1.6 Jett v5 - ACMT...3/13/13 4 Business model limitation%of% traditional pharma% Breast cancer...
Transcript of 1.6 Jett v5 - ACMT...3/13/13 4 Business model limitation%of% traditional pharma% Breast cancer...
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Building a Research Pipeline at NIH
David A. Jett, Ph.D. Program Director NIH Countermeasures Against Chemical Threats
Better Therapeutics for Treating Chemical Injury … new targets … new drugs
… re-‐purposed drugs
NIH Countermeasures Against Chemical Threats (CounterACT)
Translational Research Pipeline Funnel
FDA
Target ID
Assay Development
Screening
Proof of Principle
Optimization & Preclinical Efficacy
IND-‐Enabling
Clinical
Cost $$
Failure Rate No Good Hits
Bad Chemistry
Bad Safety Profile
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Chemical Exposure
Transport to Hospital
In Hospital Home
Pre-‐treatment Pre-‐Hospital Treatment In-‐Hospital and Follow Up Treatment
Safe drugs with no side effects
Safe drugs that work fast Drugs that can prevent long-‐term effects
Windows of Opportunity
(?)
Dose-‐Response
0.1X LD50 1X LD50 2X LD50
Time of Drug Administration (min)
Chemical Insult
2X LD50 1X LD50
0.1X LD50
Effica
cy (e
.g. S
urviva
l)
100%
0 5 30 60
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Small Window for Some
Outline
I. Building NIH CounterACT: Problems & Solutions II. Science Advances III. Opportunities for Collaborating with ACMT
Step 1: Funding
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Business model limitation of traditional pharma
Breast cancer
Prostate cancer
Lung cancer
ALS NPC
200,000 patients
6,000 diseases
Melanoma
Pharmaceutical Industry?
??
Chemical Warfare • World War I and II: thousands of fatalities • Iran-‐Iraq War (1980-‐88): thousands of fatalities • Current conflicts in the Middle East: unknown
Terrorism/Non-‐military malicious use • Tokyo Subway Attacks (1995): thousands affected; 13 fatalities • Jonestown mass suicide (1978): 900 fatalities • Tylenol and Excedrin poisonings (1980’s): few fatalities
Industrial Accidents • Occur Daily; thousands of injuries and fatalities annually • Bhopal Union Carbide disaster (1984): 5,000 fatalities
General Poisonings • 4.2 million calls to Poison Control Centers in 2009 alone
Burden of Illness: A Case for Chemical Poisons
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“…smaller than normal regional brain volumes in the insular cortex and neighboring white matter, as well as in the hippocampus in the victims. The reduced regional white matter volume correlated with decreased serum cholinesterase levels and with the severity of chronic somatic complaints related to interoceptive awareness [anxiety].” (p < 0.05) Annals of Neurology 2007 61:37-‐46
Hippo-‐ campus
Putamen and thalamus
>1,000 victims, 12 deaths
Step 2: Find the Right People
Nerve 51%
Cellular 19%
Pulmonary 17%
Blistering 13%
e.g., sulfur mustard, arsenicals
e.g., chlorine, phosgene
e.g., cyanide
e.g., nerve “gas”, GABA agents
Chemical Classes
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• Nerve agents – neurologists/neuroscientists • Pulmonary agents – COPD, Pulmonary edema • Vesicants – burn specialists, wound healing • Cellular poisons – basic researchers
The Right People
Chemical “Toxidromes”
Over 120 Chemicals grouped by mechanism and toxicity
1. Anticoagulants (e.g. brodifacoum) 2. Cellular Respiration Poisons (hydrogen cyanide, hydrogen sulfide) 3. Cholinergic warfare (sarin, soman) 4. Cholinergic pesticides (parathion, aldicarb) 5. Convulsant (picrotoxin, TETS); (strychnine) 6. Hemolytic/Metabolic (arsenic trioxide, thallium sulfate) (arsine) 7. Opioids (diacetyl morphine) 8. Lower pulmonary (chlorine, phosphine) 9. Upper pulmonary (ammonia, sulfur dioxide) (hydrogen fluoride) 10. Vesicants (sulfur and nitrogen mustard) (phosgene oxime)
Step 3: Incentivize and Empower the Research Community to Address Mission
Critical Inadequacies…
( = Funding + People)
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Assay Development Target ID
Clinical Trials
Proof of
Principle
Pre-‐IND/IDE Studies
Centers of Excellence (U54) and Individual Projects (U01)
DoD Laboratories (IAAs)
Preclinical Contract Facility
Medicinal Chemistry (proposed)
Clinical Trial Networks
Industry Partners (SBIRs, Subcontracts to Grants)
Regulatory Affairs Consultative Bureau
Optimization/ Preclinical Efficacy
Screening
NIH BARDA
Efficacy Research Facility
CounterACT Program Snapshot
U.S. Army MRICD
(Nerve Agents)
UC Davis (Nerve Agents) Rutgers/UMDNJ
(Vesicants & Nerve Agents)
Harvard/MGH (Cyanide)
U Colorado (Vesicants SM,
chlorine)
Centers of Excellence Large Grants Small Business Small Grants Contracts/IAAs
The Research Network
Step 4: Partner and Leverage Resources
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NIH CounterACT
National Toxicology Program (NIEHS)
CHEMM Tool (NLM)
Molecular Libraries (NIH OD)
Anticonvulsant Screening Program (NINDS)
Unsolicited NIH
Projects (All NIH)
Other Key Partnerships
Step 5: Science Excellence
A high-‐throughput assay for anatoxin
antidotes
Molecular Libraries (NIH OD)
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Doxycycline facilitates healing of mustard exposed eyes
• Sections of whole corneas in organ culture and exposed to NM.
• Epithelial-‐stromal border in the cornea, the epithelium falls off.
• Doxycycline prevents the epithelium from falling off!!
Catalytic Antioxidant • SOD/catalase-‐like • Inhibits Lipid Peroxidation • Scavenges Peroxynitrite
• rats were exposed to 500 ppm chlorine gas for 30 minutes.
• Forty-‐five minutes following chlorine exposure AEOL 10150 was injected subcutaneously (sc) at 5 mg/kg and then every 4 hours for 24 hours and then once daily, or no treatment (NT), or equal volume of PBS.
0.5 mm
A
0.5 mm
B
Control
CEES 7.5%
* *
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Nitrocobinamide: Cyanide antidote
Organophosphorus (OP) pesticides and chemical weapons
NERVE AGENT
INHIBITION OF AChE
RISE IN ACh
ACTIVATION OF MUSCARINIC RECEPTORS
EPILEPTIFORM ACTIVITY
NEURONAL DAMAGE
PHYSIOLOGICAL AND METABOLIC
EFFECTS
ACTIVATION OF GLUTAMATE RECEPTORS
INTRACELLULAR ACCUMULATION
OF Ca++
Seizure-‐Pathology Model
Therapeutic Approaches: • Anticholinergics • AChE Reactivators • Anticonvulsants • Neuroprotectants • Single Antidote
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Institute of Chemical Defense
In Vivo Screens
In Vitro Screens
BATTELLE
Validated In Vivo Models
Anticonvulsant Screening
A S P
A R M Y
Anticonvulsant Screening Program (ASP)
GluK1/AMPA Receptor Antagonist LY293558 Stops Seizures and Protects Neurons, without Pretreatment
IM given @ 20 min; 7 days after soman IM given @ 20 min; 24hr period after soman.
Li et al. 2012. Toxicol Appl Pharmacol. 262(2):194-‐204.
NRG-‐1 Prevents CNS Neuronal Injury following OP Exposure using Fluorojade B Labeling
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Midazolam Clinical Trial
Accompanying editorial: “…the findings in this study should lead to a systematic change in the way patients in status epilepticus are treated en route to the hospital.” −Lawrence Hirsch
Conclusion: Intramuscular midazolam is the optimal initial prehospital treatment for status epilepticus by paramedics
Hypothesis: IM midazolam is as effective as IV lorazepam at stopping convulsions prior to ED arrival.
Method: Double blinded, Double Dummy; 4,314 paramedics, 79 hospitals. 1,023 enrolled.
Midazolam Trial Details
Final Step: Showcase Results and Impact on Science
Go to ACMT!
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CounterACT has now engaged some of the best scientists in the world, and is responsible for a huge improvement in the quality of publications in the area of
therapeutics for toxic chemicals (Over 475 Publications).
from Jett DA 2010. Science Trans Med 2(23):23ps12
Basic
New screening tools for neuro-‐active drugs
Structural biology of neuronal receptors
Advances in protein
engineering
Proof of Principle
New therapies for SE and neuropathic
pain
Neuroprotectants for
neurodegenerative disease and stroke
Preclinical
Delivery of drugs across the blood-‐
brain barrier
Technologies to improve
pharmacokinetics of drugs
Clinical and Diagnostic
Development of advanced platform
technologies
Portable devices such as EEG to detect non-‐convulsive seizures
And CounterACT research can have broad implications
Funding Opportunities
For Details Go To www.ninds.nih.gov/counteract
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• Research Centers of Excellence (U54) • Research Projects (U01) • Small Grants (R21) • SBIR Grants (R43/44)
Soliciting Cooperative Agreement Grant Applications
Preclinical ADMET & Manufacturing Pilot studies to GLP IND-‐enabling
Efficacy Studies Pilot studies to Pivitol studies
Assay Development (PAR-‐12-‐058) Med School Loan Repayment !!! (call me)
No Cost Contract Services – Seeking Pre-‐proposals
Other
NIAID
NIEHS*
NIAMS*
NICHD
NIGMS
NLM
NEI*
NINDS*
Dr. Hung Tseng
Dr. David Siegel
Drs. Sri Nadadur and Elizabeth Maull
Dr. Houmam Araj
Dr. Randy Stewart
Drs. Ernie Takafuji and Gen Platoff
Dr. Richard Okita
Dr. Bert Hakkinen
* ICs with active grants
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CounterACT Central Office at NINDS
Dr. David Yeung, Program Manager
Dr. Margaret Ochocinska, Program Analyst
Wendy Vasquez, Program Coordinator
Jonlethia King, Program Assistant