NIH Introduction to the Principles and Practice of Clinical Research February 28, 2012

Transcription

1 The Impact of Genomics on Clinical Research and Drug Development Christopher P. Austin. M.D. Scientific Director, NIH Center for Translational Therapeutics Director, Division of Preclinical Innovation National Center for Advancing Translational Sciences National Institutes of Health NIH Introduction to the Principles and Practice of Clinical Research February 28, 2012

2 Stages in Deciphering the Genome Graphics: from showing the progression of the Genome

3 Types of human genetic variation Graphic: shows human genetic variation Frazier et al., Nat Rev Genet 10:241, 2009

4 Haplotypes and Tag SNPs Graphic Manolio et al., J Clin Invest. 118:1590, 2008

5 Genome-Wide Association Studies (GWAS) Method for interrogating all 10 million variable points across the human genome Variation inherited in haplotype blocks of linkage disequilibrium, so only tag SNPs need to be assayed Haplotype blocks are smaller in unrelated individuals Technology allows routine testing of 300, ,000 tag SNPs across the genomes of unrelated persons (assumes ~10 kb blocks)

6 Graphic: Nature magazine articles

7 Graphic: Published Genome-Wide Associations through 08/2011, 1449 published GWA at p<5x10 for 237 traits nd quarter NHGRI GWA Catalog

8 Graphic

9 Screen Shot: National Genome Research Institute website

10 Article: How to interpret a Genome-wide Association Study

11 Screenshot: NCBI website

12 Bar Graph Solid line: Moore s Law Dotted line: Cost per Mb

13 Nature Magazine Article A map of human genome variation from population-scale sequencing

14 Genome Sequencing as a Commodity Screenshot: Complete Genomics

15 NEJM (2010) Screen shot: Ten Years On The Human Genome and Medicine Harold Varmus, M.D.

16 Screenshot:

17 Genomic Architecture of Genetic Diseases Graphic one: Rare, Simple, Monogenic, Mendelian Mostly Coding Mutations Graphic two: Common, Complex, Multigenic, Non-Medelian Mostly Non-Coding Mutations

18 Screenshot: Whole-Genome Sequencing in a Patient with Charcot-Marie -Tooth Neuropathy NEJM (2010)

19 Article: NTSE Mutations and Arterial Calcifications

20 Screenshot: Naturenews website

21 Pharmacogenomics Use of genetic differences among individual patients to Improve specificity of diagnosis Improve likelihood of response to a drug Customize drug dose Decrease likelihood of adverse reaction to a drug

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23 Screenshot: Using Genetic Diagnosis to Determine Individual Therapeutic Utility C. Thomas Caskey

24 Screenshot: PharmGKB website

25 The Genetic Information Nondiscrimination Act of 2008 (GINA) A federal law that prohibits health insurers and employers from discriminating based on an individual s genetic information Intended to allow Americans to take advantage of genetic testing without fear of losing their health insurance or their jobs GINA prohibits health insurers from Requesting or requiring genetic information from an individual or their family members Using genetic information for decisions regarding coverage, rates, or preexisting conditions

26 The Genetic Information Nondiscrimination Act of 2008 (GINA) GINA prohibits employers from Using genetic information in decisions regarding hiring, firing, promotion or any other terms of employment (e.g., benefits) Retaliating against employees who file a complaint under GINA GINA does not Affect underwriting regarding manifest disease someone who is already sick is not protected by GINA Restrict discriminatory use of genetic information in regard to life, long-term care, or disability insurance Extend to members of the military

27 Developing Drugs from the Genome Numbers Human genes ~20,000 Human proteins (targets) ~500,000 Current drugs target ~500 proteins Gene identification only start to determining function and any therapeutic potential Validation Definition of sequence function, role in disease Demonstration of manipulability of gene product Transforms gene product into drug target

28 Genomics is changing how drugs are developed in the clinic Genetically defined subpopulations for clinical trials greater power with reduced n Smaller patient populations eligible for treatment upon drug approval Better efficacy data improves chance of formulary acceptance Financial success of drugs for genetically defined populations suggests more targeted drugs will be entering trials Herceptin for Her2+ breast cancer Gleevec for CML Crizotinib for anaplastic lymphoma kinase (ALK)- positive NSCLC Ivacaftor (VX-770, Kalydeco) for G551D cystic fibrosis All diseases may eventually be rare

29 Screenshot: the NEW ENGLAND JOURNAL of MEDICINE A CFTR Potentiator in Patients with Systic Fibrosis and G551D Mutation

30 Screenshot: The Wall Street Journal FDA Approves Cystic Fibrosis Drug Vertex s $294,000 Treatment Works for Patients with a Specific Gene Mutation Jonathan D. Rockoff and Jennifer Corbett Dooren

31 The best of times, the worst of times How to translate the genome into biological insights and therapeutics? Cover of Nature magazine and a bar graph.

32 The Problem of Rare and Neglected Diseases\ ~7,000 diseases affect humankind but only a small fraction support commercial development of therapeutic agents Two types of neglected diseases Low prevalence, i.e., rare (<200,000 prevalence in U.S.) There are >6000 rare (orphan) diseases Cumulative prevalence in U.S. ~ million Most are single gene diseases Molecular basis of >4000 known <250 have any pharmacotherapy available High prevalence but neglected Occur chiefly among impoverished and marginalized populations in developing nations (treatment costs prohibitive) Most are infectious

33 Rare Disorders with Identified Molecular Basis Graph: Source: Online Mendelian Inheritance in Man

34 Steps in the drug development process Graphic shows the steps involved in drug development.

35 Graphic shows: Two approaches to therapeutics for rare and neglected diseases.

36 Article: Enabling Comprehensive Drug Repurposing The NCGC Pharmaceutical Collection: A Comprehensive Resource of Clinically Approved Drugs Enabling Repurposing and Chemical Genomics 27 April 2011 Vol 3 Issue 80 80ps16

37 Graphic: NCGC Pharmaceutical Collection Status April 2011

38 Screenshot: THE NCGC Pharmaceutical Collection

39 Repurposing Case Study Niemann-Pick Type C (NPC) Disease Autosomal recessive neurodegenerative disorder characterized by neurovisceral lipid storage Incidence: 1/120,000 Do FDA-approved thereapy TRND project: repurposing an approved drug that can clear cholesterol from NPC patient cells

40 Article: Gene responsile for NPC discovered in 1997 at NIH Science Vol 277 July

41 Graphic: Characterization of NPC Patient Cells Denny Porter (NICHD/CC), Wei Zheng (TRND/NCATS)

42 Repurposing Case Study Niemann-Pick Type C (NPC) Disease Drug: Cyclodextrin Collaborators NIH (Bill Pavan, NHGRI - Genetics, Denny Porter, NICHD - Clinical) Washington University (Dan Ory - Biochemistry) Albert Einstein and UPenn (Steve Walkley and Charles Vite - Animal models) Johnson &Johnson Pharmaceuticals NPC disease foundations involved and facilitating TRND project milestones Proof-of-concept in animals Biomarker development Bio-analytical method development Pharmacokinetics/ pharmacodynamics, toxicology studies IND filing Proof-of-concept clinical trial

43 NIH Therapeutics for Rare and Neglected Diseases (TRND) Program Collaborative program to speed development of new drugs for rare and neglected diseases Collaboration between NIH-intramural and extramural/company/foundation labs with appropriate expertise Each project both a clinical candidate and a technology/paradigm development program Projects Enter TRND at a variety of stages of development (lead to IND-enabling) Are advanced to stage needed for external organization to adopt Complement, not duplicate, pharma projects Serve to develop new generally applicable platform technologies, paradigms, including creative partnerships and novel approaches to intellectual property

44 TRND Program Accomplishments since September 2009 Built inaugural portfolio of 15 projects through 2 rounds of public solicitations Portfolio a mix of small molecules and biologics 2 innovative platform technologies Taken two investigational drugs into humans CLL: IND filed with US FDA July 12 th, approved August 5 th, 2011 Phase I trial commenced Sept 2011 SCD: IND filed Oct 14 th, approved Nov 8 th 2011 Phase I trial commenced Dec 2011 Initiated its first natural history study HIBM natural history study at the Clinical Center: 1 st patient enrolled in Sept 2011 Recruited top talent to NIH from public and private sectors

45 TRND Pilot Project on Sickle Cell Disease Collaborator: AesRX, Boston-based biotech Steve Seiler, CEO, Warren Stern, SVP Compound: 5 hydroxymethyl-2-furfal (Aes-103) Binds to sickle hemoglobin and increases 02 affinity Roadblocks in drug development Animal toxicology studies CMC (Chemistry, Manufacturing, and Quality Control) Regulatory: Interactions with FDA, IND filing TRND collaborating with AesRX on IND-enabling pre-clinical animal tox IND filed Oct 14 th 2011 Ph I (normal volunteers) began 4Q 2011 Ph IIa (clinical proof-of-concept) 2Q 2012 API (Aes-103) manufactured via NIH-RAID and TRND programs NIH CC Pharmacy collaborated on API stability George Grimes, Bob DeChristoforo (CC) Phase I-II clinical trials at NIH Clinical Center and CRU Greg Kato, NHLBI

46 NCATS: Pursuing Opportunities for Disruptive Innovation Mission: To catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions

47 The Road to NCATS: NIH Scientific Management Review Board Recommendations May 2010 SMRB asked to determine how NIH could better support translational and therapeutic sciences. December 2010 SMRB recommends that a new translational medicine and therapeutics center be created. SMRB also recommends NIH undertake a more extensive and detailed analysis through a transparent process to evaluate the new center s impact.

48 Pursuing Opportunities for Disruptive Translational Innovation Article: Reengineering Translational Science: The Time Is Right. Francis S. Collins. Science Translational Medicine Online Issue 6 July 2011.

49 Examples of Translational Challenges Therapeutic target validation Chemistry Virtual drug design Preclinical toxicology Biomarkers Efficacy testing Phase zero clinical trials Rescuing and repurposing Clinical trial design Post-marketing research

50 NCATS Research Programs Components of Molecular Libraries Program Therapeutics for Rare and Neglected Diseases Bridging Interventional Development Gaps Office of Rare Diseases Research Clinical and Translational Science Awards FDA-NIH Regulatory Science Cures Acceleration Network Division of Preclinical Innovation Division of Clinical Innovation

51 Further Information Screenshot: NCATS.nih.gov Screenshot: NCTT.nih.gov

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