Tvardi is developing a new class of breakthrough medicines for diverse cancers, chronic inflammatory diseases and fibrotic diseases. We are focused on the key signaling molecule, STAT3, which is positioned at the intersection of many signaling pathways controlling gene networks integral to the survival and immune sequestration of cancer cells as well as to the pathogenesis of many inflammatory and fibrotic conditions.
Collectively, STAT3 driven diseases extract a significant societal and economic impact with over 50 million Americans afflicted. In cancer, greater than 50% of all cancers have activated STAT3 and compelling genetic data has established that extinction of STAT3 inhibits the growth of hepatocellular carcinoma, triple-negative breast cancer and lung cancer, among others.
Our lead drug candidate, TTI-101 is a small-molecule inhibitor of signal transducer and activator of transcription, STAT3, a protein in the cytoplasm of cancer cells. STAT3 is activated through phosphorylation on its tyrosine (Y) 705 residue by tyrosine kinases such Janus kinases (JAKs), receptor tyrosine kinases (RTKs), and members of the Src family of tyrosine kinases. After phosphorylation of Y705, pY-STAT3 dimerizes, translocates to the nucleus, binds to the promoter of genes, and activates many genetic programs that contribute to cancer development and metastasis, as well as to resistance of cancer cells to several treatment modalities. TTI-101 binds to STAT3 and prevents its recruitment to signaling complexes that contain activated tyrosine kinases. TTI-101 binding to STAT3 also prevents STAT3 homo-dimerization.
Numerous pre-clinical animal studies were conducted to evaluate the safety and efficacy of TTI-101 in animal models. Pharmacology and toxicology studies were also carried out according to U.S. FDA guidelines. Following the completion of Investigational New Drug (IND)-enabling studies, an IND was approved by the FDA for use in solid tumors.
We are currently conducting a Phase 1a clinical study at the The University of Texas MD Anderson Cancer Center in patients with advanced solid tumors. The current formulation of TTI-101 being used in the Phase 1a trial is an oral, hard capsule. The objectives of the ongoing Phase 1a study are 1) to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and tolerability of TTI-101 administered orally to patients with solid tumors, and 2) to determine the pharmacokinetics in plasma of TTI-101 following oral administration.
Tvardi has also developed an intravenous (IV) formulation of TTI-101 that it is under investigation for use in non-cancer indications. The company’s first focus outside cancer is in cachexia. Cachexia or Protein Energy Wasting (PEW) diminishes the quality of life and increases morbidity and mortality in the majority of the 2.3 million patients in the U.S. with chronic kidney disease (CKD); yet, there are no agents available in the clinic to treat it. Pre-clinical IND-enabling studies with TTI-101 (IV) have been initiated at Tvardi to support future Phase 1 studies in patients with CKD undergoing dialysis.
TTI-102 is a novel development candidate discovered by Tvardi that also demonstrates significant potential in the inhibition of STAT3. Early pre-clinical studies are underway and Tvardi believes this compound could show a benefit in both cancer and non-cancer indications.