A look into the future - International Progressive MS Alliance. Dr Dhia Chandraratna Head of Research, MSIF

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1 A look into the future - International Progressive MS Alliance Dr Dhia Chandraratna Head of Research, MSIF

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3 Neurologist: Accumulation of disability Gradual change over time Imager: Defining Progressive MS Progressive atrophy, expanding lesions Reduced MTR, NAA, fractional anisotropy Pathologist: Axonal pathology Oligodendrocyte pathology Person with MS: Loss of independence Inability to work, worsening symptoms Progressive MS is defined differently from different perspectives

4 Why is it so important? Large impact worldwide: at least half of the 2.3 million people with MS Onset of progression is the main determinant of disability Lack of effective treatments for progressive MS, despite 12 new treatments for relapsing-remitting MS Finding treatments for progressive MS is one of the top priorities of people with MS

5 A global initiative led by:

6 Mission Expedite development of effective disease modifying and symptom management therapies for progressive forms of MS Inspire and galvanise the global MS movement to focus on Progressive MS For the first time ever, MS Societies are funding research without borders Funding the best science anywhere in the world

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8 Mission

9 Addressing 4 critical questions about Progressive MS 1. How do we identify the cause of the damage? 2. How do we track progression, restoration of function or improvement from treatments? 3. How do we design clinical trials to rapidly determine if a treatment is working? 4. Can we find solutions to address challenging symptoms like pain, fatigue, and cognition?

10 Alliance Scientific Priorities 1. We will better understand progression so we can identify and test treatments 2. We will design shorter, faster trials that measure patient outcomes 3. We will conduct trials to test agents 4. We will develop and evaluate new therapies to manage symptoms

11 Alliance Research Strategy Understanding progression Smaller, faster trials to measure outcomes Trials to test agents Symptom management and rehabilitation MS societies current portfolio Challenge Awards Collaborative Network Awards

12 Funding research worldwide Challenge Awards ( 1.6M) Pilot grants to improve understanding of genetic and biological processes, repurpose existing drugs and improve clinical trials 22 projects - 75K each About 1/3 are for clinical trials or developing outcomes/ biomarkers Another 1/3 focus on understanding underlying causes of progression

13 Funding research worldwide Collaborative Network Awards ( 12.6 M) 3 large network grants - 4M each over 4 years Francisco Quintana Harvard, USA Gianvito Martino San Raffaele Inst. Italy Doug Arnold Montreal Neurological Inst., Canada

14 Collaborative Network Awardees Project 1: Identifying a biomarker of disability progression for use in clinical trials Douglas Arnold, M.D., McGill University (Canada), with 16 investigators from the Netherlands, U.K., U.S., and Switzerland Develop new MRI outcome measures that provide a more efficient readout of drug efficacy, i.e., that could be used in smaller, shorter trials that would cost less

15 Collaborative Network Awardees Project 2: Bioinformatics and cell reprogramming to develop an in vitro platform to discover new drugs for progressive MS (BRAVEinMS) Gianvito Martino, M.D., San Raffaele Hospital Milan (Italy), with 13 Investigators from Italy, France, Germany, Europe, Canada and the U.S. Bioinformatics to discover new drugs that might have a protective role on neurons and/or promote remyelination

16 Collaborative Network Awardees Project 3: Development of a drug discovery pipeline for progressive MS Francisco Quintana, Ph.D., Brigham and Women s Hospital (U.S), with 8 Investigators from the U.S., Canada, Israel and Sanofi Genzyme Screen for drugs that modulate the activity of innate immune system and identify candidates to be analyzed in clinical trials on progressive MS

17 People affected by MS on the Scientific Steering Committee Caroline Sincock, U.K. Alexis Donnelly, Ireland Jonathan Strum, USA

18 Global MS Research Portfolio - funded in 2015 by Managing Members and the Alliance 736 projects Multi-year investment = $222 million Average Annual investment = $73 million 385 projects - relevant to progressive MS Multi-year investment = $117 million Average annual investment = $40 million

19 46 Active Phase 1-4 Clinical Trials in Progressive MS Phase 1 Phase 2 Phase 3 Phase 4 # Trials Majority (33) are focused on disease modification. Rest (16) target symptoms 5 stem cell trials 22 trials funded industry, remainder - a combination of private/government and other funders. Source ClinicalTrials.Gov, April 7, 2016

20 Progressive MS Trials Underway EXPAND Siponimod in SPMS (Phase III) MS-STAT2 Simvastatin in SPMS (Phase III) SPI-2 high dose Biotin in SPMS/ PPMS (Phase III) Masitinib in SPMS /PPMS (Phase III) Phenytoin Optic Neuritis Study (Phase II) PROXIMUS Trial - oxcarbazepine in SPMS (Phase II) MS SMART Trial riluzole, amiloride, fluoxetine in SPMS (Phase II) SPRINT-MS ibudilast in PPMS/SPMS (Phase II) HSCT, mesenchymal stem cells, lipoic acid, idebenone, rehabilitation

21 Closing Thoughts 2011 No treatments on the horizon Fragmented global efforts in progressive MS 2017 First approved treatment ocrelizumab Promising results from ongoing trials Lessons learned from negative trials Raised profile and engagement by the global scientific community Coordination of research efforts with leadership by MS Societies

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