Aaron E. Miller, MD Professor of Neurology and Medical Director The Corinne Goldsmith

Daclizumab High-Yield Process in Relapsing-Remitting Multiple Sclerosis (SELECT): A Randomised, Double-blind, Placebo-controlled Trial • Gavin Giovannoni, MBBCh, PhD • Chair of Neurology • BlizardInstitute • Barts and The London School of Medicine and Dentistry • London, UK Aaron E. Miller, MD Professor of Neurology and Medical Director The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Icahn School of Medicine at Mount Sinai New York, NY

What Is Daclizumab High Yield Process (HYP)? • Daclizumab is a humanized monoclonal antibody • Blocks CD25 of the interleukin(IL)-2 receptor • Decreases IL-2 signalling at high-affinity receptor and increases signalling at intermediate-affinity receptor • Originally licensed for solid organ transplant rejection but withdrawn from market • But could it work in MS? • High yield process is a new way of processing the drug for a higher “cleaner” yield • Being evaluated for relapsing forms of MS

SELECT Trial—Design • Randomised, double-blind, placebo-controlledphase IIb trial • Part of a registration trial package • Three study arms: daclizumabHYP 150 mg (n = 208) or 300 mg (n = 209), or placebo (n = 204) • Subcutaneous every 4 weeks for 52 weeks • Primary endpoint: • Annualized relapse rate • Secondary endpoints: • New gadolinium-enhancing brain MRI lesions • New/newly enlarging T2 hyperintenselesions • Proportion relapse-free patients • Quality of life • Tertiary endpoint: • Confirmed disability progression, measured by EDSS change

SELECT Trial—Key Clinical and MRI Findings Gold R, et al. Lancet. 2013;381:2167-2175.

SELECT Trial—Safety and Tolerability • Well tolerated • Injection site reactions • Key adverse events of interest • Hypersensitivity reactions • Particularly skin reactions <1% • No Stevens-Johnson reactions • Serious infections, not opportunistic 1%–3% • Autoimmune hepatitis • Recognized by transaminitis Gold R, et al. Lancet. 2013;381:2167-2175.

Daclizumab HYP—Next Steps • Phase III trial in relapsing-remitting MS (DECIDE) • Fully recruited and running • Interferon beta as active comparator • 2years • Results expected in 2016 or 2017 • If phase III data show disability benefit relative to interferon, studies in progressive forms of MS should be considered • Future ideal candidate may be MS patients who are JC virus positive

Aaron E. Miller, MD Professor of Neurology and Medical Director The Corinne Goldsmith

Aaron E. Miller, MD Professor of Neurology and Medical Director The Corinne Goldsmith

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Professor of Neurology – K.M.School of PGMR Head, Department of Neurology – VSGH, AHD Director of Neurosciences – Ste

Professor and Acting Chair of Neurology Director, MS Comprehensive Care Center Stony Brook University Medical Center,

Conflict of Interest Disclosure Corinne E Fischer, MD

John M. Pellock, MD Professor and Chairman Division of Child Neurology

Raghu Upender, MD Assistant Professor in Neurology Medical Director

John Meurer, MD, MBA, Professor and Director

Carlos F. Cáceres, MD, PhD Professor and Director

Fred D. Lublin, MD Saunders Family Professor of Neurology

Stephen Krieger, MD Assistant P rofessor of Neurology and Medical Director

Judd E. Hollander, MD Professor Clinical Research Director

Theresa A. Zesiewicz, MD FAAN Professor of Neurology

Weijing Sun, MD Associate Professor of Medicine Director of GI Medical Oncology

Paul Y Kwo, MD Professor of Medicine Medical Director, Liver Transplantation

David Soria MD - Medical Director

Bruce Dobkin, MD, FRCP Professor of Neurology Director, Neuro-Rehabilitation Program

Michael B. Streiff, MD Associate Professor of Medicine Division of Hematology Medical Director,

Aaron Miller Insurance LLC

Conflict of Interest Disclosure Corinne E Fischer, MD

JoAnn Lindenfeld , MD Professor of Medicine Medical Director, Cardiac Transplant Program

Lisa A. Shultz, MD Medical Director, Lourdes Stroke Center Chief, Division of Neurology