Phase I clinical trial of an immunoadhesin antitoxin for anthrax

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DESCRIPTION (provided by applicant): Inhalational anthrax, caused by inhaled Bacillus anthracis spores, has a ~50% fatality rate even when treated with antibiotics. Pathogenesis is mediated by two toxic noncovalent complexes - edema toxin and lethal toxin. An essential component of both complexes, protective antigen (PA), binds to the major mammalian receptor that mediates toxin lethality in vivo, capillary morphogenesis protein-2 (CMG2). We have produced a fusion of the extracellular domain of human CMG2 and human IgG Fc, using a tobacco expression system, and demonstrated its effectiveness in treating inhalational anthrax in rabbits, both prophylactically and therapeutically. Our recombinant protein, PBI-220, binds to PA, blocks it from binding to cell-surface CMG2 and thus blocks toxicity. Significantly, PBI-220 neutralizes engineered PA variants that are poorly neutralized by anti-PA monoclonal antibodies in an in vitro assay, making it potentially superior to other anthrax therapeutics under development. We expect PBI-220 to be indicated for the pre- and post-exposure prophylaxis of individuals exposed to, or at risk of exposure to B. anthracis, and for the treatment of individual displaying signs or symptoms of inhalational anthrax. We are developing PBI-220 under FDA's "Animal Rule" for drugs that cannot be ethically tested for efficacy in humans. We have already completed pilot toxicology studies of PBI-220 in rats and cynomolgus macaques, and are developing a cGMP manufacturing process. We are collaborating with researchers the Tulane National Primate Research Center to evaluate PBI-220 as a treatment in a cynomolgus macaque model of inhalational anthrax. We have scheduled GLP toxicology testing in rats and cynomolgus macaques. All of these non-clinical activities will be completed in the next 12 months. The next step in the development of PBI-220 is to conduct safety testing in healthy volunteers. We are proposing a dose-ranging, placebo-controlled clinical trial to test the tolerability (including immunogenicity) and pharmacokinetics of a single intravenous infusion of PBI-220. The aims of this planning grant are 1) to select a clinical site and finalize the study design; 2) to complete all essential study documents, including an Investigator's Brochure, Informed Consent forms, Case Report forms, Study Manual of Operations, Essential Study Document collection (per ICH-E6 and FDA regulations), Statistical Analysis Plans, Monitoring Plans, Pharmacy and Laboratory Manuals and Data Management Plans; and 3) to prepare for a Pre-IND meeting with FDA.