NIH Translational Research for Rare Diseases and Orphan Products: NCGC and TRND

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1 NIH Translational Research for Rare Diseases and Orphan Products: NCGC and TRND Christopher P. Austin, M.D. Director, NIH Chemical Genomics Center Senior Advisor to the NHGRI Director for Translational Research National Institutes of Health IOM Commmittee on Accelerating Rare Diseases Research and Orphan Product Development February 4, 2010

2 The Problem Basic Research Drugs The Opportunity Drugs Basic Research

3 The best of times, the worst of times How to translate the genome into biological insights and therapeutics?

4 The Problem of Rare and Neglected Diseases ~7,000 diseases affect humankind Only a very small fraction of diseases support commercial development of therapeutic agents Two types of neglected diseases: Low prevalence, i.e., rare Prevalence <200,000 in USA There are >6000 rare (orphan) diseases Cumulative prevalence in U.S. ~ million Most are single gene diseases; e.g., cystic fibrosis, Huntington disease, sickle cell disease, Tay-Sachs Approximately 200 have any pharmacotherapy available from the 340 products approved by FDA High prevalence but neglected Occur chiefly among impoverished and marginalized populations in developing nations who are unable to afford treatments Most are infectious diseases, e.g., malaria, schistosomiasis, leishmaniasis, trypanosomiasis

5 Only a small % of diseases and genome-encoded targets are being addressed for drug development Current drug targets: Well understood proteins Current diseases: Prevalent diseases that affect developed world Neglected Neglected Human Genome Human Diseases

6 Conventional roles of NIH and biopharma in drug development NIH- Funded Basic Science Pharma and Biotech FDA Dedicated Chem-Biol Project Team formed Compound accepted into Clinical Development Indefinite 1 yr 1 yr 1 yr ~ 3 yrs 1 yr 2 yrs ~3 yrs 1.5 yrs Indefinite Screening (HTS or otherwise) Target identification Assay development Hit-to- Probe Lead Development, Optimization Ph I Ph II Clinical Trials Ph III Regulatory review Ph IV-V (Additional indications, Safety monitoring)

7 To empower the research community to use small molecule compounds in their research, whether as tools to perturb genes and pathways, or as starting points to the development of new therapeutics for human disease.

8 The Molecular Libraries Roadmap Compounds Repository Diversity expansion Assays Development Screening solicitation Instrumentation Development Data and Chemical Probe Generation Screening/Informatics Chemistry/Pharmacology Comprehensive Centers Specialized Centers Specialized Centers Data Probes Data Dissemination/Analysis PubChem MLPCN Centers

10 The Molecular Libraries Probe Production Network (MLPCN) Comprehensive Centers Specialized Screening Centers Specialized Chemistry Centers University of Kansas Specialized Chemistry Center Broad Institute Comprehensive Screening Center The Johns Hopkins Ion Channel Center NIH Chemical Genomics Center (NCGC) San Diego Center for Chemical Genomics (Burnham Institute) The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development New Mexico Molecular Discovery Center Scripps Research Institute Molecular Screening Center Southern Research Specialized Biocontainment Center

NIH Chemical Genomics Center Founded as part of Roadmap 75 scientists > 100 collaborations with investigators worldwide 75% NIH extramural 15% Foundations, Research Consortia,

11 NIH Chemical Genomics Center Founded as part of Roadmap 75 scientists > 100 collaborations with investigators worldwide 75% NIH extramural 15% Foundations, Research Consortia, Pharma/Biotech 10% NIH intramural Focus on novel targets, rare/neglected diseases Produces chemical probes/leads new paradigms for assay development, screening, informatics, chemistry

12 NCGC Staff Informatics, 7 Scientific and Admin Management, 6 Lab Operations, 2 Automation and Cmd Mgt, 6 Chemistry, 15 Assay Development and Biology, 18

13 NCGC Operation Assay Investigator Peer review Advice Optimize Assay Compound Repository YES NO Meets probe criteria? Candidate Probe NCGC Chemical Genomics Browser Optimization Chemistry Bioassay Screen Data

14 LTS MTS HTS 10 s/day 1000 s/day 10,000 s/day 100,000 s/day Throughput Molecular mechanism Immediate organismal relevance

15 NCGC Screening Collections MLSMR DC = Diversity Compounds NC = Non-commercial TL-KIN = Kinase Targeted Library TL-GPCR = GPCR Targeted Library TL-IC = Ion Channel Targeted Library TL-PRO = Protease Targeted Library TL-NUC = Nuclear Receptor Targeted TL-NTP = National Toxicology Program SS = Known Bioactives NP = Natural Products DEA = DEA Controlled Substances

16 NCGC Screening System 1: BSL1/Kalypsys Capacity: 3.0MM Assay Wells 5.0MM Compound Wells Throughput: Readers: New Capabilities: 1400 plates/day ViewLux (2) Acumen (2) Envision (2) Automatic Loading and Unloading stations using commercially available plate stackers Dispense Inspection Systems using integrated CCD cameras

NCGC Screening System 2: BSL2/HRE Capacity: Throughput: Readers: New Capabilities: 370K Assay Wells 370K Compound Wells ~240 plates/day ViewLux Acumen Hamamatsu Modular approach to HTS Three docking

17 NCGC Screening System 2: BSL2/HRE Capacity: Throughput: Readers: New Capabilities: 370K Assay Wells 370K Compound Wells ~240 plates/day ViewLux Acumen Hamamatsu Modular approach to HTS Three docking stations to quickly facilitate changing of both compound and assay plate storage Flexible scheduling software to allow for complex assay methods BSL2 rated to further diversify the assays capable of being run by NCGC

18 NCGC Screening System 3: BSL3/Beckman

19 Disease areas of NCGC assays Metabolic Diseases 5% Genetic Diseases 5% Other 5% Toxicology 7% Basic Research 36% Neuroscience 8% Infectious Diseases 11% Cancer 23%

20 Trans-NIH nature of Molecular Libraries Roadmap brings about synergies Tdp1 NCGC has projects on many aspects of DNA repair from different areas of science Yossi Shiloh, Tel Aviv University ATM (Neurology, cancer) Yves Pommier, NCI Tdp1 (Cancer) David Wilson, NIA Ape1 (Aging) Roger Woodgate, NICHD DNA Pol ε, ι (Development) Sam Wilson, NIEHS DNA Pol β (Environmental toxicology) Shunichi Takeda, Kyoto University XRCC1 (Aging, toxicology) Structural Genomics Consortium RecQ1 helicase (Basic research) Bloom helicase (Cancer)

21 NCGC Chemical Genomics Browser

22 Rare/neglected disease projects at NCGC Ataxia-telangiectasia Beta-thalassemia Charcot-Marie-Tooth Chordoma Chronic lymphocytic leukemia Gaucher disease Huntington s disease Leishmaniasis Lymphangioleiomyomatosis Malaria Myotonic dystrophy Niemann-Pick C Progeria Schistosomiasis Spinal muscular atrophy Trypanosomiasis

23 NCGC Drug Repurposing Program Approved drugs have safety/efficacy in at least one other disease Repurposing leapfrogs most stages of drug development, thereby offering potentially rapid therapeutic advance Pharmacology of drugs identified may confer insights into disease pathophysiology NCGC has assembled comprehensive approved drugs collection Working with large number of disease foundations to leverage this collection for rare diseases Cuts out medchem optimization but many issues remain Dose and administration different (e.g., acute v. chronic)? Formulation different? BBB penetration? Tox studies appropriate? Clinical population similar? If not, studies needed

24 Two approaches to therapeutics for rare and neglected diseases 1-2 years? >400,000 compounds, 10 yrs Target Screen Hit Lead Lead Optimization Preclinical Development Clinical Trials FDA approval 3000 drugs

25 NCGC Pharmaceutical Collection Status May 2009 Drug Source In house Need to procure Total US FDA UK/EU/Canada/Japan INN Total Approved Total Informatics sources for NPC US FDA: Orange Book, OTC, NDC, Green Book, Drugs at FDA Britain NHS EMEA Health Canada Japan NHI Physical sources for NPC Procurement from >20 suppliers worldwide In-house purification of APIs from marketed forms Synthesis

26 NPC Niemann-Pick Disease Type C Collaboration with Denny Porter (NICHD/NIH), Bill Pavan (NHGRI/NIH), Dan Ory (Wash U) Autosomal recessive disease Prevalence: 1:150,000 Clinical manifestations: progressive neurodegeneration, hepatosplenomegaly, death by teens Characterized by a lysosomal accumulation of unesterified cholesterol and other lipids. Mutated genes: NPC1 (95%) and NPC2 (5%) Purpose of project: utilize patient cells and approved drug collection to repurpose an existing drug for NPC

27 Filipin(Blue) Cell Mask (Red) NPC Corrector identified from screening of NCGC Pharmaceutical Collection Reduction in Free Cholesterol Accumulation and Lysosome Size 50 um 25 um 12.5 um 6.25 um DMSO Lysotracker (Red) Hoescht(Blue) Reduction in Cholesterol Accumulation (cholesterol oxidase assay) Normalized ATP Level GM [Compound], mm DMSO Normalized Cholesterol Level Normalized ATP Level NPC [Compound], mm 3.9 DMSO Normalized Cholesterol Level Normalized ATP Level WT (5659) [Compound], mm DMSO Normalized Cholesterol Level ATP (2 d) ATP (4 d) ATP (6 d) Cholesterol (2 d) Cholesterol (4 d) Cholesterol (6 d)

Ameliorating the Defect in Gaucher s Disease NCGC Collaboration with Ellen Sidransky, NHGRI Gaucher s Disease Rare disease caused by mutations in enzyme glucocerebrosidase (GCS) u glucosylceramide

28 Ameliorating the Defect in Gaucher s Disease NCGC Collaboration with Ellen Sidransky, NHGRI Gaucher s Disease Rare disease caused by mutations in enzyme glucocerebrosidase (GCS) u glucosylceramide Current treatment: enzyme replacement Limited efficacy, no BBB penetration, expensive Many mutations are missense, leading to trafficking defect Pharmacological chaperones a therapeutic possibility Fluorogenic substrate assay: v Resorufin β-d-glucopyranoside Cerebrosidase + Resorufin Ex 570 nm / Em 590 nm Glucose

30 Developing drugs for Schistosomiasis Livers of treated mice Ex vivo worm killing

31 Inhibitors of Schistosoma mansoni TGR NCGC Collaboration with David Williams Department of Immunology and Microbiology Rush University Medical Center Chicago, IL

32 Discovery of Pathway: 2002 Identification of Target: 2006

Quantitative HTS: 2007 70,000 compounds at 7

all compounds (PNAS 103, 11473-8 (2006))

31 hours of robot time Results: 100 compounds

33 Quantitative HTS: ,000 compounds at 7 concentrations (qhts) Dose-response curve for all compounds (PNAS 103, (2006)) ~10,000,000 data points (16 Time-Point Reads) 31 hours of robot time Results: 100 compounds with IC50 < 40 µm 71 compounds 6 different structural classes

34 Series Expansion & Target ID PhosphinicAmide S O P N HN R1 O P HN R1 Oxadiazole2-oxide R 1 R 2 N O - N O Isoxazolone O N Br O R 1 Analogue# R 1 qhts R N O O O EtO F O MeO O O O S S N N -CN O O Cl N N S OEt O O OMe O O O NA NA NA NA O -Ph NA NA NA O N N S O Confirmation TGR Assay NS NS >57 >57 >50 NS ND ND > NS NS All retested compounds were found to be inactive against Prx2, leaving TGR as the sole target for all confirmed actives. Singleton hits 3, 10 and 14 were confirmed and successfully expanded to small series. The top active compounds were highly potent, with IC 50 s approaching the limit of detection. Phosphoramidite O HN NH P O O R chlorophenyl NA 14 naphthyl NA 15 phenyl NA 16 4-ethoxyphenyl NA NS NS NS Simeonov et al, PLoS Negl. Trop. Dis., 2, e107 (2008).

35 Chemical probes: 2008

36 In vivo validation of mechanism: 2008 Livers of treated mice Ex vivo killing of S. mansoni worms by NCGC1597 S. mansoni-infected mice treated with 10 mg/kg IP for 5 days

37 Probes are just the start of drug development Cumulative Cost Probability of success Public Sector Science Pre-MLI Dedicated Chem-Biol Project Team formed Compound accepted into Clinical Development Indefinite 1 yr 1 yr 1 yr ~ 3 yrs 1 yr 2 yrs ~3 yrs 1.5 yrs Indefinite Screening (HTS or otherwise) Target identification Assay development Hit-to- Probe Lead Development, Optimization Ph I Ph II Clinical Trials Ph III Regulatory review Ph IV-V (Additional indications, Safety monitoring)

38 Probes are just the start of drug development Cumulative Cost Probability of success Public Sector Science with MLI Dedicated Chem-Biol Project Team formed Compound accepted into Clinical Development Indefinite 1 yr 1 yr 1 yr ~ 3 yrs 1 yr 2 yrs ~3 yrs 1.5 yrs Indefinite Screening (HTS or otherwise) Target identification Assay development Hit-to- Probe Lead Development, Optimization Ph I (Safety) Ph II (Dose finding, initial efficacy in patient pop.) Ph III (Efficacy and safety in large populations) Regulatory review Ph IV-V (Additional indications, Safety monitoring)

TRND program will bring compounds to point of clinical

Libraries Initiative TRND (RAID) Biotech, Pharma NIH

yrs 2 yrs 1 yr 2 yrs ~3 yrs 1 yr Indefinite Target

Lead Candidate PK/PD In vivo Tox Formulation GMP

39 TRND program will bring compounds to point of clinical testing/commercial adoption Basic Research NCGC, Molecular Libraries Initiative TRND (RAID) Biotech, Pharma NIH Clinical Center CTSAs FDA IND Indefinite 1 yr 1 yr 1 yr 2 yrs 2 yrs 1 yr 2 yrs ~3 yrs 1 yr Indefinite Target identification Assay HTS development Hit-to- Probe Probe Lead Candidate PK/PD In vivo Tox Formulation GMP Manufacture Ph I (Safety) Ph II (Dose finding, initial efficacy in patient pop.) Ph III (Efficacy and safety in large populations) Regulatory review Ph IV-V (Additional indications, Safety monitoring)

41 Analogous to NCGC TRND Operational Model In-house laboratories with expertise in preclinical drug development will collaborate with external laboratories with expertise in disease/target Projects will be taken to phase needed for external organization to adopt for clinical development Projects will enter TRND at a variety of stages of development Distinguishing features Disease agnostic, will look explicitly for cross-cutting mechanisms Processes will be established to incorporate learning from each project to operationalize continuous improvement Science of preclinical drug development Reasons for successes and failures will be investigated and published

42 Administered by NHGRI TRND Science Starting point: Chemical probe End point: Clinical candidate compound attractive for adoption by biotech/pharma Project-specific activities Medicinal chemistry in vitro efficacy, pharmacology, ADME, toxicology in vivo drug metabolism, pharmacokinetics/pharmacodynamics, toxicology Compound scale-up Technology/paradigm development At least 20% of effort to improving success rates

43 TRND Operations Initial plan, assuming $24 M per year, is to work on approximately five projects per year The average project should take approximately two years Projects will be monitored closely for progress; those making insufficient headway will be culled quickly, to allow next project in pipeline to start as soon as possible Anticipated timeline FY09: infrastructure FY10: governance, hiring, research community outreach, 2-3 pilot projects to establish operational processes FY11: solicitation of projects for adoption, 4-5 projects ongoing FY12: fully operational

44 TRND Governance (working) Centered at Office Of Rare Diseases Research Takes advantage of ORDR s inherently pan-ic nature and long-standing relationships with rare disease community Active involvement and representation of ICs and community Trans-NIH Staff Advisory Group Advise on operation Help integrate TRND with related NIH efforts Expert External Panel From academia, industry, and patient advocacy communities Helps select projects Assesses progress in an ongoing manner Performs formal periodic assessments and recommendations regarding TRND

45 TRND: Project Selection (working) Projects will be solicited from extramural and intramural researchers, foundations, and biotechs/pharmas Will look for targets, pathways, mechanisms that could apply to >1 disease (e.g., lysosomal storage diseases, diseases of DNA repair) First-level review will be performed by the External Expert Panel Second-level review will be performed by the Trans-NIH Advisory Group Stay tuned

46 TRND is interacting with many different groups in planning activities US Government NIH Institutes and centers Intramural including CC Extramural» funded researchers» programs including CTSA, CTEP, RAID, NBS research network Office of Tech Transfer Office of General Counsel FDA including CDER and OOPD Centers for Disease Control and Prevention Office of Science and Technology Policy Non-US government Biotech and pharma companies VC organizations Rare disease foundations Neglected disease organizations Advocacy groups

47 Questions?

Drug Discovery and Development at NIH for Rare and Neglected Diseases September 29, 2009

Drug Discovery and Development at NIH for Rare and Neglected Diseases September 29, 2009 Melissa Ashlock, Christopher P. Austin, Steve Groft Genetic Alliance Posted in the Resource Repository at: http://www.resourcerepository.org/documents/1692/drugdiscoveryanddevelopmentat