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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