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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
Comprehensive BioDefense
Research Agenda
DHHS
NIH BioDefense Research
Funding: FY00 – FY05
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
None
Doxycycline, Streptomycin,
Tetracycline
Tularemia
None
Doxycycline
Botulinum
None
Equine anti-toxin against
Types A and B
Viral Hemorrhagic None
Fevers
None
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.
NIH
due to market forces
beyond biodefense
Provider of
acquisition $$
NEEDS
Biodefense
Anti-infectives
(includes resistance)
Diseases of the
Developing World
PROCESS
NIAID
Infrastructure
•
Discovery
•
Preclinical
•
Clinical
CMs
Therapeutics
Vaccines
Diagnostics
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
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
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
Product Development Activities
Basic
Applied
Advanced
Unmet
Medical
Need
Clinical
Indication
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
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
Product Development Pathway
Basic
Applied
Advanced
Acquisition
Unmet
Medical
Need
Clinical
Indication
NIH
Academia
PPPs
Biotech
Traditional Large Pharma
BioShield
DOD/SIP
Developing Capacity
• Intellectual
• Facilities
• Reagents
• Services
• Clinical Testing
Reagents & Services
Biodefense and Emerging Infections
Resources (BEI Resources) Repository
Program (www.beiresources.org)
Contractor
Pool
A
B
C
D
In Vitro
Screens
Clinical
Isolate
Panels
Small
Animal
Models
NonHuman
Primate
Models
E
F
Toxicology &
Toxicology &
Immunogenicity Pharmacology
for Vaccines
for Therapeutics
Clinical Testing
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
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
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
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