NIAID BioDefense Research: Challenges, Opportunities, & Sustainability

1. NIAID BioDefense Research:Challenges, Opportunities,& Sustainability Michael G Kurilla, MD-PhD Director, Office of BioDefense Research Affairs Division of Microbiology & Infectious Diseases Associate Director, BioDefense Product Development National Institute of Allergy and Infectious Diseases November 17, 2005

2. Comprehensive BioDefense Research Agenda DHHS

4. NIH BioDefense Research Funding: FY00 – FY05

8. Current Countermeasures

10. Anti-infectivePD - A Widening Gap Demand = Pull Respond to the needs of the marketplace. Need to be flexible, contractual, committable, not to be subject to political change. Supply = Push Research provides new opportunities that lead to innovation. due to market forcesbeyond biodefense NIH Provider of acquisition $$

11. NEEDS PROCESS CMs Biodefense Anti-infectives (includes resistance) Diseases of the Developing World Therapeutics Vaccines Diagnostics • NIAID • Infrastructure • Discovery • Preclinical • Clinical

12. Reality Check • Myth: • Scientific breakthroughs lead to new products • Reality: • Scientific breakthroughs lead to new concepts that may yield a new product after decades of trial and error (mostly error) and at least 3 orders of magnitude more funding

13. Reality Check • Myth: • Phase III clinical trials are responsible for most of the costs of clinical development for new medical products • Reality: • Total clinical trial costs (including costs of goods) typically amount to only 20 – 25% of the total clinical development costs

14. Reality Check • Myth: • The ‘Animal Rule’ will drastically reduce development time and costs for biodefense products compared to traditional pharmaceutical development • Reality: • ‘Animal Rule’ models are disease models (rather than infection models), accepted by the FDA, and performed under GLP conditions with cGMP product including detailed PK/PD or correlates of protection analysis combined with human PK or immunogenecity data

15. Product Development Activities Basic Applied Advanced Acquisition Unmet Medical Need Clinical Indication • Advanced – Product Testing • Product optimization / formulation • Pilot lot product • Animal rule correlates • IND enabling studies • Phase I & II clinical trials • Animal efficacy models for EUA • Large scale reagent production • Basic – Product, what product? • Microbiology • Immunology • Pathogenesis • Applied – Product Search • Target ID • Target validation • Assay development • In vitro screening • Medicinal chemistry for SAR • Animal model development • In vivo infectious models • Acquisition – Product Demonstration • Process development • Scaled up manufacturing • Phase III clinical trials • Animal rule efficacy studies • Other BLA/NDA enabling activities

16. Product Development Pathway Basic Applied Advanced Acquisition Unmet Medical Need Clinical Indication NIH Academia PPPs Biotech Traditional Large Pharma BioShield DOD/SIP

17. Developing Capacity • Intellectual • Facilities • Reagents • Services • Clinical Testing

19. A B C D E F Contractor Pool Non- Clinical Small Toxicology & Toxicology & In Vitro Human Isolate Animal Immunogenicity Pharmacology Screens Primate Panels Models for Vaccines for Therapeutics Models Reagents & Services Biodefense and Emerging InfectionsResources (BEI Resources) Repository Program (www.beiresources.org)

20. Clinical Testing

21. Second-Generation Anthrax Vaccine:Recombinant Protective Antigen (rPA) • First generation AVA (Biothrax) • Filtered B. anthracis culture supernatant • Highly reactogenic and has a questionable safety profile • Mechanism of protection: antibodies against the Protective Antigen (PA) • Second generation rPA • Highly purified, single recombinant protein formulated with Aluminum • Goal: efficacy and safety • Multiple Contracts Awarded for Development, Production and Testing of Anthrax rPA Vaccine • Development program budget approx. $250 M • Extensive animal model development program for anthrax countermeasures evaluation • Designed to fulfill FDA/CBER 21 CFR 601.91 ‘Animal Rule’ criteria • Phase 1 and Phase 2 clinical trials completed/underway/planned

23. Additional Development Projects • Anthrax • Monoclonal antibody therapy • Botulinum • Vaccine candidates (mono E & pentavalent) • Monoclonal antibody therapy • Plague • F1+V vaccine candidate • Tularemia • Live vaccine strain (LVS) in Phase I testing • Next generation vaccine candidate • Smallpox • Small molecule therapeutics • Viral Hemorrhagic Fevers • Novel Ebola vaccine candidate

24. Mechanisms of Engineered Threats • Anti-microbial resistance • Potential to defeat existing therapies • Naturally occurring • Near term intentional activity • Enhanced virulence • Potential to enhance infectiousness and reduce therapeutic window • Mid term potential activity • Chimerism / Immunomodulators • Potential to defeat existing preventive strategies and diagnostics • Long term potential activity

25. Additional Areas of Broad Interest • Vaccines • non-needle delivery • long term stabilization • more rapid induction • Therapeutics • host based directed interventions • innate immune augmentation • Diagnostics • multiplexed adaptive platforms • host based systems