An Independent CME Lunch Program A Closer Look at S1P Immunomodulator Therapeutics to Improve Outcomes in Patients With Relapsing Multiple Sclerosis Wednesday, February 22, 2017 12:30-1:30 PM Orlando, Florida Provided by AcademicCME This activity has been supported by an independent educational grant from Actelion Pharmaceuticals Inc Sponsorship & Support §This activity is supported by an independent educational grant from Actelion Pharmaceuticals Inc §This activity is provided by AcademicCME Accreditation & Credit Designation Accreditation Statement AcademicCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation Statement AcademicCME designates this live activity for a maximum of 1.00 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Instructions for Receiving CME Credit In order to claim CME credit, please complete the evaluation form at the end of the symposium using the provided iPad. CME Lunch Symposium Evaluation Form Wednesday, February 22, 2017 You must complete this evaluation form to receive acknowledgement for completing this activity. First Name: ___________ __ __ __ __ __ __ __ Last Name: ___________ __ __ __ __ __ __ _ Degree: __________ Faculty Introductions Chair Fred D. Lublin, MD Saunders Family Professor of Neurology Director, Corinne Goldsmith Dickinson Center for MS Icahn School of Medicine at Mount Sinai New York, New York Faculty Timothy L. Vollmer, MD Mark S. Freedman, MD Professor Department of Neurology Professor of Medicine University of Colorado Health Sciences Center University of Ottawa Co-Director of the RMMSC at Anschutz Senior Scientist Medical Center and Medical Director-Rocky Ottawa Hospital Research Institute Mountain MS Center Ottawa, Ontario, Canada Aurora, Colorado Faculty Disclosures Fred D. Lublin, MD Consultant/Advisor: AbbVie Inc.; Actelion Pharmaceuticals; Acorda Therapeutics; Akros Pharma Inc.; Amgen Inc.; Atara Biotherapeutics; Bayer AG; Biogen; Celgene Corporation; EMD Serono, Inc.; Forward Pharma; Genentech, Inc.; Genzyme Corporation; Mapi-Pharma Ltd.; Medday; MedImmune; POLYPHARMA; Novartis Pharmaceuticals Corporation; sanofi-aventis U.S. LLC; Roche; Teva Pharmaceutical Industries Ltd.; TG Therapeutics, Inc.; Toyama Grant/Research Support: Biogen; Celgene Corporation; Genzyme Corporation; Novartis Pharmaceuticals Corporation; sanofi-aventis U.S. LLC; Teva Pharmaceutical Industries Ltd.; Transparency Life Sciences Speaker's Bureau: Genentech, Inc.; Genzyme Corporation Mark S. Freedman, MD Consultant/Advisor:Actelion Pharmaceuticals; Bayer AG; Biogen; Chugai Pharmaceutical Co., Ltd.; EMD Serono, Inc.; Genzyme Corporation; MedDay; Merck & Co.; Novartis Pharmaceuticals Corporation; Roche; sanofi-aventis U.S. LLC; Teva Canada Innovation Grant/Research Support:Genzyme Corporation Speaker's Bureau: Genzyme Corporation Timothy L. Vollmer, MD Consultant/Advisor: AbbVie Inc.; Alcimed; American Academy of Neurology; CB Partners; Capmaels and Rasford; Celestial IntasPharmaceuticals LTD; Compass Learning; Genetech/Roche; Genzyme/Sanofi; Goodwin Procter, LLP; Guthy Jackson Charitable Foundation; IMS Consulting Group; MedScape; Novartis Pharmaceuticals Corporation; Oxford Pharmagenesis; Patient Centered Outcomes Research Institute; Sommer Consulting; Teva Neuroscience; Xenoport, Inc. Grant/Research Support: Genzyme Corporation; Teva Pharmaceutical Industries Ltd.; NIH/NINDS; Rocky Mountain MS Center; EMD Sereno, Inc.; Biogen Idec; Ono Pharmaceuticals; Acorda Pharmaceuticals; MedImmune Educational Objectives 1. Discuss the recent scientific advancements of emerging S1P immunomodulators. 2. Analyze the current clinical trial data concerning S1P efficacy and safety including, head to head superiority data and add-on therapy data. 3. Apply the most current evidence based medicine to develop individualized treatment plans for patients with relapsing multiple sclerosis. Agenda I. Welcome and introductions Fred D. Lublin, MD II. Recent Scientific Advancements of S1P Immunomodulators Mark S. Freedman, MD III. Clinical Trial Data Analysis: Interpreting S1P Evidence Based Medicine for Relapsing MS Mark S. Freedman, MD IV. New MS Research Strategies and Approaches Timothy L. Vollmer, MD V. Panel Discussion and Conclusion Fred D. Lublin, MD Clinical Trial Development Progam for S1P Receptor Modulators in RMS Mark S. Freedman MSc MD FANA FAAN FRCPC Professor of Medicine (Neurology) University of Ottawa Sr. Scientist The Ottawa Hospital Research Institute S1P Receptors – A Pleiotropic System S1P is a phospholipid released by platelets, mast and other cells S1P stimulates 5 G-protein coupled receptors located on endothelial cells, cardiac myocytes S1P receptors are expressed in a wide variety of tissues The different S1P1 S1P2 S1P3 S1P4 S1P5 receptors induce a variety of Cellular responses: biological proliferation, angiogenesis, migration, cytoskeleton organization, endothelial cell chemotaxis, responses immune cell trafficking, mitogenesis Lymphocyte Migration: Unique Role of S1P1 Receptor Modulator This image cannot currently be displayed. Naïve T cell Antigen-presenting cell Activated T cell Effector T cell Lymph node Target organ S1P1 Receptor Modulators: Effects on the Immune System Significantly affects: Does not affect: ¡ Th17 cells ¡ Monocytes, NK-cells, and neutrophils ¡ Central memory T cells ¡ Effector memory T cells ¡ B cells involved in Sequestration in immunosurveillance lymphoid organs ¡ Killing of cells resulting in a dose- Preservation of mechanism dependent decrease in of innate immune system total lymphocyte counts Comparison of Main S1P Receptor Modulators in MS Study Agent Fingolimod Ponesimod Siponimod Ozanimod Ceralifimod# t½ (hrs/days) 6-9 days 30 hrs 30 hrs 19 hrs 85 hrs Lymphocyte 1-2 months 3-6 days 7 days 3 days 14 days Recovery S1P Receptors 1, 3, 4, 5 1 (3, 5) 1, 5 1, 5 1, 5 Pro-drug (needs to be Yes No No No No phosphorylated) Study Phase II & III II II & III* II & III II Significant effects on MRI activity Yes Yes Yes Yes Yes Significant Reduction of ARR Yes No Yes No NA *in SPMS only #not being actively pursued for further development Comparison of Main S1P Receptor Modulators in MS Study Agent Fingolimod Ponesimod Ozanimod Siponimod Drug Placebo Drug Placebo Drug Placebo Drug Placebo Trial Duration 24 6 6 6 (months) Patients (n) 425 418 119 121 83 88 50 45 Mean Gd+ Lesions 0.2 1.1 1.4 6.2 0.2 3.2 0.28 2.9 Pts free of Gd+ lesions (6 mths) 90% 62% na na 88% 59% na na Mean # new/enlarging 2.5 9.8 0.5 0.7 na na 0.2# 2.09 lesions (6 mth) ARR 0.18 0.4 0.42* 0.52 0.24+ 0.5 0.28 0.58 Bradycardia 2.1% 0.7% 2% 0 0 1% 28% 2% #2 mg dose; *20 mg dose; +1 mg dose Ponesimod: Clinical Trial Development in MS PK/PD: Rapidly absorbed, tmax 2.5 – 4 hours, t½ = 32 hours No relevant effect of food No relevant interaction with oral contraceptives Predominantly excreted in feces Comprehensive evaluation of safety and tolerability ¡>1000 subjects exposed, some treated for >6 years ¡15 Phase I, 3 Phase II studies (MS + other conditions) ¡Titration scheme for mitigation of 1st dose effect on heart rate Demonstrated efficacy in MS and psoriasis Ponesimod: Safety Issues First dose effects (bradycardiaand AV conduction delays) Pulmonary function effects (reduced FEV1), rapidly reversible Transient liver enzyme elevations with no bilirubin elevation Few cases of macular edema (<1% incidence), resolved after discontinuation Lymphocyte count reduction, rapidly reversible Phase II Dose Finding Study in MS Multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study in patients with relapsing-remitting multiple sclerosis (RRMS), 464 patients randomized Randomization Placebo (n=121) 10 mg o.d. ponesimod (n=108) 20 mg o.d. ponesimod (n=116) Baseline 40 mg o.d. ponesimod (n=119) Screening Treatment FollowFollow--upup 24 weeks Core Extension Efficacy endpoints: • Primary – cumulative number of new Gd+ T1-lesions per patient at weeks 12, 16, 20 and 24. • Secondary - ARR during 24 weeks of treatment Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85:1198–1208. Primary Endpoint: Cumulative Number of New T1 Gd+ Lesions From Week 12 to Week 24 Per-protocol population SE) ± + lesions 43% reduction Gd 1 * 77% reduction 83% reduction *** Cumulative new T new Cumulative *** from week 12 to (Meanto weekweekfrom2412 *p<0.05, ***p<0.0001 vs placebo Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85:1198–1208. Secondary Endpoint: Annualized Relapse Rate up to Week 24 All-treated population 0.9 0.8 52% 0.7 0.6 0.5 p = 0.0363 0.4 0.3 0.2 Annualized relapse rate (+ 95%CI) 0.1 0.525 0.332 0.417 0.251 0 Placebo Ponesimod 10 mg Ponesimod 20 mg Ponesimod 40 mg • Annualized confirmed relapse rate estimated from negative binomial regression model • Studies continuing with 20 mg dose due to toxicity of 40 mg Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85:1198–1208. Ponesimod: Effect on Lymphocytes All-treated set 10 0 -10 Ponesimod 40 mg -20 Ponesimod 20 mg -30 Ponesimod 10 mg Placebo -40 -50 -60 lymphocyte (%)count -70 Meanchangefromin baseline -80 Number of patients at each visit 113 110 111 99 88 92 88 87 110 107 107 101 99 96 96 96 101 96 100 95 97 91 90 90 110 113 112 110 103 105 105 105 Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85:1198–1208. Ponesimod: Adverse Events (Observed in ≥5% of Patients) All-treated population Placebo Ponesimod 10 mg Ponesimod 20 mg