Anti- IL5 therapy for Churg-Strauss Syndrome: a double blind randomized, placebo-

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DESCRIPTION (provided by applicant): Churg-Strauss syndrome (CSS) is a complex syndrome associated with asthma, anti-neutrophil cytoplasmic antibodies, and eosinophilic vasculitis involving multiple organs including the lungs, heart, skin, gastrointestinal tract, and nervous system. Characterized by significant tissue infiltration by eosinophils, it has become increasingly clear that CSS may be due to dysregulation of eosinophil function and/or production. CSS therapies, corticosteroids and cytotoxic agents such as cyclophosphamide and azathioprine, have multiple systemic side effects, do not offer the potential for long-term cure, and often fail to yield clinical benefit. To date, research to study this 'orphan disease' has been minimal, its epidemiology, pathogenesis, and genetics remain largely unknown, and no significant therapeutic advances have been realized. Blood levels of interleukin (IL)-5, a cytokine regulating eosinophil bone marrow release, activation, and tissue survival, are increased in CSS patients. Monoclonal Anti-IL5 antibody therapy is safe and effective in hypereosinophilic syndromes including asthma, decreasing eosinophil numbers in blood and bone marrow. We gave open label anti-IL5 to 10 CSS patients for 4 months, yielding significant reduction of systemic steroid dose, peripheral eosinophilia, and CSS exacerbations. We hypothesize that Anti-IL5 therapy will safely provide CSS patients a novel steroid-sparing treatment option that decreases serum markers of disease activity, and allows for steroid tapering. To test this hypothesis, we plan a double blind placebo controlled trial of Anti-IL5 therapy in CSS patients. The NIAID Clinical Trial Planning (R34) Grant supports the planning and design of investigator-initiated clinical trials (U01) in humans. In the context of the unmet treatment needs of CSS patients, we propose a 1 year program with the following specific aims: 1) Prepare a U01 CSS Anti-IL5 Protocol, with Manual of Operations & Case Report forms 2) Organize a U01 study team including clinical research sites, data team, statistical team, and communications systems 3) Prepare U01 CSS Anti-IL5 safety & data monitoring plan and oversight systems 4) Prepare U01 IRB informed consent forms 5) Develop recruitment strategies 6) Work with FDA & pharmaceutical sponsor to obtain IND and develop drug distribution plan 7) Develop mechanistic protocols to assess effect of anti-IL5 on eosinophil biology in CSS (e.g. biomarkers, genomics). With completion of these aims over the course of the 1 year proposal, we will have a research team in place ready to submit a U01 application with fully developed protocol, operations manual, forms, oversight program, approval of study medication (including an IND), and a developed mechanistic protocol to help us better understand eosinophil biology. In addition to providing effective, safe therapy for CSS patients, our ultimate goal is to learn from CSS about eosinophil biology, as well as asthma, and allergies. This proposal will allow for planning of such research to occur. PUBLIC HELATH RELEVANCE (provided by applicant): Churg-Strauss syndrome (CSS) is a complex syndrome associated with asthma, high numbers of blood eosinophils and inflammation of multiple organs. CSS therapies are often ineffective or associated with side effects. Since levels of the cytokine interleukin-5 (IL-5) are elevated in these patients, we hypothesize that antibodies to IL-5 will safely provide CSS patients with a novel steroid-sparing treatment option that will decrease serum markers of disease activity, and allow for corticosteroid tapering. The goal of this grant application is to obtain support to plan and organize a double blind placebo controlled trial of anti-IL5 therapy in CSS patients as well as mechanistic studies, so that we may gain a better understanding of the biology of the eosinophil and associated disorders.