The UAB NADs technology is mature and ready for optimization. The key to success will be a discovery program that creates a pharmaceutical product, which has appropriate stability, absorption, metabolism, and safety profiles to allow its use in animal experimentation. Following completion of this work, a formal preclinical development program will optimize the doses; institute allometric scaling; characterize the safety in at least two animal models; and complete the anthrax efficacy, dose response, and pharmacokinetic (PK) profile in animal. Then, a formal Investigational New Drug (IND) application will be submitted to the FDA, and two normal volunteer studies will be conducted: a single-dose, dose-escalating safety, tolerance, and PK Phase I clinical trial, to be followed by a multi-dose safety, tolerance, and PK Phase I clinical trial. These studies will be correlated with information from preclinical (animal) safety, PK and efficacy with the human trial experience. Since it is unethical to conduct anthrax interdiction trials in humans, surrogates of plasma and tissue concentrations obtained from animal interdiction studies will be used as correlates and inferences of the human experience.

The Food and Drug Administration has recently proposed regulations for the development of new drugs to be used against lethal or permanently disabling toxic substances, including agents that may be used in biological warfare (published in the Federal Register Vol. 64, No.192, (Oct. 1999: “Evidence Needed to Demonstrate Efficacy of New Drugs for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted). The recent approval of Ciprofloxacin for B. Anthracis treatment partially validates this approach.

In collaboration with PPD Discovery, and The University of Alabama, VDDI has developed a preclinical and clinical strategy in accordance with these new regulations, and will discuss this strategy with the FDA at a pre-IND meeting to be scheduled.

In summary, the specific design of our lead compounds, in conjunction with our preliminary in vitro and in vivo data suggest that:

The lead compounds have minimum inhibitory concentrations (MIC) values against B. Anthracis that are quite acceptable. The lead compounds have minimum inhibitory concentrations (MIC) values against MRSA and vancomycin resistant Enterococcus faecium and E. faecalis, that is as good or better than clinically approved antibiotics Some of the lead compounds show specificity against gram positive, but not gram negative strains, thus reducing some adverse effects of clinically approved antibiotics Some of the lead compounds show excellent activity against virulent and attenuated strains of B. anthracis. The mechanism of action of the compounds is specific to prokaryotic cells, thus leading to a great safety profile for clinical use. Product development issues that remain to be resolved include:

Development of parenteral agents; Development of orally active agents; and Development of a relatively long half-life product. DARPA has supported the initial funding for this program ($6 Million). USAMRIID supported the early synthetic chemistry and in vitro studies with several strains of B. anthracis and has just agreed to refund $300,000 for this work performed. VVDI has received an NIH R43 SBIR Phase I grant for $135,000. Additional support is requested from the Department of Defense and will be used to complete the synthetic chemistry and initiate the preclinical development program. Specifically $2 Million is needed immediately, and will be spent as allocated by the time and resources as outlined in the enclosed Proposal. Additional funds necessary to complete this development program and their respective utilization are shown in summary format in Table 1. A greatly detailed timescale and deliverable assessment for this program is also included in the proposal.