360 Kieran F. Geoghegan and Douglas S.Johnson

[60] Y.-M. u. M. Xu, M.-T. Lai, Q. Huang, J. L. Castro, J. DiMuzio-Mower, T. Harrison, C.Lellis, A. Nadin, J. G. Neduvelil, R. B. Register, M. K Sardana, M. S. Shearman, A. L.Smith, X.-P. Shi, K-C. Yin, J. A Shafer, and S. J. Cardell, Nature, 2000, 405, 689.

[61] C. C. Shelton, L. Zhu, D. Chau, L. Yang, R. Wang, H. Djaballah, H. Zheng, and Y-M. u.Proc. Natl. Acad. Sci. USA, 2009, 106, 20228.

[62] H. Fuwa, Y. Takahashi, Y Konno, N. Watanabe, H. Miyashita, M. Sasaki, H. Natsugari,T. Kan, T. Fukuyama, T. Tomita, and T. Iwatsubo, ACS Chem. BioI., 2007, 2, 408.

[63] G. Zhu and S. J. Lippard, Biochemistry, 2009, 48, 4916.[64] M. Winnaeker, S. Breeger, R. Strasser, and T. Carell, ChemBioChem, 2009, 10, 109.[65] J. c. Kauer, S. Erickson-Viitanen, H. R. Wolfe, and W. F. DeGrado, J. Bioi. Chem., 1986,

261,10695.[66] J. W. Chin, A B. Martin, D. S. King, L. Wang, and P. G. Schultz, Proc. Natl. Acad. Sci.

USA, 2002, 99, 11020.[67) K. Dimova, S. Kalkhof, 1. Pottratz, C. Wing, F. Rodriguez-Castaneda, T. Liepold.

C. Griesinger, N. Brose, A. Sinz, and O. [ahn, Biochemistry, 2009, 48, 5908.[68] J. K Lekostaj, J. K Natarajan, M. F. Paguio, C. Wolf, and P. D. Roepe, Biochemistrv, 2008,

47,10394.[69] C. Pardin, 1. Roy, A. Chiea Roberto, E. Bonnell, P. Thibault, W. D. Lubell, J. N. Pelletier,

and J. w. Keillor, Biochemistry, 2009, 48, 3346.[70] M. Kaneda, S. Masuda, T. Tomohiro, and Y Hatanaka, ChemBioChem, 2007, 8, 595.

NIH Translational Programs forAssisting Pre-Clinical DrugDiscovery and Development

Raj N. Misra

Contents Abbreviations1. Introduction2. NIH Molecular Libraries Probe Production Centers

Network3. NIH-RAID Program

3.1 CaseStudy 1:Safety Pharmacology Studies for anIND for Beta Thalassemia: Susan Perrine, MD.,Professor of Pediatrics, Medicine, Pharmacology,and Experimental Therapeutics, Boston UniversitySchool of Medicine

3.2 CaseStudy 2: Pre-Clinical Development of CDD-0102A for the Treatment of Alzheimer's Disease:William S. Messer, Eh.Q.,~ep-al1meot_ofPharmacology, The University of Toledo

4. National Cancer Institute: NExT Program4.1 CaseStudy: Development of lstodax'" (romidepsin,

NSC 630176,depsipeptide), Fujisawa PharmaceuticalCo.

5. National Cancer Institute: CBC Program5.1 CaseStudy: Phase0 Clinical Trial of ABT-888 in

Patients with Advanced Malignancies, AbbottLaboratories

6. National Institute of Allergy and Infectious Diseases7. National Institute of Diabetes and Digestive and Kidney

Diseases:nD-RAID Program

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369369

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National Institutes of Health, National Cancer Institute, Developmental Therapeutics Program, 6130Executive Blvd., EPN Suite 8032, Bethesda, MD 20892, USA

Annual Reports in Medicinal Chemistry, Volume 45ISSN 0065·7743, DOl 10.1016/S0065-7743(1O)45022-8

© 2010 Elsevier Inc.All rights reserved

361

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362 Raj N. Misra NIH Translational Programs for Assisting Pre-Clinical Drug Discovery and Development

NCINCI60NExTNHGRINHLBINIAIDNIDANIDDK

363

National Cancer InstituteNCI 60 Cancer Cell Line ScreenNCI Experimental TherapeuticsNational Human Genome Research InstituteNational Heart, Lung, and Blood InstituteNational InstituteofAllergyand InfectiousDiseasesNational Institute on Drug AbuseNational Institute of Diabetes and Digestive andKidney Diseases

absorption, distribution, metabolism, elimination NIH National Institutes of Healthactive pharmaceutical ingredient NINDS National Institute of Neurological Disorders andAnticonvulsant Screening Program StrokeAddiction Treatment Discovery Program NME new molecular entityChemical Biology Consortium ORDR Office of Rare Diseases ResearchCenter for Cancer Research PARP poly(ADP-ribose) polymeraseChemistry and Manufacturing Controls PEMC peripheral blood mononuclear cellcentral nervous system PD pharmacodynamicsChemistry and Pharmaceutics Branch PK pharmacokineticsCenter for Scientific Review R&D research and developmentcutaneous T-cell lymphoma RAID Rapid Access to Interventional DevelopmentDivision of Cancer Treatment and Diagnosis RAND Rapid Access to NCI Discovery ServicesDrug Development Group RNA ribonucleic acidDivision of Microbiology and Infectious Diseases SBIR Small Business Innovation ResearchDivision of Pharmacotherapies and Medical STIR Small Business Technology TransferConsequences of Drug Abuse siRNA small inhibitory RNA

DTP Developmental Therapeutics Program shRNA small hairpin RNA------------~F~D~l~~------~Feeehafl~a~iHffi~faHefl SMA Sp~in~a~ILMUilu~s~c~u~la~r_A~tr~o~plib~y~------------------------------

GLP Good Laboratory Practices TlD Type 1 DiabetesGMP Good Manufacturing Practices TID-PTP Type 1 Diabetes Pre-Clinical Testing ProgramHDAC histone deacetylase TK toxicokineticsHTS high-throughput screening TRND Therapeutics for Rare and Neglected DiseasesIDE Investigational Device ExemptionIND Investigational New DrugINDA Investigational New Drug ApplicationIP intellectual propertyMDD Medications Development DivisionMDP Medications Development ProgramMDTP Medications Discovery and ToxicologyBranchmiRNA microRNAMLPCN Molecular Libraries Probe Production Centers

NetworkMolecular Libraries Small Molecule RepositoryNIH Chemical Genomics Center

8. National Institute on Drug Abuse: MedicationsDevelopment Program

9. National Institute of Neurological Disorders and Stroke

10. ORDR TRND Program11. SBIR/STIR Programs

References

373375375376377

ABBREVIATIONS

ADMEAPIASPATDPCBCCCRCMCCNSCPBCSRCTCLDCTDDDGDMIDDPMCDA

MLSMRNCGC

1. INTRODUCTION

The National Institutes of Health (NIH) is the largest government-fundedmedical research institution in the world. Its origins trace back to theLaboratory of Hygiene at the Marine Hospital in Staten Island, NY.Thelaboratory was created by Congress in 1887 to study cholera, yellowfever, and other infectious diseases of returning US. sailors [1,2]. In1891 the Laboratory moved to Washington, D.C, and in 1930 wasexpanded and designated by the Ransdell Act of Congress as theNational Institute of Health. In 1948 the designation was changed to the

plural, National Institutes of Health, as research moved into the addi-tional areas of mental health, dental disease, and heart disease. The NIHhas since grown to 18,000employees spread over 27 semi-autonomousInstitutes and Centers (ICs) that are focused on basic medical researchand organized primarily along specific disease areas. The NIH is locatedon a rangy 300-acre campus in Bethesda, MD, on the outskirts ofWashington, D.C. The vast majority of the current $28billion NIH budgetis invested in supporting medical research at institutions throughout theUnited States through the distribution and administration of competitiveextramural research grants. About 10% of the NIH budget is directedtoward the support of intramural programs carried out by its own 6000scientists. In addition to supporting basic medical research, the NIH alsosupports and had re-emphasized, as part of the NIH Roadmap for ~ed-ical Research (http://nihroadmap.nih.gov), a number of translationalmedicine initiatives, including the pre-clinical development of agents Purpose: The NIH-RAID (Rapid Access to Interventional Development)for the diagnosis and treatment of disease. The goals of these programs program was developed to provide core pre-clinical drug developmentare to resurrect fallow pipelines and stimulate the discovery of new servicesas part of the NIH Roadmap "bench to bedside" translationalmed-agents by providing critical resources that can overcome translational icine initiative. NIH-RAID provides a path forward to clinical trials forroadblocks on the route to clinical evaluation. These programs are often academics, non-profits, and small businesses, and is meant to serve as athe only bridge forward for investigators, especially in the costly late pre- bridge to future funding.Theprogram potentiallyencompassesall therapeu-clinical stages of the development process. tic areas, and is currently administered through the National Institute of

This review is an overview of current and major NIH translational NeurologicalDisorders and Stroke (NINDS)and the National Heart, Lungprograms that support pre-clinical drug discovery and development. and Blood Institute (NHLBI)with scientificoversight of tasks by NationalThis review is not comprehensive in its scope, for example, focused CancerInstitute (NeI) scientists.discovery-related services (e.g., in vitro screening) provided by many Website: http:/ / commonfund.nih.gov / raid/ICs outside of full-development programs are generally not included. Eligibility: Academic and government investigators (U'.S, and for-Additional program information can be found through the NIH website eign), non-profit organizations, SBIR-eligiblesmall businesses

-------thttp;-/-j-wwwonih,gevj-er-inel:ivid·uaHE-websi-tes-;-Suppert-tlTinvestigaters n e IectuaJ-Property: In general, the investigator retains ownershipfrom the cited programs is generally provided as pre-clinical services at and development rights to their invention, consistent with Bayh-Doleno charge, rather than as direct funding grants. SBIR/STTR(Small Busi- provisions [4].The investigator is expected to submit an Investigationalness Innovation Research and Small Business Technology Transfer) pro- New Drug Application (INDA) with the FDA under their own sponsor-grams are available, which can provide direct funding. It is suggested ship. Specific information can be found at the NIH-RAID website.that the referenced websites be reviewed for updated information since Background:The NIH Roadmap for Medical Researchwas launched inprograms evolve in response to changing needs and budgetary September2004,by formerNIH DirectorDr.EliasA. Zerhouni.Theprogramconditions. wasproposed inorder toaddress roadblocksto research,and totransformthe

manner in which publically funded biomedical research is conducted byovercoming specifichurdles or filling defined knowledge gaps. As part oftheRoadmap themeofRe-engineeringthe ClinicalResearchEnterprise,therehas been a re-invigorated effort to bring new medicines from the basicresearch laboratory to the patient. Although the role that NIH should playin drug development has been controversial, there is growing support forthis effort.The NIH-RAIDprogram is one of the key initiativesin this area.NIH-RAIDis a drug development program designed to aid investigatorsinobtaining the data and material necessary to initiate a Phase 1 clinicaltrial.

364 RajN. Misra

2. NIH MOLECULAR LIBRARIES PROBE PRODUCTIONCENTERS NETWORK

Purpose: The Molecular Libraries Roadmap offers public sector biomedi-cal researchers access to the large-scale screening resources through theMolecular Libraries Probe Production Centers Network (MLPCN). TheMLPCN has established a collection of -250,000chemically diverse small

NIH Translational Programs for Assisting Pre-Clinical Drug Discovery and Development 365

molecules in the Molecular Libraries Small Molecule Repository(MLSMR)for use by the MLPCN. The collectioncontainsmoleculeswithknown biologicalactivities,while othershave the potentialto modulate novelbiologicalfunctions.Theresourcescanbe used to identifysmall-moleculeche-micalprobes to study the functionsof genes,cells,and biochemicalpathways.Theseprobesmayalsobesuitableasstartingpointsfordrugdiscoveryprograms.

Website: http://mli.nih.gov/mli/Eligibility:Academic and nonprofit institutionsBackground: For additional information, a detailed review recently

appeared in this series [3].

3. NIH-RAID PROGRAM

The emphasis of the program is to support projects that complement, ratherthan compete with the private sector.Some examples are projects related tohigh-risk and novel targets, orphan diseases,and areas in which the monetaryreturn may not be immediately clear.

Logistics:NII-I-RAIDprojects are operated as a collaborative effort withadministrative responsibilities lying within NINDS, and scientific responsi-bilities with the Institute/Center (IC) staff. Applications to the Nlli-RAIDprogram are accepted three times a year and undergo Center for ScientificReview (CSR)-peerreview and scoring. Selected proposals are discussed ina collaborative meeting with the investigator and Nlli-RAID and IC staffwith the goalofestablishing firm development tasks, milestones, and projectplan. Once these are determined, a funding decision occurs. If funded, themutually agreed development tasks are executed with scientific oversightby NCIand NHLBI staff.Regular updates between Nlli -RAID,IC staff, andthe investigator are scheduled to monitor progress. Oncecomplete, the dataand materials are transferred to the investigator.

Program Capabilities: The Nlli-RAID program is capable of performingall the necessary development tasks to support the submission of anINDA.A summary of the services is below. A complete listing can be found at theNlli-RAID website.

For small molecules, natural products, peptides, oligonucleotides,gene vectors, recombinant proteins and monoclonal antibodies:

• Synthesis and scale-up production of active pharmaceutical ingredient(API)

• Development of analytical methods 3.2 Case Study 2: Pre-Clin' I D .• Development, manufacture, and stability of clinical formulation Treatment of AlzheimlC~ D~velo~m~n~ of CDD-0102A for the• Isolation and purification of natural products Department of Pharm:~ sl Isea;e. Wil~lam.5. Messer, Ph.D.,• Pharmacokinetic/ ADME (absorption, distribution, metabolism, S oogy, he University of Toledo

r elimination) studies including bioanalytical.method development " ummary: Muscarinic agonists have the potential to tr t", .. .._- -' . " cogrutive deficits . d . • ea memory andRange-fmdmg andiND-:alredea fOXlcOttfgy to s ow ass~cIate WIthAlzheimeLs disease,-aRG-the__eter .. _

• Product development planning and advice in IND preparation di or stop the dIsease process. CDD-OI02A a small I flul filialIScovered at The University of 't I d ' mo ec e, was

selec~ivemuscarinic agonist. It dis l~:d 0, an~ .was charact~rized as a!unctional selectivity, in vivo effica~ ~d prorrusmg blOcheIDlcalactivity,Improve memory function in . Yal' was well tolerated at doses thath arum models NIH RAID .t e development of CDD-OI02A b '. - contnbuted to

development of a clinical formulan Y preparation of GMF bulk drug. ormu ation and m f r

ical supplies. These Chemistry and M~uf m:u acture of Phase 1clin-were part of alarO'er full-devel actunng Controls (CMC)tasks. o opment program c . d bhgator and was supported thr h arne out y the inves-

IN oug several fund' haniDA was submitted for CDD-OI02A d mg mee arusms. AnTIle clinical development has b an alloW:d by the FDA in 2009.Mithridion Inc The azent dee~partnered WIth a biotech company

,. o (re- esignated MCD 'clinical trials [7J. as -386) is currently in

366 Raj N, Misra

it~

NIH Translational Programs for Assisting Pre-Clinical Drug Discovery and Development367

treatment of beta thalassemia [5J. As part of a drug development pro-gram, sodium ST20,a short-chain fatty acid, was identified as exhibitingbeneficial actions in thalassemia models. ST20had shown favorable oralPK in baboons and an acceptable safety profile and was selectedfor clinical development by the investigators prior to applying toNII-I-RAID. Good Manufacturing Practices (GMP) synthesis and pre-clinical lND-enabling toxiCOlogystudies in two species had also beenperformed using several funding mechanisms; however, additionalsafety studies were requested in discussions between the investigatorand FDA reviewers before a first-in-human clinical trial would beallowed to proceed. Subsequent to discussions with the FDA, the inves-tigator submitted a proposal and requested Good Laboratory Practices(GLP)central nervous system (CNS)and cardiovascular safety studies, aswell as a genotoxicity study from NIB-RAID. The program successfullycompleted all required safety studies, developed a clinically acceptableformulation, and manufactured early clinical supplies for the project. AnINDA was submitted by the investigator and allowed by the FDA in early2008. The clinical development was subsequently partnered with a bio-tech company, HemaQuest. The agent (re-designated as HQK-IOOl)hasdemonstrated safety and tolerability in healthy volunteers and encoura-ging clinical trials are ongoing in the United States, Thailand, Lebanon,and the United Kingdom [6J.

3.1 Case Study 1:Safety Pharmacology Studies for an IND for BetaThalassemia: Susan Perrine, M.D., Professor of Pediatrics,Medicine, Pharmacology, and Experimental Therapeutics,Boston University School of Medicine

Summary: Thalassemias as a group are the most common genetic dis-eases in the world. Beta thalassemia is an inherited blood disorder inwhich the body produces an abnormal form of hemoglobin. The dis-order results in excessive destruction of red blood cells, which in asevere form manifests as life-shortening anemia shortly after birth.Short-chain fatty acids had previously been shown to be useful in the

368 Raj N. MisraNIH TranslationalProgramsfor AssistingPre-Clinical Drug Discovery and Development 369

4. NATIONAL CANCER INSTITUTE: NEXT PROGRAM

Purpose: The NCI Experimental Therapeutics (NExT)program is designedto assist investigators in "bench to bedside" translation of novel anticancertherapeutic interventions, synthetic, natural product, or biologic, arisingfrom academic, industrial, or government entities. The program providesthe resources for selected discovery tasks, comprehensive pre-clinicalIND-enabling tasks, and biomarker development for Phase 0 clinical stu-dies. The tasks are completed by NCI staff and contractors, rather thanthrough direct investigator grants. The program goal is to provide NCIwith an integrated pre-clinical pipeline of novel anticancer agents.

Website: http://next.cancer.gov /Eligibility: Academic investigators, non-profit organizations, SBIR-

eligible small businessesIntellectual Property: A review of intellectual property, relevant to the

project, is requested as part of the application. The guidelines for owner-ship of intellectual property generated will vary with each project andgenerally depend on the stage of the project.

Background: The NCI has traditionally had a strong pre-clinical drugdevelopment program, dating back over 50 years. These programsinclude Drug Development Network, Rapid Access to NCI DiscoveryServices (RAND), RAID, and Drug Development Group (DDG). TheNexT program is a consolidation of these programs into a single inte-grated pipeline. The purpose of an integrated pipeline is to ensure thatthe available NCI resources are allocated to the most meritorious pro-grams. The pipeline is managed by multiple collaborative governancecommittees using a milestone and stage-gate approach.

Logistics:Applications to the NExT program are submitted electronicallys:/ / proposalcentral.altum.com/ default.asp?GMID:76) and reviewed

by a panel of experts. Application aeaal:ffiesare on a-quarterly cycle-.--Program Capabilities: The NExT program has the capability of perform-

ing both discovery and development tasks including target identification,lead small-molecule optimization, and early toxicology and pharmacoki-netic analysis. The NexT program will also support all the necessarydevelopment tasks for the submission of an INDA for both small moleculesand biological products. A summary of the services is given below.

Discovery: Projects classified as discovery would include, but are notlimited to, the following tasks:

Identification of targets (genes, pathways, molecules, biologics, etc.)Biological function of targets (pathway dissection, miRNA/ siRNA/shRNA studies, model building in vitro and in vivo)Exploratory screen development and high-throughput screening (HTS)optimization

• Novel leads for medicinal chemistry optimization• Exploratory toxicology studies and pharmacokinetic evaluation

Development: Projects classified as development Would include, butare not limited to, the following activities to support INDA submission:• In vivo efficacy studies

• Bulk API synthesis (GMP or non-GMP) including analytical methodsdevelopment

• Formulation development, production, and stability testing of clinicaldosage form• Development of pharmacology assays• Pharmacokinetic (PK) and pharmacodynamic (PD) studies• Range-finding and IND-enabling toxicity studies• Planning of clinical trials• INDA submission consultation

4.1 Case Study: Development of Istodax® (romidepsin, NSC630176,depsipeptide), Fujisawa Pharmaceutical Co.

Summary: ROmidepsin is a novel natural product histone deacetylase(HDAC) inhibitor that was developed in collaboration with FujisawaPharmaceuticals (now Astellas Pharma). Fujisawa originally submittedromidepsin as NSC 630176 in 1990 for NCI60 anti-proliferative activityevaluation [8]. Based partly on its unique, bicyclic peptide structure, andpattern of activity in the NCI60, the DTP within NCI subsequently per-formed animal PK and efficacy evaluation, as well as in vitro and in vivosafety studies under the oversight of the Decision Network cOmmittee, aforerunner to NExT. Importantly, DTP studies defined a specific dosingschedule that ameliorated FJrofound.cardiQtoxicigr,-..normalLy_assQG.iateEl__

.(.. with-thearug, and had derailed earlier development. NCI-sponsoredPhase 1 studies began in 1997and romidepsin for injection was approvedby the FDA in 2009 for treatment of cutaneous T-cell lymphoma (CTCL).Romidepsin is marketed under the brand name Istodax'" by the CelgeneCorporation and clinical trials are continuing for other indications [9].

~i:

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.'-IIII,

s. NATIONAL CANCER INSTITUTE: CBC PROGRAM

Purpose: The NCI Chemical Biology Consortium (CBq is a developingbiotech-like venture designed to assist investigators in the development ofnovel cancer therapeutics. The program goal is to increase the number ofearly-stage drug candidates entering the NCI development pipeline byestabliShing a drug discovery consortium on the scale of a small biotech

company. The focus of the group will be on high-risk, underrepresentedareas, and in significantly advancing the discovery of novel agents againstspecific molecular and genetic cancer targets. The program will provideaccess to cutting-edge tools for iterative drug discovery, optimization, anddevelopment including, when necessary, Phase a clinical trials. Projecttasksare generally to be completed in collaboration with CBCinvestigators, NCI'sDivision of Cancer Treatment and Diagnosis (DCTD),the Center for CancerResearch (CCR) staff, and NCIjDTP staff and contractors, rather thanthrough directed investigator grants. The program differs significantlyfrom other NCI drug development programs in that eligibility for resourcesrequires information sharing by members in a collaborative consortium(as noted under Intellectual Property below).

Website: http:j j dctd.cancer.gov j CurrentResearchj ChemicalBioCon-sortium.htrn

Eligibility: Government, academia, and industryIntellectual Property: All consortium members will be required to sign a

good-faith Intellectual Property Agreement. This agreement details the man-agement structure of the CBC,and provides amechanism for cooperationandinformation sharing among the participants. The agreement outlines confi-dentiality requirements, resource and data sharing, and describes intellectualproperty protections under the existing statutory Bayh-Dole statutory frame-work. NCI will have the option to clinically develop successful compounds(new molecular entities (NMEs))created by the CBC.

Background: The NCI has historically supported a vigorous andsuccessful pre-clinical drug development program for identified drugcandidates. The effort has focused on late-stage development leading tofirst-in-man studies. Within this effort, the NCI has supported, among

, other tasks, animal toxicology and the manufacture of both bulk drug andf) clinica~~osage form. These specific task~ have. traditionally presented a. formlual5le monetary roadlJlb-clno-many-mvestrgators-and NeI's-role-has:----," 6. NA TIUNAT

been to provide a bridge for academic investigators to move their agents I, DISEASES INSTITUTE OF ALLERGY AND INFECTIOUSfrom the lab into clinical trials. Lesser emphasis has been placed on the 'early discovery tasks, such as target identification and validation, leadidentification, and optimization. A major goal of the CBC will be tore-invigorate NCI's early discovery effort, and establish the frameworkfor state-of-the-art iterative drug discovery. Resource allocation for projectswithin the CBCwill be managed as part of the integrated NExT pipeline.

Logistics: Applications to the CBCwill be managed through the NExTprogram application (https:j j dctd.cancer.gov j nextapp j setUp.do), andare to be submitted electronically and will be reviewed by a panel ofexperts. Questions should be directed to individuals listed on the website.

Program Capabilities: The CBC program has the capability of per-forming a full range of standard drug discovery and development tasks,in addition to the more specialized tasks listed below.

370 Raj N. Misra

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NIH Translational Programs for Assisting Pre-Clinical Drug Discovery and Development371

• HTS of compound libraries, including natural productsAccess to a network of highly experienced medicinal chemists

• Molecular and small-animal imagingAnimal modeling of targeted therapies, including pre-clinical PK andPD

• Development and validation of PD assays to confirm drug effect onmolecular target in pre-clinical studies and clinical trials conductedunder an exploratory INDA, or in a traditional Phase IIII setting

5.1 Case Study: Phase 0 Clinical Trial of ABT-888 in Patientswith Advanced Malignancies, Abbott Laboratories

Summary: This example demonstrates the early clinical developmentcapabilities of the CBC program, although the reported study was per-formed outside of the formal confines of the CBC program. The NCI, incollaboration with Abbott Laboratories, conducted the first oncologyclinical trial under the FDA Exploratory IND Guidance with novelPARP inhibitor, ABT-888. ABT-888 was administered as a single oraldose to determine the time course in which it inhibits PARP activity intumor biopsies and peripheral blood mononuclear cells (PBMCs). Thestudy determined that ABT-888inhibited PARPactivity in tumor biopsiesand PBMCs at clinically achievable concentrations. PARP inhibition wasobserved in tumor biopsies and PBMCs at 25- and 50-mg doses. Initialbiochemical data was available within 5 months of initiation, and showedthe value of a Phase a trial in accelerating proof-of-principle studies inearly clinical development. In this case, pivotal data was rapidly obtainedand employed in the design of subsequent Phase 1 trials [10].

Purpose: The Division of Microbiology and Infectious Diseases (DMID)atthe National Institute for Allergy and Infectious Disease (NlAID) supportsdrug discovery and development services for researchers, The purpose is tofacilitate the translation of ideas, generated through basic research, into safeand effectivedrugs, vaccines, and diagnostics to control and prevent infec-tious diseases. Pre-clinical drug development services are focused only ontherapeutics, and must fill a gap in the drug development pathway.

Website: http://wWW3.niaid.nih,gov/LabsAndResources/resources/dmid

Eligibility: Academia, not-for-profit organizations, industry, andgovernment worldwide

372 Raj N. Misra

Intellectual Property: In general the investigator retains ownershipand development rights to their invention, consistent with Bayh-Doleprovisions

Logistics: Applications are written to include the information outlinedon the website (http://www3.niaid.nih.gov/LabsAndResources/resources/ dmid/pretheraagents/preclinapp.htm), and submitted to therelevant Program Officer. The application should include the informationbelow, in addition to, other specific information listed.

A description of the overall product development plan

Background and significance (including why the service requested fitsinto the overall development plan for the product)

• Preliminary data that supports the request to advance the productthrough provision of contract servicesA list of other support from NIAID or other Federal agencies, includingfunded and pending grant applications, and a brief description of whatactivities are covered

• Description of the overall plan for advancing the product beyondcompletion of the services requested

Program Capabilities: The NIAID program has the capability of per-forming all the necessary development tasks to support the submission ofan INDA for small molecules and biological products, including, but notlimited to, the services below:

• Chemical screeningSynthesis of chemical analogues including limited lead optimizationUse in silica systems to predict ADME and toxic properties

• In vitro microbiological characterizationGMP bulk drug synthesis, including stability studiesFormulation development

• IND-ena5ling toxicity stUdIesPharmacokinetic/ toxicokinetic (PK/TK)

• Bioavailability and ADME studiesPre-clinical development planning and evaluation service

7. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVEAND KIDNEY DISEASES: TlD-RAID PROGRAM

Purpose: TlD-RAID is a cooperative program of the NIDDK and NCI thatis designed to facilitate translation to the clinic of novel, scientificallymeritorious, therapeutic interventions for the treatment of Type-I dia-betes. The goal of TlD-RAID is to support the pre-clinical tasks neededfor the clinical "proof of principle" to determine if a new molecule merits

~

NIH Translational Programsfor AssistingPre-ClinicalDrug Discovery and Development 373

expanded clinical evaluation. TlD-RAID helps bridge the resource gapbetween discovery and clinical testing. It is assumed that agents will bestudied clinically under investigator-held INDA within the originating(or a collaborating) institution.

Websites: http:j /www.t1diabetes.nih.gov/TlD_RAIDhttp://WWW2.niddknih.gov/Research/Resources/AlIServices.htmEligibility: Academic institutions, non-profit research institutions, bio-

technology and pharmaceutical companies, U.S. and non-U.S. entitiesIntellectual Property: It is anticipated that submissions will involve a

potential therapeutic that.either already has protected IP or will be in thepublic domain. Specific information can be obtained by contacting TlD-RAID Program officials.

Application Logistics:NIDDK receives requests twice per year (April 1and November 1). Requests consist of a written description of the Request,a technology transfer form, and, if required, a letter ofcommitment. Once aproject has been approved, NIDDK staff interact directly with the investi-gator. NCI contractors perform the TlD-RAID tasks under the direction ofNIDDK and NCI staff. There is also a related program for agents thatrequire additional pre-clinical testing prior to entering TlD-RAID, calledType 1 Diabetes Pre-Clinical TestingProgram (TlD-PTP). Information canbe found at the NIDDK Research Resources website above.

Program Capabilities: The full set of tasks for submission of an INDA.Examples of tasks that can be supported by TlD-RAID include but arenot limited to

• Definition or optimization of dose and schedule for in vivo activity• Development of pharmacology assays• Pharmacology studies with a pre-determined assay• Manufacture of bulk substance (GMP and non-GMP) and stabilitystudies

• Development, production, and stability of dosage forms• Range-finding initial toxicology• IND-directed toxicology, with correlative pharmacology and

histopathology• Planning of clinical trials• INDA filing advice

8. NATIONAL INSTITUTE ON DRUG ABUSE: MEDICATIONSDEVELOPMENT PROGRAM

Purpose: The Division of Pharmacotherapies and Medical Consequencesof Drug Abuse (DPMCDA) includes a Medications Development Pro-gram (MDP). The Medications Discovery and Toxicology Branch

Purpose: The mission of the National Institute of Neurological Disordersand Stroke (NINDS) Office of Translational Research is to facilitate thepre-clinical discovery and development of new therapeutic interventionsfor neurological disorders. The Officesupports pre-clinical projects fromthe discovery of candidate therapeutics through IND and InvestigationalDevice Exemption (IDE) applications to the FDA. This is accomplishedthrough both access to NINDS contract resources and direct fundingmechanisms.

Website: http://www.ninds.nih.gov / funding/ areas/ technology_development!

Programs: The Anticonvulsant Screening Program (ASP) and theSpinal Muscular Atrophy (SMA) Project are examples of NINDS pro-grams with goals of developing therapeutic agents. The ASP providesboth in vitro and in vivo screening services to investigators, while the SMAProject is a full discovery and development program that Can lead toINDA submission.

I' ~ogistics:-A€€ess to-services-arrd-fund"ingare program specific. Addi-tional information can be found at the NINDS website above, and bycontacting the appropriate program director.

Program Capabilities: Services are program specific.Additional infor-mation can be found at the NINDS website above and by contacting theappropriate Program Director.

374 Raj N Misra

(MDTB), the Chemistry and Pharmaceutics Branch (CPB) within theMedication Program support a pre-clinical translational therapeutics pro-gram. Their mission is to develop medications for the treatment of drugabuse, and to facilitate the. translation of basic research findings intopharmacotherapies. The program supports a full range of drug develop-ment activities from chemistry to INDA submission. The MDTB/CPBalso includes the pre-clinical Addiction Treatment Discovery Program(ATDP).The goal of the ATDP is to identify agents to treat drug depen-dence disorders. The ATDP supports both in vitro and animal efficacyevaluation as well as predicative safety testing at no charge. Tasks areaccomplished primarily through contract resources within DPMC, aswell as grants aimed at developing and evaluating potential new phar-macotherapies to treat drug dependence.

Website:http://www.drugabuse.gov / about/ organization/DPMCDA/Eligibility: Academics, government, non-profits, small and large

businessesIntellectual Property: In general, the investigator retains ownership

and development rights to their invention consistent with Bayh-Doleprovisions

Background: In 1989, the U.S. Congress mandated that an MDP beestablished within NIDA. In 1990, NIDA created the Medications Devel-opment Division (MDD) (now the DPMCDA) to operationalize the goalsof the MDP.

Program Capabilities: In addition to the in vitro and in vivo evaluationsfor potential efficacy performed by the ATDp, the MDP includes thefollowing capabilities to support the full range of drug development:

• In vitro receptor activity profiling• Efficacy evaluation in animal models

_____ ..••_Ln..s.ilic.o_and in vitro 12redictivetoxicolog):': _• In vitro estimates of risk for Q-T prolongation and in vivo assessments

of hemodynamic interactions with cocaine and methamphetamine• Medicinal chemistry for the design and synthesis ofnew molecules and

structural classes• Bulk API synthesis (GMP and non-GMP) and clinical dosage forms

development and manufacture• Development of new dosage forms to improve their therapeutic

effectiveness and/ or to minimize the abuse potential of potentialtreatment medications

• Pharmacokinetics (PK) and pharmacodynamics (PD) studies• Bioanalytical resources (including bioanalytical methods to support PK

studies), biomarker studies• Range-finding and IND-enabling toxicology• INDA preparation and filing advice

.,..

NIH Translational Programs for Assisting Pre-Clinical Drug Discovery and Development375

Logistics:These resources are limited, and are used only for approvedprojects of high programmatic priority. They are also used to assistindividuals and organizations who are developing projects based onmolecular targets of interest to the program. Additional information onthe Medication Development Program, its capabilities, and contact infor-mation to determine access to reSOurces can be found at the MDTPwebsite.

9. NATIONAL INSTITUTE OF NEUROLOGICALDISORDERS AND STROKE

10. ORDR TRND PROGRAM

Purpose: The Therapeutics for Rare and Neglected Diseases (TRND)program was established in 2009 to encourage and accelerate the pre-clinical development of therapeutics directed at rare and neglected dis-eases. These are diseases that are classified as effecting fewer than 20,000people in the United States at a given time, and are also known as orphan

376 Raj N. Misra

diseases. The program will support drug discovery and developmentactivities directed at submission of an INDA with the FDA. Governanceand oversight of the program will be handled through the Office of RareDiseases Research (ORDR) within the Office of the Director. Programoperations will be within the intramural research program adjacent tothe NIH Chemical Genomics Center (NCGq and will be administered bythe NHGRI. The program is in the formative stages and updates will beavailable through the ORDRwebsite.

Websites: https.z' /www.rarediseases.info.nih.gov (see "Research andClinical Trials")

http://rarediseases.info.nih.gov /Resources.aspx?PageID=32Program Capabilities:

• Optimization of lead candidates• Animal efficacy studies• IND-enabling toxicology studies• Re-positioning of FDA-approved drugs for use in rare and neglected

diseases

11. SBIR/STTR PROGRAMS

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NIH Translational Programs for Assisting Pre-Clinical Drug Discovery and Development377

REFERENCES

[1] See NlH Website: http://history.nih.gov/exhibits/historY/index.html.[2] V. A. Harden in Inoeniino the NIH: federal biomedical research policv, 1887-1937, Johns

Hopkins University Press, Baltimore, MD, c1986.[3] D. M. Huryn and N. D. P. Cosford, Annu. Rep. Med. Chem., 42 (ed, J. E. Macer), Elsevier

Press, London, 2007, p. 401.[4] L. Nelsen, Science, 1998, 279 (5356), 1460.[5] E. Liakopoulou, C. A. Blau, Q. u. B. Josephson, J. A. Wolf, B. Founrnarakis, V. Raisys,

G. Dover, T. Papayannopoulou, and G. Stamatoyannopoulos, Blood, 1995, 8, 3227.[6a] S. Perrine, M. S. Boosalis, L. Shen, G. White, A. Thomson, H. Cao, R. Fei, R. Berenson,

and D. V. Faller, Blood (ASH Annual Meeting Abstract), 2009, IH, Abstract 4754.[6b] S. Perrine, W. C. Welch, J. Keefer, R. L. Downey, M. S. Boosalis, S. Case, D. V. Faller,

and R. Berenson, Blood, 2008, 112, Abstract 130.[6c] R. Bohacek, M. S. Boosalis, C. McMartin, D. V. Faller, and S. Perrine, Chern, Bioi. Drug

Des., 2006, 67, 318.[7a] W. S. Messer, Curro Top. Med. Chem., 2002, 2, 353.[7b] W. S. Messer, W. G. Rajeswaran, Y. Cao, H. J. Zhang, A. A. El-Assadi, C. Dockery,

J. Liske, J. O'Brien, F. E. Williams, X. P. Huang, M. E. Wroblewski, P. 1. Nagy, andS. M. Peseckis, Pharm, Acta. Helo., 2000, 74, 135.

[8] R. H. Shoemaker, Nat. Rev. Cancer, 2005, 6, 813.[9a] H. Veda, H. Nakajima, Y. Hori, T. Fujita, M. Nishimura, T. Coto, and M. Okuhara,

]. Antibiot. (Tokyo), 1994, 47, 301.[9b] W. Zhou and W. G. Zhu, Curro Cancer Drug Targets, 2009, 9, 91.

[lOa] S. Kummar, R. Kinders, M. E. Gutierrez, L.Rubinstein, R. E. Parchment, L. R. Phillips,J. j. A. Monks, J. A. Low, A. Chen, A. J. Murgo, J. Collins, S. M. Steinberg,H. Eliopoulos, V. L. Giranda, G. Gordon, L. Helman, R. Wiltout, J. E. Tomaszewski,and J. H. Doroshow, J. cu« Oncoi., 2009, 27, 2705.

[lOb] R. Kinders, R. E. Parchment, J. Ji, S. Kurnmar, A. J. Murgo, M. Gutierrez, J. Collins,L. Rubinstein, O. Pickeral, S. M. Steinberg, S. Yang, M. Hollingshead, A. Chen, L.Helman, R. Wiltrout, M. Simpson, J. E. Tomaszewski, and J. H. Doroshow, Mol. lniern,2007, 7, 325.

Purpose: The objectives of the SBIR/STTR programs are for small busi-nesses to stimulate technological innovation, strengthen the role of smallbusiness in meeting Federal R&Dneeds, increase private sector commer-cialization of innovations developed through Federal SBIRR&D,increasesmall business participation in Federal R&D,and encourage participationby socially and economically disadvantaged small businesses, andwomen-owned business. Grants to assist biomedical research by small

------Glusinesses,-inGluding-dr..u.g-del/:elopment,-hal/:e-a-monetar-y-ceiling-and---_Ilf-.·' --------------------------------------time limit with initial feasibility Phase I awards limited to $100,000over6-12 months and subsequent Phase II awards limited to $750,000over 24months.

Website:http://grants.nih.gov/grants/funding/sbirsttcprograms.htmEligibility:U.S. for profit businesses of 500 or less employeesLogistics: Grant applications are accepted on AprilS, August 5, and

December 5, annually. Areas of interest are described in the fundingopportunity announcements and solicitations available at the NIHSmall Business Funding Opportunities website.

Disclaimer: The views expressed here are those of the author and donot represent the views of, nor are they an endorsement by, the U.S.Government or the National Institutes of Health.