1.6 jett v2 - acmt · 2013. 8. 7. · • aldicarb& nerve agent inhibition of ache rise in ach...
TRANSCRIPT
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($$(
Business model limitation of traditional pharma
Breast cancer Prostate cancer
Lung cancer
ALS NPC
200,000 patients
6,000 diseases
Melanoma
CollabRx,&May&2008&
Maybe(pharma(will(do(it?(
??&
Chemical)Warfare)
• World)War)I)and)II:)thousands)of)fatalities)• Iran2Iraq)War)(1980288):)thousands)of)fatalities)• Current)conflicts)in)the)Middle)East:)unknown)
Terrorism/Non2military)malicious)use)
• Tokyo)Subway)Attacks)(1995):)thousands)affected;)13)fatalities)
• Jonestown)mass)suicide)(1978):)900)fatalities)• Tylenol)and)Excedrin)poisonings)(1980’s):)few)fatalities)
Industrial)Accidents)
• Occur)Daily;)thousands)of)injuries)and)fatalities)annually)• Bhopal)Union)Carbide)disaster)(1984):)5,000)fatalities)
General)Poisonings)
• 4.2)million)calls)to)Poison)Control)Centers)in)2009)alone)
Burden(of(Illness:(A(Case(for(Chemical(Poisons(
“…smaller&than&normal®ional&brain&volumes&in&the&insular&cortex&and&
neighboring&white&matter,&as&well&as&in&the&hippocampus&in&the&victims.&The&
reduced®ional&white&matter&volume&correlated&with&decreased&serum&
cholinesterase&levels&and&with&the&severity&of&chronic&somatic&complaints&related&
to&interoceptive&awareness&[anxiety].”&(p&<&0.05)&Annals&of&Neurology&2007&
61:37W46&
Hippo%&campus&
Putamen&&
and&thalamus&
>1,000&victims,&12&deaths&
Step(2:(Find(People(
Engage(NIH’s(Best(and(Brightest,(but(first(…(
• “We)want)you)to)slow)down)on)your)highly)successful)work)on)epilepsy,)or)COPD,)or)wound)
healing,)and)work)on)antidotes)for)chemical)
toxins.)
• And)by)the)way,)you)will)bring)some)of)the)most)
dangerous)chemicals)known)to)man)into)your)lab.)• Oh)yeah,)and)there)are)little)to)no)human)data)
from)which)you)can)design)good)animal)models”)
Step(3:(Incentivize(and(Empower(the(Research(Community(to(Address(Mission(
Critical(Inadequacies…(
(Give($$(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?&