Tvardi TTI-109 Prodrug Delivers 60% STAT3 Cell Reduction, 0.46-Day Diarrhea
TVRD•Tvardi’s Phase 1 study showed TTI-109 converted to TTI-101 within two hours, achieving dose-proportional pharmacokinetics with plasma levels above the STAT3 IC₅₀. The prodrug demonstrated up to 60% reductions in STAT3-driven Th17, Tfh and B cells and cut diarrhea duration to 0.46 days versus 3.35 days.
1. Study Design and Prodrug Conversion
Tvardi conducted a randomized, double-blind Phase 1 trial in three parts: single-ascending dose, bioequivalence crossover, and multiple-ascending dose with 21-day twice-daily dosing. TTI-109 rapidly converted to TTI-101 within two hours at all tested doses, confirming its prodrug design and equivalent systemic exposure.
2. Pharmacokinetic and Pharmacodynamic Results
Dose-proportional pharmacokinetics showed plasma TTI-101 levels consistently above the STAT3 IC₅₀. Exploratory pharmacodynamic analysis revealed up to 60% reductions in STAT3-driven immune cell populations, including Th17, T follicular helper, and B cell subsets.
3. Improved Tolerability Profile
TTI-109 demonstrated similar diarrhea incidence versus placebo, with events transient and self-resolving. Compared head-to-head with TTI-101 at equivalent molar doses, diarrhea duration was markedly shorter (0.46 vs. 3.35 days), signaling a significant tolerability enhancement.
4. Development Path Forward
Based on these results, Tvardi plans to advance TTI-109 into STAT3-driven dermatologic and gastrointestinal indications, pending IND clearance and additional funding. Management will host an investor webcast to discuss findings and next steps.
