Clinical Trials in IBD. Bruce Yacyshyn MD Professor of Medicine Division of Digestive Diseases

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1 Clinical Trials in IBD Bruce Yacyshyn MD Professor of Medicine Division of Digestive Diseases

2 Objectives Today s discussion will address the following topics: Similarities and differences between Crohn s Disease (CD) and Ulcerative Colitis (UC) and how studies may differ Rationale and examples of clinical trials of medication and integrative treatments in Inflammatory Bowel Diseases (IBD) Role of personalization of clinical trial outcomes Talking with your health care team about clinical trial options

3 Life with IBD-WHY we do research More than 1.4 million Americans are currently living with IBD Symptoms, course of disease, and prognosis differ from one person to the next How do you determine your best treatment plan and include new clinical research as an option?

4 Inflammatory Bowel Diseases Are Not Irritable bowel syndrome (IBS) An allergy An immune deficiency Are Inflammatory = activated immune system in the intestinal tract Chronic = lasts a long time (maybe a lifetime) Treatable

5 What are the Potential Causes of IBD? Genetic Predisposition Immune System Abnormalities 20%-25% of patients have a close relative with IBD Environmental Factors Infections, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), diet, smoking, stress An inappropriate reaction by the body s immune system

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7 The Spectrum of IBD CROHN S DISEASE Patchy, full-thickness inflammation Mouth to anus involvement Fistulas, abscesses, strictures Extraintestinal manifestations ULCERATIVE COLITIS Continuous, superficial inflammation Colon and/or rectum Extraintestinal manifestations Indeterminate Colitis 10%-15%

8 Anatomical Location of Ulcerative Colitis Pancolitis Left-sided colitis 15-25% 75% Rectal involvement 95% (Shading indicates the frequency with which differing portions of the bowel are involved in ulcerative colitis)

9 Early, Consistent Treatment = Increased Chance of Staying Well New Targets of Clinical Research

10 Different Aspects of Clinical Trial Design Minimize treatment toxicity Provide emotional support Prevent cancer Treat complications Treat inflammation IBD clinical trial targets Improve quality of life Ensure adequate nutrition Control symptoms Maintain remissions

11 Clinical Trials & Needs of Patients with IBD: Diagnostic markers of IBD* Predictors of natural history and therapeutic response* Prophylactic therapy (prevention of relapse) Effective, non-toxic therapy Definitive therapeutics i.e.: personalizedmedicine

12 Serologic Markers-Early Biomarkers Antibody DNAasesensitive panca ASCA Antigen Histone H 1, bacterial antigen? Anti Saccharomyces cerevisiae antibody Non-IBD (%) CD (%) UC (%) < < OmpC Escherichia coli < Anti-I2 Pseudomonas fluorescens Abreu MT et al. Clin Perspect Gastroenterol. 2001:

13 Discovery Development To establish a SUSTAINABLE BIOMARKER PROGRAM THAT SPANS DISCOVERY and DEVELOPMENT Understanding Disease, Mechanism of Action and Response to Therapy To Improve Drug Efficacy To Reduce Drug Toxicity To Enhance Patient Compliance

14 4P OMICS Technologies Pharmacogenetics (PGt) study of variations in DNA sequence related to disease states and drug response Pharmacogenomics (PGx) study of variations in expression of individual genes relevant to disease states and drug response Proteomics (PPx) study of variations in expression of individual proteins relevant to disease states and drug response Metabonomics (PMx) study of variations in levels of endogenous metabolites relevant to disease states and drug response DNA RNA Protein Metabolite

15 Genomics Recent meta-analysis of GWAS and ImmunoChip data of more than 75,000 cases and controls and more than 1.23 million SNPs has identified a further 64 loci bringing the total of IBD associated loci to over 200. This is significantly more than any other complex disease. Jostins L, Ripke S, Weersma RK et al. Nature 2012;490:

16 The Patient: I can tell whether this drug is working or not. The Physician: I can tell which patients are more likely to benefit from this therapy in terms of efficacy side effects. The Health Care System: I can tell which drug I can put on formulary or reimburse with the best efficacy and compliance, and the least chance of causing side effects that would otherwise increase costs further. Pharma s R&D Development Organization: I can reduce program time and cost. I can identify which patients will benefit the most. Pharma s Discovery Organization: I can select targets with better clinical promise. I can help Development ask better questions.

17 ASCEND: Clinical Programme; an Example of Clinical Trial Research 1,2,3 Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA Three double blind, randomized, multi-site active controlled studies in active UC patients Primary efficacy population ASCEND I: Patients with mild and moderately active UC ASCEND II and III: Patients with moderately active UC Study arms 2.4g/day (mesalazine 400mg* MR tablets) x 6 weeks 4.8g/day (Asacol 800mg MR tablets) x 6 weeks Delivered using US Asacol 400mg MR tablets. UK and US Asacol MR tablets should not be considered interchangeable as clinical equivalence has not been established 1. Hanauer S et al Can. J. Gastroenterol. 2007;21: Hanauer S. et al. Am. J. Gastroenterol. 2005; 100: Sandborn WJ et al. Gastroenterology (2009), doi: /j.gastro

18 Needs of Patients with IBD: ASCEND III Biomarkers Diagnostic markers of IBD* Predictors of natural history and therapeutic response* Prophylactic therapy (prevention of relapse) Effective, non-toxic therapy Definitive therapeutics

19 ASCEND: Efficacy endpoints 1,2,3 Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA Primary endpoint = Treatment Success at week 6 Complete Remission = Physician s Global Assessment (PGA* ) and all clinical assessments = 0 or Response = Improvement from baseline PGA, improvement in at least one clinical assessment and no worsening in any clinical assessment Secondary endpoints Time to symptom improvement and resolution Treatment success at week 3 Treatment success in each clinical assessment at week 3 & 6 * Physician s Global Assessment (PGA), scored between 0-3, based on the clinical assessments (rectal bleeding, stool frequency, sigmoidoscopy and patient functional assessment (PFA)) and the physician s overall clinical judgment of disease severity ASCEND III PGA was measured differently to ASCEND I&II. PFA was not included in the PGA of ASCEND III and sigmoidoscopy included a novel contact friability test 1. Hanauer S et al Can. J. Gastroenterol. 2007;21: Hanauer S. et al. Am. J. Gastroenterol. 2005; 100: Sandborn WJ et al. Gastroenterology (2009), doi: /j.gastro

20 Efficacy Comparisons Across 5-ASA Products are Difficult 5-ASAs have been evaluated in UC using various criteria Definition of remission Inclusion and exclusion criteria Disease severity Disease activity indices Duration of study Extent of disease Therefore, it is difficult to directly translate clinical trial results into clinical practice

21 Implications Steroid previous exposure for Asacol females - is this a disease modification or surrogate marker for disease severity? Up to 80% of patients do not respond to 5-ASAcan we help more? Crohn s colitis - benefit of subgroups?

22 Biomarkers Earlier and better diagnosis Aid with patient management Preventative management of IBD Identify at-risk populations Find new targets for drug development Courtesy of Dr Bruce Yacyshyn, University of

23 Examples of Biomarkers of IBD GENETIC POLYMORPHISMS TNF NOD2/CARD 15 TPMT CD14 VDR IL18 IL11 ICAM-1 NRAMP2 KININ B1 Receptor IBD1-9 DLG5 MUC2 GENE EXPRESSION MRP14 GROγ SAA1 TIMP1 ELAFIN TMPT FABP1 Metallothioneins SMALL MOLECULE NO Oxidative Stress Markers N-methylhistamine Substance P

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25 The IBD Medicine Cabinet Over-the-Counter Antibiotics Aminosalicylates Corticosteroids Immunomodulators Biologics

26 What Drugs/What Targets? General classes of drugs to select targets - these examples include: - 5-ASA - other anti-inflammatories - anti-tnf biologics - anti-integrins - S1P agonists - SMAD-7 antisense - JAK inhibitors

27 JAK Inhibitors for IBD

28 Discussion Serum proteomics vary over time in patients that develop CD and UC Specific proteomics are different between UC and CD Future studies are needed to confirm the presence of biomarkers to guide in diagnosis, prevention, and management of IBD patients

29 Summary Biomarkers are an area of research and development for IBD. Improvements in our understanding of genomics, proteomics, and disease biology is important in the process of personalizing medicine for IBD patients.

30 Drugs Don t Work in Patients Who Don t Take Them C. Everett Koop, MD Adherence generally associated with improved outcomes Decreased risk of disease progression Reduced inflammation and increased healing of GI lining Possible decreased risk of colorectal cancer Evidence demonstrates patients who continue their maintenance medications are less likely to experience flares

31 Acknowledgments Yacyshyn Laboratory: Mary Beth Yacyshyn, PhD John Hudson - Laboratory Technician Supported by Merck IISP grant Luminal GI Clinical Trial Group: Missy Randolph BSN, RN Renee Henry ADN, CRC

32 Thank you.