Goodbye Needles! M. Anthony Sofia, MD Assistant Professor of Medicine Division of Gastroenterology and Hepatology Oregon Health and Science University @AnthonySofiaMD Tuesday February 26 th, 2019 Disclosures • None 2 Disclaimer Emerging therapies are interesting and exciting! But… Many of the medications I will discuss are still in early clinical development. They are not FDA approved for these indications and studies are ongoing. Safety and efficacy still needs to be clarified and ultimately judged according to pivotal trial data prior to broad application in IBD. Clinical trials are enrolling and require informed consent with a knowledgeable physician in the field. 3 Outline • Review currently available therapies • Introduce investigational treatments • FDA drug development pathway – Example development histories • Small molecule inhibitors – New and developing therapeutics • Fecal microbiota transplant – Promises, concerns, and (many) unresolved questions 4 Current Medications for IBD (Circa 1/1/2018) Sulfasalazine 5-ASA Mesalamine Oral/Enema/Suppository Prednisone Corticosteroids Budesonide Foams/Enemas/Suppository Azathioprine/6MP Immunomodulators Cyclosporine Tacrolimus Infliximab Adalimumab Certolizumab pegol Biologics Golimumab Vedolizumab 5 Ustekinumab Therapies in Development (Circa 3/1/2019) Tofacitinib* Filgotinib Upadacitinib Janus Kinase (JAK) Itacitinib Inhibition PF-06700841 BMS-986165 TD-1473 PF-6651600 Sphingosine-1-phosphate (S1P) Ozanimod Etrasimod Modulation Amiselimod Selective Integrin AJM300 Therapy Enemas Fecal Microbiota Transplant Colonic infusions Oral capsules 6 FDA Approval Process • 100’s of patients enrolled • Goal to gather preliminary efficacy data • Continue evaluation for side effects Pre-clinical Investigational “Drug discovery and New Drug Phase 1 Phase 2 screening phase” Application • Drug composition data • 20-80 healthy volunteers • Manufacturing processes • Determine most frequent side • Evidence based on cellular and effects 7 animal models • Understand drug metabolism FDA Approval Process • Sponsor is required to submit periodic safety updates to the FDA Phase 4 New Drug Phase 3 FDA Approval Application “Post Marketing Study” • >1000 patients • Evaluate efficacy and safety • Study different populations 8 and dosages Tofacitinib experience pt 1 1996 2003-2010 2012 2012 2017 2018 Pfizer and NIH partner to study JAK CP-690550 Tofacitinib approved for RA • Prevention of organ allograft rejection by a specific Janus • Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled kinase 3 inhibitor. Science 2003 trial of tofacitinib monotherapy in rheumatoid arthritis. N • CP- 690,550. Drugs Future 2007 Engl J Med. 2012 • CP-690550, a JAK3 inhibitor as an immunosuppressant for • van Vollenhoven RF, Fleischmann R, Cohen S, et al. the treatment of rheumatoid arthritis, transplant rejection, Tofacitinib or adalimumab versus placebo in rheumatoid psoriasis and other immune-mediated disorders. Curr. Opin. arthritis. N Engl J Med. 2012 Invest. Drugs 2009 • FDA Approvals: Tofacitinib for Rheumatoid Arthritis 5/2012 • Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases9 and organ transplant rejection. J Med Chem. 2010 Tofacitinib experience pt 2 2012 2017 2018 Tofacitinib in UC Tofacitinib in UC FDA Approval (Phase 2 NEJM) (Phase 3 NEJM) • Sandborn WJ, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012 • Sandborn WJ et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017 10 Therapies in Development (Circa 3/1/2019) Tofacitinib* Filgotinib Upadacitinib Janus Kinase (JAK) Itacitinib Inhibition PF-06700841 Small BMS-986165 TD-1473 Molecule PF-6651600 Inhibitors Sphingosine-1-phosphate (S1P) Ozanimod Etrasimod Modulation Amiselimod Selective Integrin AJM300 Therapy Enemas Fecal Microbiota Transplant Colonic infusions Oral capsules 11 Small molecule inhibitors Tofacitinib Aspirin Ozanimod Molecular weight = 504 Da Molecular weight = 180 Da Molecular weight = 404 Da 12 Monoclonal Antibody Molecular weight = 150,000 Da Aspirin Molecular weight = 180 Da https://www.fda.gov/downloads/aboutfda/tra13 nsparency/basics/ucm356666.pdf Oral small molecule inhibitors JAK Inhibition Tofacitinib* Filgotinib Upadacitinib Itacitinib S1P Inhibition PF-06700841 BMS-986165 TD-1473 Integrin Inhibition PF-6651600 14 JAK Inhibitors in IBD Pro-inflammatory molecules Bind to cellular receptors Activate JAK JAK Inhibitors molecules Create more inflammation 15 **** https://doi.org/10.1016/j.immuni.2012.03.014 JAK Inhibitors in IBD Name Target Studied Indication Tofacitinib JAK Non-selective FDA Approved - UC Phase 3 – UC Filgotinib JAK 1 Phase 3 – CD Phase 3 - UC Upadacitinib JAK 1 Phase 3 – CD Itacitinib JAK 1 Phase 2 – UC Phase 2/3 – UC TD-1473 JAK Non-selective Phase 2 – CD PF-06700841 JAK 3 Phase 2 – CD PF-6651600 JAK 3 Phase 2 – CD BMS-986165 TYK 2 Phase 2 – CD 16 Tofacitinib in ulcerative colitis Remission Mucosal Healing p< 0.001 40% p< 0.001 31% 28% 30% p= 0.007 p< 0.001 19% 20% 17% 16% Placebo 12% 7% Tofacitinib 10mg 10% 4% 0% OCTAVE 1 OCTAVE 2 OCTAVE 1 OCTAVE 2 • Two 8 week induction trials • Randomized, double blind, placebo controlled • OCTAVE 1 → 614 patients 17 • OCTAVE 2 → 547 patients Sandborn WJ, et al. N Engl J Med 2017; 376:1723-1736 Tofacitinib in ulcerative colitis Remission Mucosal Healing p< 0.001 p< 0.001 50% p< 0.001 p< 0.001 46% 41% 40% 37% 34% Placebo 30% Tofacitinib 5mg 20% 11% 13% Tofacitinib 10mg 10% 0% • 52 week maintenance trial • Randomized, double blind, placebo controlled • 593 patients 18 Sandborn WJ, et al. N Engl J Med 2017; 376:1723-1736 Significant Symptomatic Improvements Were Observed with Tofacitinib as Early as Day 3 Diarrhea ** p < 0.01 *** p < 0.0001 19 Hanauer S, et al. Clin Gastroenterol Hepatol. 2019 Jan;17(1):139-147. Significant Symptomatic Improvements Were Observed with Tofacitinib as Early as Day 3 Rectal Bleeding ** p < 0.01 *** p < 0.0001 20 Hanauer S, et al. Clin Gastroenterol Hepatol. 2019 Jan;17(1):139-147. Herpes Zoster Infection in UC on Tofacitinib Tofacitinib Tofacitinib Placebo (N=198) 5 mg BID 10 mg BID • Post-hoc analysis of Phase 2 (N=198) (N=196) induction, OCTAVE 1, 2, Sustain 0.97 HZV All 2.05 • Dose dependent increased risk 6.64 0 for HZ Serious 0 0 0.97 • Duration of treatment does not > 1 Dermatome 0.68 affect risk 2.6 0 Disseminated 0.68 • Age >65 years, prior TNF failure, 0 steroids at baseline, diabetes 0 2 4 6 8 10 12 IR (95% CI) 21 Withrop KL, et al. Inflamm Bowel Dis. 2018 Oct; 24(10): 2258–2265. Upadacitinib in Crohn’s disease • Phase 2, 16 week induction trial • Randomized, double blind, placebo controlled • 220 people with moderate to severe Crohn’s disease • 99% had previous exposures to one or more TNF inhibitor 22 Pannacione R. Abstract P601. ECCO 2018. Oral small molecule inhibitors JAK Inhibition Tofacitinib* Filgotinib Upadacitinib OzanimodItacitinib S1P Inhibition PFEtrasimod-06700841 BMS-986165 TD-1473 Integrin Inhibition PF-6651600 23 S1P Inhibition in IBD • S1P = Sphingosine-1-phosphate • Active immune cells are attracted to S1P • Lymph nodes have little S1P Lymph node • Blood vessels and tissue have high S1P • Immune cells move from lymph nodes to blood vessels to follow S1P • S1P inhibitors block immune cells from seeing S1P, keeping them in lymph nodes 24 Out to blood vessels Ozanimod in ulcerative colitis • Phase 2 Mucosal Healing at 8w • Randomized p= 0.002 • Double-blind 40.0% p= 0.03 34.3% • Placebo controlled 35.0% • 8 week induction 30.0% 27.7% 25.0% • 197 people with moderate to severe UC 20.0% 15.0% 12.3% • Improvement in clinical remission and 10.0% clinical response compared to placebo 5.0% 0.0% Placebo Ozanimod 0.5mg Ozanimod 1.0 mg 25 Sandborn WJ, et al. N Engl J Med 2016; 374:1754-1762 CD Trials: ClinicalTrials.gov NCT03440372 NCT03440385 NCT03464097 NCT03467958 UC Trials: ClinicalTrials.gov NCT02435992 NCT02531126 Etrasimod in ulcerative colitis • Phase 2 Mucosal Healing at 12w • Randomized • Double-blind 25.0% p= 0.010 • Placebo controlled 19.5% • 12 week induction 20.0% 15.0% • 156 people with moderate to severe UC p= 0.231 10.0% 8.2% • Improvement in mucosal healing, 4.1% endoscopic improvement, and histological 5.0% remission compared to placebo 0.0% Placebo Etrasimod 1mg Etrasimod 2mg 26 Peyrin-Biroulet L et al. Abstract. ECCO 2019. Presented 3/8/2019 Oral small molecule inhibitors JAK Inhibition Ozanimod S1P Inhibition Etrasimod Integrin Inhibition AJM300 27 Integrin Inhibition Integrin inhibitors Intestinal stop this interaction tissues → Inside blood vessels Immune cells Attach to Move into searching for integrin tissue to a location molecules cause inflammation 28 AJM300 in ulcerative colitis • Phase 2 Mucosal Healing 8w • Randomized p= 0.0014 • Double-blind 70.0% 58.8% • Placebo controlled 60.0% • 8 week induction 50.0% 40.0% • 102 people with moderately active UC 29.4% 30.0% • Improvement in mucosal healing, histologic 20.0% improvement, and symptomatic response 10.0% compared to placebo 0.0% • Phase 3 trial now enrolling in Japan Placebo AJM300 29 Yoshimura N, et al. Gastroenterology. 2015;149(1775–1783):e2 Phase 3 trial ClinicalTrials.jp identifier 152862 S1P JAK 30 Integrins Fecal Microbiota Transplant • Delivery of an entire excreted microbial community from a healthy individual(s) to an individual with a disease • Identification of a “healthy donor” – Extensive medical and social screening – Screen for infections in blood and stool • Samples must be rigorously collected and prepared • Delivery by enema, nasogastric tube, colonoscopy, upper endoscopy 31 32 FMT in ulcerative colitis Steroid free clinical • Randomized, double-blind, placebo remission or response 8w controlled p= 0.021 30% 27% • 81 people with active UC 25% 20% • 8 week induction 15% • First infusion by colonoscopy, then 5 enemas 10% 8% per week for 8 weeks 5% • FMT derived from 4-7 donors 0% Placebo FMT 33 Paramsothy S, et al. Lancet. 2017 Mar 25;389(10075):1218-1228. Negative effect Positive effect 277 total 34 Paramsothy S, et al.