a study of TTI-109 in patients with moderate-to-severe UC in 2027, subject to clearance of Investigational New Drug (IND) application and additional funding. The primary endpoint will be safety, and the secondary endpoint will be clinical remission at 12 weeks. Exploratory pharmacodynamic endpoints will include serum/tissue biomarkers and analysis of single nucleotide polymorphisms (SNPs). Price Target Changed • Jul 09
Price target increased by 18% to US$9.75 Up from US$8.29, the current price target is an average from 8 analysts. New target price is 157% above last closing price of US$3.80. Stock is down 83% over the past year. The company is forecast to post a net loss per share of US$2.27 next year compared to a net loss per share of US$2.46 last year. Announcement • Jul 07
Tvardi Therapeutics Announces Phase 1 Results For TTI-109 And Plans Advancement Into Dermatologic And Gastrointestinal Diseases Tvardi Therapeutics announced Phase 1 results for TTI-109, its next-generation STAT3 inhibitor. TTI-109 is a phosphate prodrug of TTI-101 designed to improve delivery and tolerability while preserving the parent compound's mechanism of action. The study confirmed rapid prodrug conversion, dose-proportional pharmacokinetics with exposures above the STAT3 IC50 and, in an exploratory pharmacodynamic analysis, reductions of up to 60% in STAT3-driven immune cell populations across Th17, Tfh and B cell subsets. Key findings include: Confirmed prodrug conversion and exposure equivalence: Validating its prodrug design, TTI-109 rapidly converted to TTI-101 within two hours and produced nearly identical plasma levels at molar-equivalent doses. Sustained target-level exposure: 21-day repeat dosing showed stable, dose-proportional pharmacokinetics, with TTI-101 concentrations above the STAT3 IC50. Evidence of target engagement: Pharmacodynamic data showed reductions of up to 60% across disease-relevant STAT3-driven immune cell populations including Th17 cells, Tfh and B cell subsets. Improved tolerability vs. TTI-101: Compared with placebo, diarrhea events with TTI-109 were similar in duration, transient, and resolved without treatment interruption. Compared with TTI-101 at near-equivalent doses, diarrhea events with TTI-109 were substantially shorter in duration (0.46 vs. 3.35 days). The study was conducted in three parts. Part A was a randomized, double-blind, placebo-controlled single ascending dose study of TTI-109 at four doses (n=8/cohort). Part B was a bioequivalence crossover comparing TTI-101 and TTI-109 in both sequences with a 48-hour washout (n=6/sequence). Part C was a randomized, double-blind, placebo-controlled multiple ascending dose study with 21 days of twice-daily dosing at four doses, plus a TTI-101 reference arm (n=8/cohort). Primary objectives were to confirm rapid conversion of TTI-109 to TTI-101, demonstrate equivalent exposures at molar-equivalent doses, demonstrate dose-dependent increases in TTI-101 exposure and characterize safety and tolerability versus TTI-101 and placebo. Pharmacodynamic effects were an exploratory objective. The Company has identified dermatologic and gastrointestinal therapeutic areas with shared STAT3-driven disease biology, specifically the convergence of cytokines, growth factors and Th17 and B cell immune pathways at the STAT3 node. TTI-109 is designed to address both the cellular and humoral components of inflammation and proliferation with a single oral agent. Recent programs in related STAT3-driven indications have validated the underlying biology, but each acts on a single upstream target, while TTI-109 targets STAT3, the downstream node where these pathways converge. STAT3 sits at the center of the core disease processes in dermatologic and gastrointestinal diseases, including inflammation, proliferation and cellular and humoral dysregulation. Tvardi's STAT3 inhibitors have demonstrated biologic activity in these pathways in both preclinical models and in the clinic. In preclinical disease models, the Company’s STAT3 inhibitors reduced inflammatory cascades, fibrosis and modulated immune activity. Similarly, in humans, TTI-101 reduced activated STAT3 levels, inflammatory cascades and fibrosis. The TTI-109 healthy volunteer study extended this translational profile, with reductions in STAT3-driven immune cell populations. Tvardi's ability to initiate these programs is subject to clearance of an Investigational New Drug application (IND) and the availability of additional funding. 
