© 2014 Direct One Communications, Inc. All rights reserved. 1 The Current Clinical Arena of Progressive Multiple Sclerosis Carrie M. Hersh, DO Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio A REPORT FROM THE 29TH CONGRESS OF THE EUROPEAN COMMITTEE FOR TREATMENT AND RESEARCH IN MULTIPLE SCLEROSIS (ECTRIMS 2013)

© 2014 Direct One Communications, Inc. All rights reserved. 2 Progressive MS: An Unmet Challenge The vast majority of patients with relapsing- remitting multiple sclerosis (RRMS) eventually develop secondary progressive multiple sclerosis (SPMS). We now have 10 approved drug therapies for RRMS, whereas treatment for progressive MS is still limited. International efforts to address this crucial unmet challenge: » Multiple Sclerosis Outcome Assessments Consortium » International Progressive Multiple Sclerosis Alliance » International Progressive Multiple Sclerosis Collaborative

© 2014 Direct One Communications, Inc. All rights reserved. 3 Clinical Trials in Progressive MS MS-SMART (phase 2) » Four treatment arms: riluzole, amiloride, ibudilast, placebo SPRINT-MS (phase 2) » Ibudilast vs placebo in patients with primary progressive multiple sclerosis (PPMS) and SPMS PROXIMUS (phase 2) » Oxcarbazepine vs placebo in patients with SPMS INFORMS (phase 3) » Fingolimod vs placebo in patients with SPMS ASCEND (phase 3) » Natalizumab vs placebo in patients with SPMS

© 2014 Direct One Communications, Inc. All rights reserved. 4 Spinal Cord and PPMS Spinal cord MR spectroscopy as a tool to measure metabolite concentrations in patients with early PPMS compared with matched healthy controls: » tNAA: axonal integrity and metabolic function » Myo-inositol: astrocytic activation and proliferation » Glx: neuronal integrity and neurotransmitter pool Lower tNAA and Glx seen in patients with PPMS: » Suggests a role for neuronal loss and metabolic dysfunction in the glutamatergic pathway in the spinal cord » Association between tNAA and Glx suggests that these pathologic abnormalities may contribute to disability Abdel-Aziz K et al, ECTRIMS 2013, Abstract 197

© 2014 Direct One Communications, Inc. All rights reserved. 5 Radiologically Isolated Syndrome (RIS) and Progressive MS Cranial and spinal cord MRI findings at the time of PPMS diagnosis can be remarkably similar to SPMS. Asymptomatic pre-progression disease course in PPMS is difficult to study systematically. Longitudinal follow-up of RIS cohort: » PPMS incidence (9%) and sex ratio (43% female) in this RIS cohort mirrored population-based studies » Cerebrospinal fluid was positive in 83% of RIS patients that developed PPMS » Higher cervical and thoracic cord lesion load in PPMS than in other symptomatic patients Kantarci OH et al, ECTRIMS 2013, Abstract 198

© 2014 Direct One Communications, Inc. All rights reserved. 6 Relapses and Post-Progression Disability Determinants of progression are incompletely understood » Not all MS patients develop disease progression » Distribution of age at onset of progression varies » Wide range of disability accumulation among patients Presence of pre-progression relapses predicts a shorter time from onset of progression to an EDSS score of 6.0 Post-progression disability accumulation: » Slowest in patients with PPMS (50% of patients in 10 years) » Somewhat faster in patients with SAPMS (50% in 7 years) » Fastest in patients with SPMS (50% in 4 years) Paz Soldan MM et al, ECTRIMS 2013, Abstract 199

© 2014 Direct One Communications, Inc. All rights reserved. 7 Relapses and Post-Progression Disability Ongoing relapses following the onset of progressive disease course independently predicted shorter time from progression onset to EDSS 6.0, which was about 2 years faster (P = ). Most post-progression relapses (91.6 %) occurred within 5 years after the onset of progression and before the age of 55 years (95.2 %). Relapses prior to or following the onset of disease progression increase the rate of accumulation of post-progression disability. Gender and age at the onset of progressive disease have minor influences on disability accumulation. Paz Soldan MM et al, ECTRIMS 2013, Abstract 199

© 2014 Direct One Communications, Inc. All rights reserved. 8 ASCEND Clinical Trial Natalizumab, a recombinant humanized anti-  4 integrin antibody, is an FDA-approved therapy for relapsing forms of MS. Recent retrospective studies of clinical data suggest that natalizumab may have the ability to reduce disease progression in SPMS. ASCEND (phase 3, ongoing): » Multinational, randomized, double-blinded, placebo- controlled trial » Study objective: efficacy of natalizumab in reducing the progression of disability in patients with SPMS Mikol D et al, ECTRIMS 2013, Abstract P1087

© 2014 Direct One Communications, Inc. All rights reserved. 9 ASCEND Clinical Trial Over 800 patients from various countries with functional disability test scores consistent with disability progression enrolled as of August % have “low” EDSS scores (3.0–5.5) and 38% “high” EDSS scores (6.0–6.5) Randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 2 years Primary endpoint: percentage of patients with confirmed progression of disability by one or more of the following measures: EDSS, T25FW, and 9HPT Mikol D et al, ECTRIMS 2013, Abstract P1087

© 2014 Direct One Communications, Inc. All rights reserved. 10 ASCEND Substudy: MS-COG Objective: explore the effects of natalizumab on cognition using a novel composite measure, MS-COG Learning/memory: » SRT-DR: Selective Reminding Test–Delayed Recall » SRT-TL: SRT–Total Learned » BVMTR-DR: Brief Visuospatial Memory Test Revised– Delayed Recall » BVMTR-TL: BVMTR–Total Learned Processing speed: » SDMT: Symbol Digit Modalities Test » PASAT-2: Paced Auditory Serial Addition Test–2 seconds » PASAT-3: PASAT–3 seconds Cadavid D et al, ECTRIMS 2013, Abstract P1088

© 2014 Direct One Communications, Inc. All rights reserved. 11 ASCEND Substudy: MS-COG Baseline data currently are available for 112 participants, most of whom have changed their occupation because of MS. Overall, average performance on tests of memory and processing speed and on the total MS-COG composite score were lower than those in the reference (placebo) control group. Approximately 75% of participants had at least mild cognitive impairment (z score  –0.5), and about 20% had evidence of severe cognitive impairment (z score  –2.0). Cadavid D et al, ECTRIMS 2013, Abstract P1088

© 2014 Direct One Communications, Inc. All rights reserved. 12 Goals of Current Studies Validate a pre-clinical model of progressive MS that emulates human pathology Develop high-throughput screening tools Validate outcome biomarkers Develop accepted clinical outcome measures to help better understand progressive MS pathology Use these tools to guide development of targeted disease-modifying and symptomatic treatments for patients with progressive MS Expand and unify international collaborations to better understand and treat progressive MS