STA-5326 Meslylate to Treat Gut Inflammation Associated With Common Variable Immunodeficiency

The purpose of this study is to assess the toxicity of the oral IL-12/23 inhibitor STA-5326 mesylate in subjects with common variable immunodeficiency (CVID) and associated symptomatic gastrointestinal inflammation. Common variable immunodeficiency is a clinically heterogeneous disorder characterized by decreased serum immunoglobulin IgG and IgA levels. In addition to chronic or recurrent pyogenic sino-pulmonary infections, many patients develop non-infectious gastrointestinal manifestations that can be disabling or fatal. Currently there is no standard therapy for the associated gastrointestinal disease outside of empiric nutritional intervention for weight loss and non-specific anti-diarrheal agents. Recently gut inflammation complicating CVID has been characterized as a Th1 inflammatory response, with excess cytokine production associated with diarrhea and weight loss as well as reduced D-xylose absorption and steatorrhea. This protocol represents the first attempt to test specific anti-IL-12 therapy in this patient group; it has been previously shown that therapy targeted to IL-12/23 successfully treated the Th1 gut inflammation of Crohn's disease. While this protocol is designed to measure the safety of STA-5326 mesylate in CVID patients, it will also measure effects on symptoms, gut function, expression of immune cell surface markers and production of cytokines from blood and gut mucosal mononuclear cells. CVID patients with gastrointestinal symptoms of malabsorption, maldigestion, and chronic diarrhea will be enrolled into this study. Subjects (up to a total of 10 individuals) will receive STA-5326 mesylate 100 mg per os (PO) once daily (QD) (equivalent to 70 mg STA-5326 free base) for 8 weeks. Subjects will have pretreatment and end-of-study procedures, including upper and lower endoscopies, to measure changes in immune responses and physiologic measures of gut function, as well as routine safety monitoring throughout the treatment period. Variables will include safety (adverse event rate), clinical (weight, stool frequency, results of gut absorption tests), and laboratory (lymphocyte and cytokine assays) parameters for descriptive summary statistical analysis (n, mean, median, standard deviation, minimum and maximum range).