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
Category A Agent
Licensed Vaccine
Licensed & Labeled Therapies
Anthrax
AVA
Ciprofloxacin, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Penicillin G and Procaine Penicillin
Smallpox
DryVax
None
Plague
Doxycycline, Streptomycin, Tetracycline
Tularemia
Doxycycline
Botulinum
Equine anti-toxin against Types A and B
Viral Hemorrhagic Fevers

10. Anti-infective PD - 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 forces beyond biodefense
NIH
Provider of acquisition $$

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

12. Reality Check Myth: Reality:
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: Reality:
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: Reality:
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. Reagents & Services
Biodefense and Emerging Infections Resources (BEI Resources) Repository Program ( A B C D E F
In Vitro
Screens
Clinical
Isolate
Panels
Small
Animal
Models
Non-
Human
Primate
Toxicology &
Immunogenicity
for Vaccines
Pharmacology
for Therapeutics
Contractor
Pool

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 ‘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)
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