Building(a(Research(Pipeline(at(NIH(

David&A.&Jett,&Ph.D.&

Program&Director&

NIH&Countermeasures&Against&Chemical&Threats&

Translational Basic

Assay Development Target ID Clinical

Trials

Proof of

Principle

Pre-IND/IDE Studies

Clinical

Optimization/ Preclinical Efficacy

Screening

Translational(Research(Pipeline(

Drug(Discovery(and(Development(

Outline(

I.  Building(NIH(CounterACT:(Problems(&(Solutions(II.  Science(Advances(III.  Opportunities(for(Collaborating(with(ACTM(

Countermeasures+Against+Chemical+Threats+(CounterACT)+

Chemical))Exposure)

Transport)to))Hospital)

In)Hospital) Home)

Pre7treatment) Pre7Hospital)Treatment) In7Hospital)and)Follow))Up)Treatment)

Safe)drugs)with)no)side)effects)

Safe)drugs)that)work)fast) Drugs)that))can)prevent))long7term)effects)

Opportunities)to)Treat)Chemical)Victims)

Step(1:(Find($$(

Business model limitation of traditional pharma

Breast cancer Prostate cancer

Lung cancer

ALS NPC

200,000 patients

6,000 diseases

Melanoma

CollabRx,&May&2008&

Maybe(pharma(will(do(it?(

??&

Chemical)Warfare)

•  World)War)I)and)II:)thousands)of)fatalities)•  Iran2Iraq)War)(1980288):)thousands)of)fatalities)•  Current)conflicts)in)the)Middle)East:)unknown)

Terrorism/Non2military)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(

“…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&

61:37W46&

Hippo%&campus&

Putamen&&

and&thalamus&

>1,000&victims,&12&deaths&

Step(2:(Find(People(

Engage(NIH’s(Best(and(Brightest,(but(first(…(

•  “We)want)you)to)slow)down)on)your)highly)successful)work)on)epilepsy,)or)COPD,)or)wound)

healing,)and)work)on)antidotes)for)chemical)

toxins.)

•  And)by)the)way,)you)will)bring)some)of)the)most)

dangerous)chemicals)known)to)man)into)your)lab.)•  Oh)yeah,)and)there)are)little)to)no)human)data)

from)which)you)can)design)good)animal)models”)

Step(3:(Incentivize(and(Empower(the(Research(Community(to(Address(Mission(

Critical(Inadequacies…(

(Give($$(to(People)((

Translational+Basic+

((((((((Assay(((((((Development++Target(ID(

((((Clinical((((Trials(

(((Proof((((of(

((((Principle(

(((((PreWIND/IDE(((((((((((Studies(

Clinical+

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)

U.S. Army MRICD (Nerve Agents)

UC Davis (Nerve Agents)

Rutgers/UMDNJ (Vesicants & Nerve

Agents)

Harvard/MGH (Cyanide)

U Colorado (Vesicants SM, chlorine)

U01 U54 R44 R21 Contracts/IAAs

Research(Network(

Step(4:(Partner(and(Leverage(Resources(

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:(Do(Really(Good(Science(

Nerve 51%

Metabolic 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)

A(highWthroughput(assay(for(anatoxin(antidotes(

0.5 mm

A&

0.5 mm

B

Control&

CEES&7.5%&

*&*

AEOL&10150:&Sulfur&Mustard&antidote&

Place&holder&for&doxycyline&

AEOL&10150:&Chlorine&antidote&

Catalytic&Antioxidant&• Superoxide&• Hydrogen&Peroxide&• Lipid&Peroxides&• 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.!

Total&Exposure&Time&40&min;&IM&Injection&of&Antidote&after&15&min&Sodium&Nitrite&Corresponds&to&Amount&of&Nitrite&in&Nitrocobinamide&

Cobinamide:)Cyanide)antidote)

Infusion&Time&10&min;&IM&Injection&of&antidote&at&10&min.&&Sodium&nitrite&corresponds&to&amount&of&nitrite&in&nitrocobinamide.&Rabbits&Not&Ventilated&

Cobinamide:)Cyanide)antidote)

Types(of(chemicals(

Increase)Excitatory)Neurotransmission)

• Organophosphorus)pesticides)and)chemical)weapons)

• Ion)channel)modulators)–)OC)pesticides,)bio2toxins)

• DDT)&)Na)channels)• Anatoxin)&)nicotinic)receptors)

Organophosphorus(Agents((

Chemical&Warfare&

GA&(Tabun)&

GB&(Sarin)&

GD&(Soman)&

GF&

VX&

Acetylcholinesterase&Inhibitors&

Pesticides&

•  Parathion&•  Chlorpyrifos&•  Diazinon&•  DFP&•  Aldicarb&

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(

Chemical(Nerve(Agents(

Therapeutic Approaches: •  Anticholinergics •  AChE Reactivators •  Anticonvulsants •  Neuroprotectants •  Single Antidote

Neuregulin:&Neuroprotectant&

Li&et&al.&2012.&Toxicol&Appl&

Pharmacol.&262(2):194W204.&

Place&holder&for&LY35882&

Institute&of&Chemical&Defense&

In&Vivo&Screens&

In&Vitro&Screens&

BATTELLE

Validated In Vivo Models

CounterACT(and(ASP(Partnership(

A S P

A R M Y

New(FDAWApproved(Nerve(Agent(Therapy(in(2013(

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!(

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.))

from&Jett&DA&2010.&Science&Trans&Med&2(23):23ps12&&

Basic&

New&screening&tools&for&neuroWactive&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&bloodW

brain&barrier&

Technologies&to&improve&

pharmacokinetics&of&&drugs&

Clinical&and&Diagnostic&

Development&of&advanced&platform&

technologies&

Portable&devices&such&as&EEG&to&detect&nonWconvulsive&seizures&

And(CounterACT(research(can(have(broad(implications(

Funding(Opportunities(

For(Details(Go(To(www.ninds.nih.gov/counteract(

•  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(INDWenabling(

Efficacy(Studies(Pilot(studies(to(Pivitol(studies(

Assay(Development((PARW12W058)(

No(Cost(Contract(Services(–(Seeking(PreWproposals(

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&

CounterACT(Central(Office(at(NINDS(

Dr.)David)Yeung,)Program)Manager)

Dr.)Margaret)Ochocinska,)Program)Analyst)

Wendy)Vasquez,)Program)Coordinator)

Jonlethia)King,)Program)Assistant)

Thank&You&and&Questions?&