The long-term goal of this Challenge Grant project is develop on a fast-track several existing new drugs which are already known to have activity in animal models of tuberculosis (TB), but which will not be developed by the respective companies in which they were discovered. Sequella, Inc. is in licensing negotiations for the rights to at least two, and possibly a third promising drug lead, selected with an emphasis on the following criteria: 1. Evidence of efficacy in a mouse model of tuberculosis 2. Simple chemical composition and synthesis, for ease of production and pricing 3. Representation of different drug classes 4. Evidence that they do not share cross-resistance with existing TB drugs. Sequella, Inc. will cost share with the NIAID to support the necessary remaining preclinical studies for each drug lead, according to the compound's present state of development. Preclinical studies include medicinal chemistry to enhance solubility and bioavailability, pharmacodynamic studies in animals, toxicological tests in animals and/or in vitro systems, and purity/stability testing in bulk drug prepared under GMP guidelines. Based upon the data obtained from the preclinical studies, Sequella, Inc. will apply for Investigational New Drug (IND) approvals for all compounds that show a duration of pharmacodynamic effects consistent with dosing intervals of no greater than once a day, and that appear likely to have an acceptable therapeutic ratio. The decision to proceed with Phase I/II trials of individual drug leads will be made cooperatively with NIAID staff. For each drug to be tested further, Phase I trials to determine tolerability will be carried out in volunteers at the NIH Clinical Research Center (if approved) or under contract. Phase II studies of each individual drug to test for efficacy in human TB patients will be carried out using a clinical trial design intended to reduce the risk of drug-resistant strains arising or spreading.
The aims of the two-month Phase I time period would be to complete licensing agreements on targeted drugs (PA-824), identify promising TB drug leads in addition to those of which we are already aware, to meet with investigators who have worked with these compounds, to begin the negotiating process with Universities or companies to secure right-to-license agreements, and to outline clinical development plans for each TB drug candidate.
