IND Enabling Studies for Small Molecule Anthrax Lethal Factor Inhibitors

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): PanThera's goal for the proposed research is to identify a clinical candidate that demonstrates in vivo efficacy in animal models of post-exposure inhalation anthrax and has a safety profile suitable for use in humans as an antidote to anthrax lethal factor intoxication. The 2001 anthrax spore attack via the U.S. mail caused 11 confirmed cases of inhalation anthrax. Despite the administration of frontline antibiotics and modern day intensive care support, only six of these patients survived. This high mortality rate, along with the widespread panic and considerable cleanup cost, starkly defined the seriousness of this bioterrorist event and the extreme threat anthrax poses to national security. Therapeutics currently available to treat anthrax, such as antibiotics and immunotherapeutic agents (vaccines and monoclonal antibodies), show complete protection in animal models when administered pre-exposure. However, their protective capability diminishes dramatically as post-exposure treatment delay times increase, suggesting that toxemia remains a threat to host survival. The complex pathogenesis of anthrax disease includes both bacterial and toxin components, although antibiotics can clear the system of bacteria and shut off the source of the toxins, and biological agents can block the transport of toxins into the cells, no therapeutic is currently available to disarm the toxins already present in the cells. PanThera has identified novel anthrax lethal factor inhibitors (LFIs) with picomolar potency and demonstrated in vivo efficacy in rat, mouse, and rabbit models of anthrax. These LFIs are designed to mitigate both early and late-stage toxemia by acting intracellularly and extracellularly, in contrast to biologics which ac only extracellularly. Small molecule LFIs should also provide a countermeasure against antibiotic resistant strains of B. anthracis (Enhanced Agents) and against novel viral vectors engineered to deliver intracellular anthrax LF toxin (Advanced Agents). The specific aims of the proposed project are: 1) complete lead optimization studies and select a preclinical candidate; 2) conduct early IND-enabling studies sufficient for a pre-IND meeting with the FDA; and 3) complete the remaining IND studies needed for submission of an IND to the FDA. To achieve these aims we have assembled a team of scientists who are leaders in the field of bacterial toxins and anthrax disease. This team of expert collaborators provides us with unique animal models: rat toxin and mouse spore challenge models of anthrax (Leppla lab; NIH), as well as a rabbit inhalation spore challenge model of anthrax infection (Peterson lab; UTMB).