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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 Slide 2 Comprehensive BioDefense Research Agenda DHHS Slide 3 Slide 4 NIH BioDefense Research Funding: FY00 FY05 Slide 5 Slide 6 Slide 7 Slide 8 Current Countermeasures Category A AgentLicensed Vaccine Licensed & Labeled Therapies AnthraxAVACiprofloxacin, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Penicillin G and Procaine Penicillin SmallpoxDryVaxNone PlagueNone Doxycycline, Streptomycin, Tetracycline TularemiaNoneDoxycycline BotulinumNoneEquine anti-toxin against Types A and B Viral Hemorrhagic Fevers None Slide 9 Slide 10 Anti-infective PD - A Widening Gap Provider of acquisition $$ NIH Supply = Push Research provides new opportunities that lead to innovation. Demand = Pull Respond to the needs of the marketplace. Need to be flexible, contractual, committable, not to be subject to political change. due to market forces beyond biodefense Slide 11 NEEDS PROCESS CMs Biodefense Anti-infectives (includes resistance) Diseases of the Developing World NIAID Infrastructure Discovery Preclinical Clinical Therapeutics Vaccines Diagnostics Slide 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 Slide 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 Slide 14 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 Reality Check Slide 15 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 Acquisition Product Demonstration Process development Scaled up manufacturing Phase III clinical trials Animal rule efficacy studies Other BLA/NDA enabling activities Applied Product Search Target ID Target validation Assay development In vitro screening Medicinal chemistry for SAR Animal model development In vivo infectious models Clinical Indication Unmet Medical Need Basic Applied Advanced Acquisition Product Development Activities Basic Product, what product? Microbiology Immunology Pathogenesis Slide 16 Clinical Indication Unmet Medical Need Basic Applied Advanced Acquisition Product Development Pathway NIH Academia PPPs Biotech Traditional Large Pharma BioShield DOD/SIP Slide 17 Developing Capacity Intellectual Facilities Reagents Services Clinical Testing Slide 18 Slide 19 Biodefense and Emerging Infections Resources (BEI Resources) Repository Program (www.beiresources.org) Reagents & Services ABCDEF In Vitro Screens Clinical Isolate Panels Small Animal Models Non- Human Primate Models Toxicology & Immunogenicity for Vaccines Toxicology & Pharmacology for Therapeutics Contractor Pool Slide 20 Clinical Testing Slide 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 Slide 22 Slide 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 Slide 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 Slide 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 Slide 26 Slide 27