US Army Medical Research Institute of Chemical Defense

2. Mission and Vision Organizational Structure Research Programs Education Consultation Facilities Human Capital Development Contracting Opportunities Patents Available for Licensing

3. Vision The leader in innovative, comprehensive solutions to advance medical chemical defense. Mission Provide a strong medical defense against chemical warfare agents and toxins.

5. USAMRICD Organizational Structure

6. Primary mission � war fighter: healthy, physically fit; 18-45 yr First Responders Civilian Communities Geriatric Pediatric Sensitive population groups

7. RESEARCH PROGRAMS

8. Molecular & Cellular Therapeutics Objective: Deliverables: 1) Stoichiometric Bioscavenger + Oxime (Pseudo-catalytic) 2) Catalytic Bioscavenger 3) Encapsulation Methods 4) Stem cell Therapies and Model Systems 5) Small molecule therapies

9. Cutaneous & Ocular Therapeutics and Permeation Objective: Eliminate or mitigate the toxic manifestations of mustard (HD) and other CWA exposures to the skin and eyes of military and civilian populations at risk. Deliverables: 1) Wound Healing of the HD-induced Wound 2) Therapy for the HD Ocular Injury 3) Improved Concepts for Therapy of HD Skin Injury 4) Understand transport through skin

10. Medical Diagnostics & Forensics Objective: Develop, validate and implement definitive analytical methods to verify human exposure to nerve agents and sulfur mustard using relevant biomarkers. Deliverables: 1) Nerve agent urinary metabolites � solid phase micro-extraction (SPME) 2) Beta lyase HD urinary metabolites � LC-MS-MS method 3) HD plasma protein adduct � population background study 4) Fluoride regeneration (nerve agents) � sub ng/ml method 5) Nerve and mustard agent metabolites � Proof of concept 6) Single amino acid-adduct screen for nerve and mustard

11. Neuroprotection Objective: To eliminate or mitigate the acute and long-term toxic manifestations of nerve agent (NA) exposures of military and civilian populations at risk. Deliverables: 1) PB-less NA treatment 2) Latent neuroprotection from NA-induced injury

12. Neurologic Therapeutics Objective: Identify, evaluate, and transition to Drug Development new products for treating nerve agent intoxication. Deliverables: 1) Cholinergic adjunct to NA treatment 2) Broad spectrum AChE reactivator

13. Respiratory Toxicity &Therapeutics Objective: To develop and test in vivo and in vitro animal inhalation, percutaneous and cardio-exposure models and evaluate protective and therapeutic compounds by assessing the scope of immediate and/or temporal mechanistic events associated with exposure/treatment. Deliverables: Establish inhalation, percutaneous, and cardio exposure models to assess chemical agent-induced injury Identify therapeutic windows for proper medical intervention Assess FDA-approved medical countermeasures against chemical agent injury Next generation cyanide medical countermeasure Cyanide detection in biological tissue

14. Agents of Biologic Origin Objective: To develop medical countermeasures which eliminate or mitigate the toxic manifestations BoNT in military and civilian populations at risk. Deliverables: Establish new integrated drug screening platform Develop post-exposure therapeutic agents: small molecule inhibitors, peptides and physiological antagonists Accelerate recovery from BoNT intoxication: role of ubiquitin-proteosome system (UPS) and growth factors

16. 1. AAS (Midazolam): Midazolam is ~2X more potent than diazepam. Being water-soluble it has improved pharmacokinetics and pharmacodynamics IM - it acts ~2X faster than equipotent doses of diazepam. It works against all!! agents, like diazepam, but again at a lower dose and faster. Operationally, instead of three diazepam CANAs (one w/ soldier, 2 extra w/ medic), there will now be only two (1 w/ soldier, other w/ medic). Human use trial (RAMPARTS), supported by CBMS but not sponsored by them, shows IM autoinjector delivered midazolam equieffective to IV lorazepam (Ativan) which is current standard of care in most of country for EMT Rx of seizing patients before delivery to ER. Data from our lab in conjunction w/ tony and Ben Capacio, shows effectiveness Vs diazepam against all agents in guinea pigs, pharmacokinetics against GD in GP, effectiveness against GD in rhesus along w/ pharmacokinetics and pharmacodynamics in same animals. Battelle now (May 2010) finishing up GLP study w/ ~1800 instrumented GP (vs 8 agents) and 220+ instrumented rhesus against 6 agents. Estimate that Meridian will file NDA by end of this year and first doses available to troops shortly after approval. Phase 2 Clinical Studies 1st study completed on Dec 20, 2008; No serious or unexpected adverse events 24 subject safety / PK study 2nd study completed Apr 20, 2009; One SAE reported (idiopathic thrombocytopenia) 250 subject safety and tolerability study 3rd study completed May 4, 2009; No serious or unexpected adverse events 24 subject safety / PK study evaluating midazolam when administered with atropine 4th study scheduled completed August 14, 2009 24 subject safety / PK study evaluating midazolam when administered with atropine and 2-PAM 5th study scheduled for September 30 2009 24 subject safety / PK study evaluating midazolam when administered with PB, Atropine, and 2-PAM 2. Bioscavenger: Incremental Solutions Increment I: Plasma-derived butyrylcholinesterase human (HuBChE; pBioscavenger) Increment II: Recombinant HuBChE or small molecule Increment III: Catalytic product is currently in early tech base 3. INATS The goal of the INATS program is to develop a treatment system that offers optimal protection against a broad spectrum of nerve agents.� INATS will be licensed by the U.S. Food and Drug Administration (FDA) and will be issued to Service Members performing military operations where there is risk of nerve agent attack. The program objective is to develop the oxime, MMB4 DMS, and atropine loaded in a two-chambered autoinjector delivery system and to obtain sufficient data to support new indications for PB, the component of Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP). FDA Clinical Hold Letter Received April 13, 2009 � lung damage found in rabbits NOAEL 25 mg/kg in Rabbit Will Result in Max Starting Dose of 0.27mg/kg Efficacious dose for 5LD50 estimated at 5mg/kg 4. SNAPP FDA approved Pyridostigmine Bromide, 30 mg tablet Feb 5, 2003 For pretreatment to soman threat only First drug approved under FDA �Animal Rule� As a condition of approval under the �Animal Rule,� FDA mandated four Phase 4 post-marketing studies Marmoset study (USAMRICD) Human intercostal muscle study (University of California-Davis) Guinea pig study (USAMRICD) Human blood acetylcholinesterase study (WRAIR) 1. AAS (Midazolam): Midazolam is ~2X more potent than diazepam. Being water-soluble it has improved pharmacokinetics and pharmacodynamics IM - it acts ~2X faster than equipotent doses of diazepam. It works against all!! agents, like diazepam, but again at a lower dose and faster. Operationally, instead of three diazepam CANAs (one w/ soldier, 2 extra w/ medic), there will now be only two (1 w/ soldier, other w/ medic). Human use trial (RAMPARTS), supported by CBMS but not sponsored by them, shows IM autoinjector delivered midazolam equieffective to IV lorazepam (Ativan) which is current standard of care in most of country for EMT Rx of seizing patients before delivery to ER. Data from our lab in conjunction w/ tony and Ben Capacio, shows effectiveness Vs diazepam against all agents in guinea pigs, pharmacokinetics against GD in GP, effectiveness against GD in rhesus along w/ pharmacokinetics and pharmacodynamics in same animals. Battelle now (May 2010) finishing up GLP study w/ ~1800 instrumented GP (vs 8 agents) and 220+ instrumented rhesus against 6 agents. Estimate that Meridian will file NDA by end of this year and first doses available to troops shortly after approval. Phase 2 Clinical Studies 1st study completed on Dec 20, 2008; No serious or unexpected adverse events 24 subject safety / PK study 2nd study completed Apr 20, 2009; One SAE reported (idiopathic thrombocytopenia) 250 subject safety and tolerability study 3rd study completed May 4, 2009; No serious or unexpected adverse events 24 subject safety / PK study evaluating midazolam when administered with atropine 4th study scheduled completed August 14, 2009 24 subject safety / PK study evaluating midazolam when administered with atropine and 2-PAM 5th study scheduled for September 30 2009 24 subject safety / PK study evaluating midazolam when administered with PB, Atropine, and 2-PAM 2. Bioscavenger: Incremental Solutions Increment I: Plasma-derived butyrylcholinesterase human (HuBChE; pBioscavenger) Increment II: Recombinant HuBChE or small molecule Increment III: Catalytic product is currently in early tech base 3. INATS The goal of the INATS program is to develop a treatment system that offers optimal protection against a broad spectrum of nerve agents.� INATS will be licensed by the U.S. Food and Drug Administration (FDA) and will be issued to Service Members performing military operations where there is risk of nerve agent attack. The program objective is to develop the oxime, MMB4 DMS, and atropine loaded in a two-chambered autoinjector delivery system and to obtain sufficient data to support new indications for PB, the component of Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP). FDA Clinical Hold Letter Received April 13, 2009 � lung damage found in rabbits NOAEL 25 mg/kg in Rabbit Will Result in Max Starting Dose of 0.27mg/kg Efficacious dose for 5LD50 estimated at 5mg/kg 4. SNAPP FDA approved Pyridostigmine Bromide, 30 mg tablet Feb 5, 2003 For pretreatment to soman threat only First drug approved under FDA �Animal Rule� As a condition of approval under the �Animal Rule,� FDA mandated four Phase 4 post-marketing studies Marmoset study (USAMRICD) Human intercostal muscle study (University of California-Davis) Guinea pig study (USAMRICD) Human blood acetylcholinesterase study (WRAIR)

18. Training Facilities/Capabilities: These are Academy of Health Sciences numbered courses for which both continuing medical education (CME) and CEU credit may be earned. Training Facilities/Capabilities: These are Academy of Health Sciences numbered courses for which both continuing medical education (CME) and CEU credit may be earned.

19. Consultation Mission Government agencies come to us as SMEs while writing their own policies regarding CWAs Government agencies come to us as SMEs while writing their own policies regarding CWAs

20. Unique Facilities

21. Recapitalization - 2014

22. Human Capital Development

23. Human Capital Development MRICD�s work force of over 300 people is a mix of civilian, military, contractor and post-doctoral level scientists With research expertise in: Biochemistry Toxicology Pharmacology Immunology Neuroscience With administrative expertise in: Budget management Program management Facilities Maintenance Safety/surety Civilians may apply through the civil service system http://cpol.army.mil The scientific and technical staff makes up a large percentage of our work force, but other functions � including Budget Administration, Security, Safety/Surety, Personnel, Logistics, Maintenance and Consultation � are performed as well. The scientific and technical staff makes up a large percentage of our work force, but other functions � including Budget Administration, Security, Safety/Surety, Personnel, Logistics, Maintenance and Consultation � are performed as well.

24. CONTRACTING OPPORTUNITIES

25. Types of Contracts Personal Services Research Collaborations Other Research Opportunities

26. Personal Services George Washington University - Science and Engineering Apprentice Program (SEAP) George Washington University � College Qualified Leaders (CQL) Oak Ridge Institute for Science and Education (ORISE) U.S. Army Research Office, Scientific Services Program (SSP) National Research Council

27. For high school students Placed in Department of Defense (DoD) laboratories for eight continuous weeks during the summer Students work with scientists and engineers who act as mentors

28. George Washington University � Science and Engineering Apprentice Program (SEAP) Program offers students a unique and positive experience encouraging them to pursue careers in science and engineering Contacts: Dr. Douglas Cerasoli, (410) 436-1338, douglas.cerasoli@us.army.mil Dr. John McDonough, (410) 436-1942, john.mcdonough1@us.army.mil

29. George Washington University � College Qualified Leaders (CQL)

30. Oak Ridge Institute for Science and Education (ORISE) U.S. Department of Energy institute focusing on scientific initiatives to research health risks from occupational hazards assess environmental cleanup respond to radiation medical emergencies support national security and emergency preparedness educate the next generation of scientists Undergraduate students, graduate students, college graduates (B.S., M.S., Ph.D.) Employed as laboratory technicians, research assistants, post docs Contacts: Christina Weber , MRICD Marketing Manager, (410) 436-3042, Christina.L.Weber@us.army.mil Laura Cook, ORISE Recruiter, (410) 306-9204, Laura.Cook@orau.org

31. U.S. Army Research Office, Scientific Services Program (SSP) Accelerated contract mechanism Enables all federal government organizations to obtain scientific/technical services to accomplish organizational goals and mission objectives Non-government scientists, engineers, analysts, consultants and subject matter experts can be quickly subcontracted to perform short term, well defined efforts when the expertise required is not available at the requesting government organization

32. U.S. Army Research Office, Scientific Services Program (SSP) Scope Laboratory basic and applied research Life Sciences Medical and Health Sciences Modeling and Simulation Contact: Kathryn C. Terry, ARO, (919) 549-4337, terry@arl.aro.army.mil

33. The National Research Council

34. Research Collaborations Outside entities have the capability to have medical chemical defense research conducted at the MRICD Cooperative Research and Development Agreements (CRADAs) MRICD currently supports a $1.2 M collaborative research program Contact Dr. John Graham, (410) 436-1197, john.s.graham1@us.army.mil

35. Research Collaborations Academia Private industry Other government agencies National International

37. Outside entities can apply for research grants through several mechanisms Small Business Innovation Research (SBIR) Broad Agency Announcements (BAA) National Institutes of Health, CounterACT Program

38. Administered by the U.S. Small Business Administration Office of Technology Ensures that the nation's small, high-tech, innovative businesses are a significant part of the federal government's research and development efforts

39. Each year, several topics are authored by MRICD scientists to supplement their research programs Contact: J.R. Myers, (301) 619-7377, james.myers@amedd.army.mil www.sbir.com

40. Defense Threat Reduction Agency Conducts basic and applied research aimed at the discovery and/or identification of better therapeutic and diagnostic medical countermeasures against chemical threat agents and toxins Overarching goal of this research program is to enhance diagnostic and treatment response capabilities on the battlefield Geared toward protecting the military population

41. CWA exposures and other collaborative efforts can be conducted at the MRICD in support of these grants Contact: Dr. Judith Laney, (703) 767-6045, judith.laney@dtra.mil http://www.dtra.mil/Missions/ChemicalBiologicalDefense/ChemicalBiologicalDefenseHome.aspx Defense Threat Reduction Agency

42. Countermeasures Against Chemical Threats (CounterACT) Conducts basic, translational, and clinical research aimed at the discovery and/or identification of better therapeutic and diagnostic medical countermeasures against chemical threat agents Overarching goal of this research program is to enhance diagnostic and treatment response capabilities during an emergency Geared toward protecting the civilian population

43. CWA exposures and other collaborative efforts can be conducted at the MRICD in support of these grants Contact: Dr. David Jett, (301) 496-6035, jettd@ninds.nih.gov http://www.ninds.nih.gov/research/counterterrorism/counterACT_home.htm

44. Grant opportunities are available at the following websites: http://www.grants.gov http://www.usamraa.army.mil/pages/Baa_Paa/baa_choice.cfm CWA exposures and other collaborative efforts can be conducted at the MRICD in support of these grants

45. Patents Available for Licensing Topical Skin Protectant Against Chemical Warfare Agents Using Perfluoro Ether/PTFE Technology. McCreery, Michael J. US Patent No. 5,607,979, issued 4 March 1997.  Site-Directed Mutagenesis of Esterases. Broomfield, Clarence A., Millard, Charles B., Lockridge, Oksana. US Patent Number 6,001,625, issued 14 December 1999.  Method of Reducing Brain Damage Resulting From Seizures. Filbert, Margaret G., Ballough, Gerald P.H. Patent Number 6,211,230, issued 3 April 2001. Active Topical Skin Protectants Using Reactive Nanoparticles. Hobson, Stephen T., Braue, Ernest H., Jr., Lehnert, Erich K., Klabunde, Kenneth J., Koper, Olga P., Decker, Shawn. Patent Number 6,403,653 issued, 11 June 2002.  Active Topical Skin Protectants Containing OPAA Enzymes and CLECs. Braue, Ernest H, Jr., Hobson, Stephen T., Govardhan, Chandrike, Khalaf , Nazar. Patent Number 6,410,604, issued 25 June 2002.  Active Topical Skin Protectants Using Combinations of Reactive Nanoparticles and Polyoxometalates or Metal Salts. Hobson, Stephen T., Braue, Ernest H, Jr., Lehnert, Erich K., Klabunde, Kenneth J., Decker, Shawn, Hill, Craig L, Rhule, Jeffrey, Boring, Eric, Koper, Olga. Patent Number 6,410,603, issued 25 June 2002.

46. Patents Available for Licensing Active Topical Skin Protectants Containing Polyoxometalates and/or Coinage Metal Complexes. Braue, Ernest H, Jr., Hobson, Stephen T., Hill, Craig L, Boring, Eric, Rhule, Jeff. Patent Number 6,414,039, issued 2 July 2002.  Active Topical Skin Protectants Using Hybrid Organic Polysilsesquioxane Materiels. Hobson, Stephen T., Braue, Ernest H, Jr., Shea, Kenneth. Patent Number 6,417,236, issued 9 July 2002.  Active Topical Skin Protectants Using Hybrid Organic Polyoxometallates. Braue, Ernest H, Jr., Hobson, Stephen T., White, James, Bley, Richard. Patent Number 6,420,434, issued 16 July 2002. Active Topical Skin Protectants Using Polymer Coated Metal Alloys. Hobson, Stephen T., Braue, Ernest H, Jr., Back, Dwight. Patent Number 6,437,005, issued 20 August 2002.  Active Topical Skin Protectants. Braue, Ernest H, Jr., Hobson, Stephen T., Lehnert, Erich K. Patent Number 6,472,437, issued 29 October 2002.

47. Patents Available for Licensing Active Topical Skin Protectants Containing S-330. Braue, Ernest H., Mershon, Millard M., Braue, Catherine R., Way, Ruth A. Patent Number 6,472,438, issued 29 October 2002.� Floating Cryostat Sections for use in Light and Electron Microscopy. Petrali, John P., Kan, Robert Kwai, Hamilton, Tracey A., Oglesby-McGee.� Patent Number 6,555,334, issued 29 April 2003.�  Method for Self-Detection of Pupillary Response. Petrali, John P.� Patent Number 6,637,885, issued 28 October 2003.�  Automated Method of Identifying and Archiving Nucleic Acid Sequences. Schlager, John J., Sweeney, Richard E., US Patent Number 6,871,147, issued 22 March 2005.  Compositions and Methods for Reducing Blood and Fluid Loss from Open Wounds. Mershon, Millard M., US Patent Number 7,303,759, issued 4 December 2007.

48. Patents Available for Licensing Chemical agent decontamination composition comprising a perfluorinated alkyl bromide. Johnston, D; Platoff, G; Baskin, S; Logan, T. US Patent Number 7,371,714, issued 13 May 2008. Compositions & Methods for Reducing Blood & Fluid Loss from Open Wounds. Mershon, Millard M., 7,303,759, issued 4 December 2007. Contact: Suaquita Perry, (410) 436-1339, MRICD-ORTA@amedd.us.army.mil

50. QUESTIONS?