Anti-Fibrotic Therapy for Scleroderma/SSc

DESCRIPTION (provided by applicant): Scleroderma (also known as systemic sclerosis-SSc) is characterized primarily by progressive dermal and vascular fibrosis. Other organs are affected too, including lung, heart, blood vessels, GI and kidney. Many patients who suffer from scleroderma/SSc also have a loss of pulmonary function. Scleroderma/SSc affects approximately 400,000 to 900,000 people in the USA every year. Mortality and morbidity in SSc are very high and are directly related to the extent of fibrosis in the involved organs. According to one study, the total cost attributed to scleroderma/SSc in the USA reached 1.5 billion annually. In this study, morbidity represented the major cost burden, associated with 820 million (56%) of the total costs. There is no known cure for scleroderma/SSc and the underlying cause remains unknown, though it is attributed to having an autoimmune component. Treatment is currently limited to management of symptoms in order to improve quality of life and limit long-term complications. Common treatments for scleroderma/SSc include immunosuppressive agents, anti-inflammatory agents, vasodilators and anti-fibrotic agents. Immunosuppressive agents such as corticosteroids and cyclophosphamide have demonstrated marginal efficacy,or have side effects. Therefore there is a critical need for effective and affordable therapeutic strategy. Increased expression of both platelet derived growth factor (PDGF) and its receptors (PDGFR? and PDGFR?) have been demonstrated in skin of scleroderma patients. Furthermore, the possibility of PDGFR activation through auto-antibodies is a novel and provocative concept in autoimmune fibrotic diseases. Recent studies have indicated that another growth factor, vascular endothelial growth factor (VEGF), apotent angiogenic molecule, is over expressed in SSc patients. From an extensive review of the literature, we concluded that inhibiting both PDGFR and KDR (VEGFRII) may be an effective novel therapeutic strategy to benefit scleroderma/SSc patients. We identified a small molecule receptor tyrosine kinase inhibitor/s with activity against both PDGFR and KDR and optimized for solubility in Phase I program. We have characterized ANG- 3070 dual kinase inhibitor in vitro and in vivo and found that ANG3070 has significant anti-fibrotic activity in animal models of skin, lung and kidney fibrosis. The objective of the proposed new work under the SBIR Phase II program is to further expand the efficacy profile to identify the optimal dose and therapeutic time window in other preclinical animal models of SSc involving several organ fibrosis. These studies will aid in selecting the dose regimen and selecting SSc patient population for clinical studies regardless of etiology. We will also evaluate the safety/toxicology profile of ANG3070, in order to assemble a complete IND-enabling preclinical data package to submit to FDA for advancing to human studies. PUBLIC HEALTH RELEVANCE: Mortality and morbidity in scleroderma/SSc are very high and are directly related tothe extent of fibrosis in the involved organs. A small molecule anti-fibrotc compound will be an effective disease modifying therapy to significantly reduce scleroderma/SSc patient deaths with the devastating effects associated multiple organ fibrosis. Our small molecule represents a novel therapeutic approach for an incurable debilitating disease.