Millions are diagnosed with cancer each year. STAT3 activation is present in greater than 50% of all cancers and plays a central role in immune suppression in the tumor microenvironment. Tvardi is focused on the development of safe and effective small molecule inhibitors of STAT3 for use across many cancers both as a single agent and in combination with chemotherapy, immunotherapy or radiotherapy.
Tvardi is also focused on the development of resistance mechanisms underlying the failure of chemo- and radio-therapy, providing opportunities for the use of STAT3 inhibitors in the re-sensitization of tumors to standard of care. Tvardi also has developed a CLIA-certified test for STAT3 activation in human tumor specimens.
Agent activity in cancer models
In preclinical studies, TTI-101 has shown anti-tumor activity in multiple human cancer models including liver cancer (hepatocellular carcinoma), non-small cell lung cancer, head and neck squamous cell cancer, amongst others. Redell et al, Blood, 2011.
Hepatocellular carcinoma (HCC)
As one of the most common cancers worldwide, there is currently a major unmet need in treatment for non-resectable HCC and for prevention of recurrence in resectable HCC. Sorafenib is the current standard of care providing only 3 months survival benefit.
STAT3 is activated in most HCC tumors. In HCC mouse models, TTI-101 treatment stops tumor growth and reverses fibrosis and liver injury (secondary endpoint in clinical trials). Jung et al, Clinical Cancer Research, 2017.
Non-small cell lung cancer (NSCLC)
Lung cancer is the number one cancer killer and NSCLC is the most common type of lung cancer. Recent approvals of immunotherapy agents have revolutionized the treatment of metastatic NSCLC. Notably, the majority of patients do not respond to current immunotherapy protocols due, in part, to mechanisms governed by STAT3-mediated immunosuppression. Thus, STAT3 inhibitors represent an ideal combination agent in the setting of immunotherapy.
In most of the world, osimertinib (OSI), an EGFR inhibitor, is the first line treatment option in NSCLC tumors containing for EGFR mutations. While resistance mechanisms in these tumors are diverse and largely EGFR independent, many are mediated by activation of STAT3.
TTI-101 treatment has been shown to potently block human NSCLC tumor growth in mouse models. Lewis et al, Elsevier, 2015.
Head & neck squamous cell carcinoma (HNSCC)
HNSCC is the sixth leading type of cancer worldwide with over half of the cases diagnosed resulting in death. Cisplatin plus 5-FU and cetuximab have been the first line standard of care for locally advanced HNSCC. For refractory disease, anti-PD-1 therapy is the standard of care.
STAT3 is activated in the majority of cases of HNSCC, including radio resistance disease. Bharadwaj et al, Oncotarget, 2016.
In mouse models, TTI-101 treatment blocks growth and reverses radiation resistance of human papilloma virus (HPV)-negative HNSCC tumors.
CLIA-certified immunohistorchemistry (IHC) test
Tvardi has developed a CLIA-certified immunohistochemistry assay to score tumors for presence of activated STAT3 (pY-STAT3). This test will be used for the assessment of pharmcodynamic activity of STAT3 inhibitors and patient selection.