Inflammation is the body’s attempt to self-protect by removing harmful stimuli and begin healing. Left unchecked, inflammation can lead to several diseases – including inflammatory bowel disease, cachexia, and cancer – diseases that affect tens of millions every year in the United States alone. STAT3 plays an integral role in activating immune mechanisms that drive and sustain inflammation. Kasembeli et al, International Journal of Molecular Sciences, 2018.
To address the needs of the significant numbers of patients suffering from inflammatory diseases, Tvardi is focused on the development of safe and effective small molecule inhibitors of STAT3 for use across a range of inflammatory diseases. Tvardi’s STAT3 inhibitor has shown robust activity in animal models of inflammatory bowel disease, asthma, and cachexia, among other conditions.
Inflammatory bowel disease (IBD)
IBD is an idiopathic disease of the gastrointestinal (GI) tract with an estimated prevalence of 3.1 million in the United States. The two major types of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). Each is distinguished by the location and depth of inflammation within the GI tract. Patients with IBD have a 20- to 30-fold higher risk of developing colorectal cancer (CRC) compared to the general population.
STAT3 i activated in diseased areas of the GI tract in IBD patients. Mouse models of UC and CD, which recapitulate the pathological changes of the human disease, also exhibit STAT3 activation. TTI-101 treatment in these models completely prevented pathological intestinal inflammation and alleviated the signs and symptoms of disease.
Cachexia and asthma
Cachexia is a metabolic syndrome characterized by progressive muscle and fat wasting and a systemic negative energy balance. Cachexia is a major cause of mortality and a common feature of many chronic, low-grade inflammatory conditions, including congestive heart failure (CHF), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, and cancer. STAT3 plays a central and essential role in mediating cachexia. Correspondingly, TTI-101 alleviates cachexia in a partial nephrectomy model of CKD, Zhang et al, Cell Metabolism, 2013, as well as in cancer models with cachexia-inducing tumors of the colon and lung Silva et al, Journal Biological Chemistry, 2015. (see below image).
STAT3 also was shown to be critical for the development of asthma, and in mouse models, TTI-101 showed potent activity in steroid-resistant asthma. Gavino et al, Allergy, 2016.