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Potential Clinical Implications of the CME Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

Course Director Aaron Boster, MD OhioHealth Physicians Group Columbus, Ohio

What’s Inside 3 Updates on MS Diagnostic Criteria and Injectable Disease- Modifying Therapies 5 Recent Data on Approved Oral Disease-Modifying Therapies in MS

8 Latest Findings on Approved Monoclonal Antibodies in MS

12 Data on Emerging Therapies for MS

Participate in interactive questions, download activity slides, and obtain your instant CME credit online. This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. www.peerview.com/SQK900 Activity Information

Expert commentary is based on data presented at the 7th Joint Congress of CME Reviewer the European Committee for Treatment and Research in Multiple Sclerosis Randy M. Rosenberg, MD, FACP, FAAN (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Temple University School of Medicine Sclerosis (ACTRIMS)* Philadelphia, Pennsylvania *PeerView is an independent publisher of conference news and medical education programs. Randy M. Rosenberg, MD, FACP, FAAN, has no financial interests/relationships or affiliations in relation to this activity. Activity Description and Educational Objectives In this activity, an expert on multiple sclerosis (MS) discusses key findings and Medical Director potential clinical implications of the latest data on disease-modifying therapies Kirk A. Tacka, PhD (DMTs) for MS management presented at the 7th Joint ECTRIMS-ACTRIMS PVI, PeerView Institute for Medical Education Meeting held in Paris, France. Kirk A. Tacka, PhD, has no financial interests/relationships or affiliations in Upon completion of this activity, participants should be better able to: relation to this activity. • Apply new data on the efficacy, safety, and tolerability of approved DMTs when managing patients with MS Disclaimer • Assess the potential clinical utility of late-breaking data on the efficacy, The information provided at this CME activity is for continuing education safety, and tolerability of emerging DMTs for the treatment of MS purposes only and is not meant to substitute for the independent medical • Identify the potential impact of emerging DMTs on the future management judgment of a healthcare provider relative to diagnostic and treatment of MS options of a specific patient's medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific Target Audience evidence and current clinical guidelines. No bias towards or promotion for any This activity has been designed to meet the educational needs of neurologists agent discussed in this program should be inferred. and other clinicians involved in managing patients with MS. Providership, Credit & Support Requirements for Successful Completion This activity has been planned and implemented in accordance with the In order to receive credit, participants must view the activity and complete the accreditation requirements and policies of the Accreditation Council for post-test and evaluation form. A score of 70% or higher is needed to obtain Continuing Medical Education (ACCME) through the joint providership CME credit. There are no pre-requisites and there is no fee to participate in of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical this activity or to receive CME credit. Statements of Credit are awarded upon Education. The Medical Learning Institute, Inc. is accredited by the ACCME to successful completion of the post-test and evaluation form. provide continuing medical education for physicians.

Media: Enduring Material The Medical Learning Institute, Inc. designates this enduring material for a Release and Expiration Dates: January 24, 2018 - January 23, 2019 maximum of 0.75 AMA PRA Category 1 CreditTM. Physicians should claim only the Time to Complete: 45 minutes credit commensurate with the extent of their participation in the activity.

Faculty & Disclosure / Conflict of Interest Policy Providership Before the activity, all faculty and anyone who is in a position to have control This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, over the content of this activity and their spouse/life partner will disclose the PeerView Institute for Medical Education. existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed Support during their presentation(s): honoraria, expenses, grants, consulting roles, This activity is supported by educational grants from Biogen and Sanofi speakers bureau membership, stock ownership, or other special relationships. Genzyme. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc. for Disclosure of Unlabeled Use fair balance, scientific objectivity of studies mentioned in the materials or used The faculty of this educational activity may include discussions of products as the basis for content, and appropriateness of patient care recommendations. or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or The associates of Medical Learning Institute, Inc., the accredited provider for investigational use. this activity, and PVI, PeerView Institute for Medical Education do not have any financial relationships or relationships to products or devices with any No endorsement of unapproved products or uses is made or implied by commercial interest related to the content of this CME activity during the past coverage of these products or uses in our reports. No responsibility is taken for 12 months. errors or omissions in reports. For approved prescribing information, please consult the manufacturer’s product labeling. Course Director Aaron Boster, MD The materials presented here are used with the permission of the authors Systems Medical Chief, Neuroimmunology and Clinical Research and/or other sources. These materials do not necessarily reflect the views of OhioHealth Physicians Group PeerView or any of its partners, providers, and/or supporters. Columbus, Ohio About This CME Activity Aaron Boster, MD, has a financial interest/relationship or affiliation in the form PVI, PeerView Institute for Medical Education, and Medical Learning Institute, of: Inc. are responsible for the selection of this activity’s topics, the preparation Consultant for Biogen Idec; Genentech, Inc.; Genzyme Corporation; Medtronic, of editorial content, and the distribution of this activity. Our activities may Inc.; and Novartis Corporation. contain references to unapproved products or uses of these products in Grant/Research Support from Actelion Pharmaceuticals US, Inc.; Biogen Idec; F. certain jurisdictions. The preparation of PeerView activities is supported by Hoffmann-La Roche Ltd.; and Teva Pharmaceuticals. educational grants subject to written agreements that clearly stipulate and Aaron Boster, MD, does intend to discuss either non-FDA-approved or enforce the editorial independence of PVI and Medical Learning Institute, Inc. investigational use for the following products/devices: investigation for the treatment of MS.

2 Go online to complete the post-test and evaluation for CME credit www.peerview.com/SQK900 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

Updates on MS Diagnostic Criteria Number four—aside from the removal of the distinction between symptomatic and asymptomatic lesions, and the fact that cortical and Injectable Disease-Modifying lesions are now allowed to be used, the diagnostic criteria for primary Therapies progressive MS is the same in 2017 as it was in the 2010 revised McDonald Criteria.

Dr. Boster: Howdy. My name’s Aaron Boster, Systems Medical Chief Number five—at the time of diagnosis, a provisional disease course or of Neuroimmunology and Director of the OhioHealth MS Center at phenotype should be specified and periodically re-evaluated based on OhioHealth Physicians Group in Columbus, Ohio. Welcome to this accumulated information. This is an addition to the 2010 Criteria. video-based educational activity on multiple sclerosis, focusing on updates from the recent Joint ECTRIMS-ACTRIMS Meeting in Paris, Post Hoc Analysis of REFLEXION Study: Impact of GEL at France. Baseline on NEDA Status in SubQ IFN β-1a–Treated Patients1 Time to First Disease Activity Event in Patients With/Without GEL at Baseline for Thrice Weekly SubQ IFN β-1a 44 mcg 1 2017 Revisions to the McDonald Diagnostic Criteria for MS NEDA defined as: No relapses, 1.1 In a patient with a typical CIS and fulfillment of clinical or MRI criteria for DIS and no increases in EDSS, better explanation for the clinical presentation, demonstration of CSF-specific oligoclonal new GEL, and NEL bands allows an MS diagnosis to be made without the previously required DIT. 2.2 Symptomatic and asymptomatic MRI lesions can be considered in the determination of DIS or DIT. 3.3 Cortical and juxtacortical lesions can be used in fulfilling MRI criteria for DIS. 4.4 Aside from the removal of the distinction between symptomatic and asymptomatic lesions and that cortical lesions can be used, the diagnostic criteria for primary

progressive MS are the same in the 2017 McDonald Criteria as in the 2010 McDonald 1. Freedman M et al. MSParis2017. Abstract P1144. Criteria. 5.5 At the time of diagnosis, provisional disease course or phenotype should be specified and periodically re-evaluated based on accumulated information. Now let’s turn our attention to some updates on the various approved 1. Cohen J et al. 7th Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis Meeting (MSParis2017). Abstract 93. interferon β preparations and glatiramer acetate.

Before we delve into all of that data, I would like to begin by discussing In the REFLEX study, clinically isolated syndrome patients were the 2017 proposed revisions to the McDonald diagnostic criteria for MS, randomly assigned to receive subcutaneous interferon β-1a, 44 mcg which were also presented at the MSParis2017 meeting. thrice weekly, once weekly, or placebo for a period of 24 months. Upon conversion to clinically definite MS, patients switched to open-label The 2017 revisions to the McDonald diagnostic criteria for MS can subcutaneous interferon β-1a thrice weekly. be summarized as follows. Number one—in a patient with a typical clinically isolated syndrome fulfilling the clinical and MRI criteria for In the REFLEXION extension study, all placebo patients were switched dissemination in space and no better explanation for the clinical to subcutaneous interferon β-1a thrice weekly in a delayed treatment presentation, demonstration of CSF with unpaired oligoclonal bands arm. Subcutaneous interferon β-1a patients continued their initial allows an MS diagnosis to be made. This is an addition to the old way, regimen up to 60 months. using the 2010 revised McDonald Criteria, that would require further MRI evidence of dissemination in time. At the 7th Joint ECTRIMS-ACTRIMS Meeting, Dr. Freedman and colleagues presented the results of a post hoc analysis of the Number two—symptomatic and asymptomatic MRI lesions can now REFLEXION study. The results of this analysis showed the presence of be both considered in the determination of dissemination in space or in baseline gad lesions was associated with a lower chance of remaining dissemination in time, as compared to the 2010 revised criteria, which NEDA-3 after a 3-month MRI compared to those who had no gad only allowed asymptomatic lesions. lesions at their baseline. In addition, early treatment with subcutaneous interferon β-1a was associated with a higher chance of achieving NEDA- Number three—cortical and juxtacortical lesions can now both be used 3 beyond the 3-month MRI as compared to the delayed treatment arm, in fulfilling MRI criteria for dissemination in space. In the 2010 McDonald regardless of baseline MRI gad lesion status. Criteria, cortical lesions were not allowed to be used and would not fulfill criteria for dissemination in space. Now they do.

3 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

ADVANCE Trial Post Hoc Analysis: Clinical/Radiological Activity Treatment-naïve patients were more likely to experience AEs and in Newly Diagnosed RRMS Treated With SubQ PEG IFN β-1a1 discontinue treatment due to injection-site reactions and flu-like

Endpoint Continuous Tx Every 2 Weeks vs Delayed Tx symptoms, as compared to those who had more experience with Newly Dx Non–Newly Dx Overall the therapy. Treatment-experienced patients were more likely to ↓ 32% ↓ 41% ↓ 37% ARR over 2 y discontinue treatment due to lack of efficacy. P = .0352 P = .0003 P < .0001 ↓ 61% ↓ 74% ↓ 67% NEL (BL to 96 wk) P < .0001 P < .0001 P < .0001 Phase 4, Open-Label, Global CONFIDENCE Study ↓ 25% ↓ 60% ↓ 60% 1 Mean GEL (96 wk) of Glatiramer Acetate Daily vs 3x/Week: 6-Month Results NS P = .0003 P = .0002 • Proportion of patients with 24-wk CDW trended lower in the continuous every-2-weeks group compared with the delayed treatment group for both Significantly higher subgroups; in the overall ITT population, this difference was significant perception of convenience, reduced impact of fatigue on activities, higher 1. Newsome SD et al. MSParis2017. Abstract P662. adherence, and better mental health also reported with GA40 vs GA20 Moving our attention to pegylated interferon β-1a, the efficacy, safety, and tolerability of subcutaneous pegylated interferon β-1a 125 mcg AE profile consistent with given every other week was established in the ADVANCE trial, a phase 3 previously reported data investigation.

1. Veneziano A et al. MSParis2017. Abstract 1210. At the MSParis2017 meeting, Dr. Newsome and colleagues presented the results of a post hoc analysis, which showed newly diagnosed Moving on, let’s discuss some new data on glatiramer acetate. The treatment-naïve patients with relapsing MS had improved clinical and CONFIDENCE study was a phase 4, open-label, global trial with a MRI outcomes when administered continuous pegylated interferon 6-month core phase and a 6-month extension phase. Patients were β-1a every 2 weeks as compared to a delay in treatment initiation. randomly assigned 1:1 to receive either glatiramer 20 mg or glatiramer These results were generally consistent with the non–newly diagnosed 40 mg. The primary endpoint was medication satisfaction over a patients and the overall intent-to-treat population in the ADVANCE trial. 6-month time frame. Secondary endpoints included convenience perception and symptomatic changes. Treatment adherence was an 5-Year Phase 4 Observational POP Study of PEG IFN β-1a exploratory endpoint. Every 2 Weeks: First Interim Analysis1

Proportion of Relapse-Free Patients At the 7th Joint ECTRIMS-ACTRIMS Meeting, Veneziano and colleagues presented the 6-month results of the CONFIDENCE study, which showed patients treated with glatiramer 40 mg reported significantly higher medication satisfaction than those treated with glatiramer 20 mg over 6 months. In addition, patients reported significantly higher perception of convenience, reduced impact of fatigue on patient activities, higher adherence, and better mental health with glatiramer • Safety profile of PEG IFN β-1a every 2 wk consistent with ADVANCE trial; no additional safety signals observed 40 mg as compared to glatiramer 20 mg. Lastly, the AE profile was • Treatment-naïve patients more likely to experience AEs and discontinue therapy due to ISRs and FLS; treatment-experienced patients more likely to discontinue due to lack of efficacy consistent with previously reported data.

1. Salvetti M et al. MSParis2017. Abstract EP1627. In summary, I am most struck by the newly revised 2017 McDonald In addition, the first interim analysis of the phase 4 POP study looking at Criteria to diagnose multiple sclerosis. It has already assisted me pegylated interferon every 2 weeks was presented in Paris. The 5-year multiple times in clinical practice. And I’ll give you a quick example. observational POP study provides an opportunity for us to explore the long-term safety and effectiveness of pegylated interferon β-1a every 2 The week after returning from the ECTRIMS meeting, I saw a gentleman weeks in the real-world setting. who suffered a transverse myelitis affecting his thoracic spinal cord. He had a clinically isolated syndrome. We did an MRI of his brain, and The results of the first interim analysis of POP showed the safety profile he had four lesions. They were all periventricular. Because we are now of pegylated interferon β-1a every 2 weeks was consistent with that allowed to consider symptomatic and asymptomatic lesions, he met previously reported in the ADVANCE trial, and no additional safety dissemination in space criteria. He did not meet dissemination in time. signals were observed. The proportion of treated patients who were However, we performed a lumbar puncture, and he was found to have relapse-free was high. multiple unpaired oligoclonal bands. The presence of the unpaired bands takes the place of dissemination in time. And based on the new diagnostic criteria, we were able to diagnose him with relapsing MS at that time. As a result, we were able to start him on therapy early, evidence that the new revised criteria are already helping us in clinical practice.

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Recent Data on Approved Oral teriflunomide 14 mg daily were similar in the population with grade 1 Disease-Modifying Therapies in MS and grade 2 lymphopenia as compared to those without lymphopenia. Collectively, these data demonstrate a limited impact of teriflunomide on protective immunity and further support evidence that Long-Term Disability in TEMSO and TOWER Core and immunomodulatory rather than immunosuppressive mechanisms of Extension Studies: Pooled Subgroup Analysis1 action are at work.

Other Long-Term Outcomes of Teriflunomide in TEMSO and/or TOWER Core and Extension Studies

1 Cognitive Outcomes Brain Volume (BV) Loss1 LS Mean Change From BL • Significant association of early BV loss with in PASAT-3: Z-Scores long-term cognitive changes in TEMSO • Patients with slower rates of BV loss over 2 y showed longer-term PASAT-3 improvement vs group with greater rates of BV loss at 5 y in TEMSO population

Disability2

1. Vermersch P et al. MSParis2017. P1191. • Long-term disability stable after 5 y in majority of patients with RRMS or progressive forms of relapsing MS Dr. Boster: We also saw new data on approved oral disease-modifying a Time point at which teriflunomide treatment was started. therapies at the 7th Joint ECTRIMS-ACTRIMS Meeting in Paris, France. 1. Sprenger T et al. MSParis2017. Abstract P685. 2. Lublin F et al. MSParis2017. Abstract EP1715. So, let’s begin by discussing some of the recently presented data on teriflunomide from the core and extension studies of TEMSO and In addition, long-term data showed, in terms of cognitive outcomes, TOWER. teriflunomide 14 mg daily significantly improved the PASAT-3 performance versus placebo over 96 weeks in the TEMSO core trial. This The randomized, phase 3 TEMSO and TOWER studies showed effect was also maintained over the course of the extension study. teriflunomide 14 mg daily to be significant in its reduction of annualized relapse rate and 12-week confirmed disability worsening in patients Moreover, a significant association of early brain volume loss with long- with relapsing MS as compared to placebo. term cognitive changes was observed, suggesting that brain volume loss earlier in the disease course predicts long-term cognitive function. At the MSParis2017 meeting, long-term disability outcomes in Slower rates of brain volume loss over 2 years were associated with subgroups of patients defined by demographics and baseline longer-term PASAT-3 improvements versus the group with greater rates characteristics from the pooled data set of the phase 3 TEMSO and of brain volume loss at 5 years in the TEMSO population—core plus TOWER trials and their extension studies were presented. The results of extension—regardless of the treatment allocation. these analyses show the percentage of stable and improved disability, as measured by EDSS, during the overall period of treatment with TOPIC Core and Extensions Studies: Relationship Between teriflunomide 14 mg daily remained high across all studied subgroups. Cortical Gray Matter Atrophy and Risk of Conversion to CDMS1 CDMS Conversion According to Grouping Based on Annualized Percentage Change From Baseline in CGMVa Lymphocyte Counts and Infection in TEMSO and TOWER Core and Extension Studies: Pooled Subgroup Analysis1 Lymphopenia in Teriflunomide 14 mg Group Significant association Lymphopenia in Pooled TEMSO in Pooled TEMSO and TOWER Core + Extension and TOWER Core Studies Studies (Based on 4,499 Patient-Years) of early CGMV loss with long-term CDMS also observed, suggesting CGMV loss earlier in disease course predicts longer term CDMS conversion

a Analyses based on pooled data from placebo and active treatment groups (total population). b Derived from Kaplan-Meier estimates. 1. Zivadinov R et al. MSParis2017. Abstract P671. • Infection rates in patients treated with teriflunomide 14 mg/day were similar in the populations with grades 1-2 lymphopenia and without lymphopenia

Data demonstrate teriflunomide has a limited impact on protective immunity, further supporting evidence of an immunomodulatory MOA Lastly, new data from the TOPIC core and extension studies were 1. Comi G et al. MSParis2017. Abstract P742. also presented. In the phase 3 TOPIC trial, teriflunomide significantly reduced the risk of conversion to clinically definite MS in patients after Another pooled analysis of the TOWER and TEMSO core and extension experiencing their first clinically isolated syndrome suggestive of data showed low-grade lymphopenia was infrequent, with no reports possible MS. of high-grade lymphopenia. Infection rates in patients treated with

5 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

At the MSParis2017 meeting, data on the relationship between cortical Another integrated analysis of DEFINE, CONFIRM, and ENDORSE shows gray matter atrophy and the risk of conversion to clinically definite MS absolute lymphocyte counts were closely correlated with CD4 and was presented. The results of this analysis showed teriflunomide 14 mg CD8 T-cell subsets, indicating that lymphocyte subset monitoring demonstrated a statistically significant effect on reducing cortical gray is not necessary for patient safety vigilance. Absolute lymphocyte matter volume loss versus placebo. counts followed a consistent pattern of decline within the first year and generally remained stable thereafter, regardless of category of A significant association of early cortical gray matter volume loss with lymphocyte decline. long-term clinically definite MS was also observed, suggesting that cortical gray matter volume loss earlier in the disease course predicts Low incidence of serious infections, opportunistic infections, and conversion to clinically definite MS. malignancy were observed, even when stratified by ALC or T-cell subset. Dimethyl Fumarate: Integrated Analysis of DEFINE, CONFIRM, and ENDORSE—Relapse Rates and Disability1 EFFECT Study of Dimethyl Fumarate: Adjusted ARR over 8 Years (ENDORSE 6 Years) Real-World Comparative Effectiveness Analyses DMF/DMF (DMF years 0-8) 0.14 Patients Relapsed at 1 Year Patients Relapsed at 1 Year PBO/DMF (PBO years 0-2, DMF years 3-8) 0.16 After DMF/GA Inititation1 After DMF/Fingolimod Inititation2 Mean EDSS Scores Over Time

1. Gold R et al. MSParis2017. Abstract P661.

1. Chan A et al. MSParis2017. Abstract P1160. 2. Sloane J et al. MSParis2017. Abstract EP1630. Now let’s shift our attention to some of the more recently presented data on dimethyl fumarate. Dimethyl fumarate demonstrated strong Data on dimethyl fumarate from the real-world EFFECT study were efficacy and a favorable benefit-risk profile in patients with RRMS in the also presented in Paris. EFFECT was a retrospective, multicenter, phase 3 DEFINE and CONFIRM trials, as well as the associated ongoing international, single-time-point medical record review study in extension study ENDORSE. greater than 1,700 patients with relapsing-remitting multiple sclerosis evaluating the effectiveness of dimethyl fumarate and other disease- At the 7th Joint ECTRIMS-ACTRIMS meeting in Paris, the integrated modifying therapies. analysis of DEFINE, CONFIRM, and ENDORSE showed that over approximately 8 years, annualized relapse rates remained low in both An analysis of this study showed treatment with dimethyl fumarate newly diagnosed patients treated with dimethyl fumarate in DEFINE, was associated with a significantly higher proportion of relapse-free CONFIRM, and ENDORSE, and those who were treated with placebo patients and lower annualized relapse rate compared with glatiramer in DEFINE and CONFIRM and then later switched to dimethyl fumarate acetate at 12 months. when they entered ENDORSE. In fact, the adjusted annualized relapse rate was significantly reduced in placebo patients after switching to A separate analysis of this study showed treatment with dimethyl dimethyl fumarate. fumarate demonstrated no difference in the risk of relapses and annualized relapse rate compared to treatment with fingolimod. Lastly, EDSS scores also remained stable over 8 years, with greater than 90% of patients maintaining walking abilities after 8 years of treatment. PARADIGMS Trial: Efficacy of Fingolimod vs IFN β-1a IM in Pediatric Patients With MS1 Dimethyl Fumarate: Integrated Analysis of DEFINE, CONFIRM, and ENDORSE—Absolute Lymphocyte Counts and Lymphopenia1 Fingolimod also significantly  ALC falling to <0.5 x 109/L at least ALCs Over Time on Treatment With DMF reduced MRI endpoints, 3-mo once within 1st year of initiating CDP, and brain atrophy from DMF: a predictor of risk for developing subsequent severe, baseline when compared with prolonged lymphopenia IFN β-1a IM in pediatric  In DMF-treated patients, severe, patients with MS prolonged lymphopenia associated with further lymphopenia if patients remained on treatment Safety profile of fingolimod consistent with that seen in  Treatment discontinuation should be adult clinical trials considered if ALCs are <0.5 x 109/L

for 6 months a Adjusted ARR (95% CI) and between-treatment comparison obtained from fitting a negative binomial regression model adjusted for treatment, region, pubertal status (stratification factor in IVRS), and number of relapses in last 2 years (offset: time in study).  ALCs generally increase following 1. Chitnis T et al. MSParis2017. Abstract 276. DMF discontinuation, although reconstitution time varied by individual patient a ALCs ≥0.5 to <0.8 x 109/L for ≥6 mo. b ALCs <0.5 x 109/L for ≥6 mo. 1. Fox RJ et al. MSParis2017. Abstract P743.

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Let’s turn our focus on some key, new data presented on fingolimod. PARADIGMS is an up-to-2-year, double-blind, double-dummy, active- controlled, parallel-group, multicenter study evaluating the efficacy of fingolimod versus intramuscular interferon β-1a in pediatric patients with multiple sclerosis aged 10 to less than 18 years at randomization.

The results of this study showed fingolimod significantly reduced relapse rates, MRI endpoints, 3-month confirmed disability progression, and brain atrophy from baseline when compared to interferon β-1a in pediatric patients with MS.

The safety profile of fingolimod was consistent with that seen in the adult clinical trials. Moreover, more AEs were reported with the intramuscular interferon β-1a group.

Post Hoc Analysis of FREEDOMS Study: Neurofilament Light Chain as Potential Endpoint for Phase 2 Trials1

Correlation of Month 6 NfL and MRI Lesions With Month 24 Relapses and PBVC

Blood NfL levels were shown to be significantly lower in patients taking fingolimod vs placebo at 6 mo, demonstrating early effect of drug on disease progression

Points to the potential use of NfL—a biomarker for neuronal damage measured from a blood sample—as an endpoint in phase 2 clinical trials

1. Sormani MP et al. MSParis2017. Abstract 277.

Additionally, a new analysis of the FREEDOMS trial showed a strong correlation between neurofilament levels and key measurements of MS disease activity. This showed that neurofilament, which is a biomarker of neuronal damage measured in a blood sample, could in the future potentially serve as an endpoint for phase 2 clinical trials in MS.

Moreover, blood neurofilament levels were shown to be statistically significantly lower in patients receiving fingolimod compared to placebo at 6 months, demonstrating an early effect of the drug on disease progression.

I personally am most excited about the data that were presented on neurofilament. We desperately need a biomarker to tell us when a patient is stable or when they’re active, and whether or not they’re responding to a drug. And these early data on neurofilament are extremely encouraging.

7 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

Latest Findings on Approved Data from the ASCEND trial were also presented. ASCEND was a multicenter, randomized, double-blind, phase 3 trial of natalizumab- Monoclonal Antibodies in MS naïve patients diagnosed with secondary progressive multiple sclerosis at least 2 years prior, with disability progression unrelated to clinical STRIVE Trial: Cognitive Impairment With Early Initiation attacks in the year prior. Patients recei ved IV 300 mg of natalizumab or of Natalizumab1 placebo for a period of 2 years. Mean MSIS-29 Scores SDMT Scores At the 7th Joint ECTRIMS-ACTRIMS meeting, Giovannoni and colleagues presented data from a post hoc area-under-the-curve analysis indicating that natalizumab significantly improved the overall disability experience for walking and upper-limb function compared to placebo in SPMS patients. Consistent with the primary endpoints of ASCEND, natalizumab treatment effects were greater for upper- WPAI scores extremity function. Significant improvements from BL in work capacity: • Hours/week missed from work due to MS (P = .024) a Increase of ≥4 points. • Regular activities affected by MS (P = .011) 1. Perumal J et al. MSParis2017. Abstract P1264. TOPAZ Phase 3b/4 Study: Year 7 Results for Patients Originally Treated With Alemtuzumab in CARE-MS I

Dr. Boster: Data on approved monoclonal antibodies also continue to Year 0-2 Year 7 Outcome accumulate, as evidenced by the number of abstracts presented at the CARE-MS I TOPAZ ARR1 0.16 (0-2 y) 0.13 7th Joint ECTRIMS-ACTRIMS meeting in Paris. Improved or stable EDSS, %1 89 (2 y) 78 NEDA, %1 68 (2 y) 61 Let’s start this section by discussing some of the key data on No NEL, %2 78 (2 y) 68 natalizumab that were presented, beginning with the STRIVE study. No new GEL, %2 93 (2 y) 91 The STRIVE study investigated cognitive impairments as measured by No new non-enhancing T1-hypointense lesions, %2 93 (2 y) 85 2 the Symbol Digit Modalities Test, health-related quality of life measured BV loss (median yearly BPF change), % -0.25 (2 y) -0.16 No additional treatment after 2 initial courses of alemtuzumab, %1,2 59 by the Multiple Sclerosis Impact Scale 29, and work capacity measured by the Work Productivity and Activity Impairment Questionnaire, in a 1. Coles AJ et al. MSParis2017. Abstract P1188. 2. Arnold DL et al. MSParis2017. Abstract P1189. JC virus antibody-negative cohort initializing natalizumab early in their disease course. In the CARE MS I and II studies, two courses of alemtuzumab demonstrated significantly greater improvements on clinical and MRI Data from this study presented at the MSParis2017 meeting showed outcomes versus subcutaneous interferon β-1a over 2 years in patients that after 2 years of natalizumab treatment, patients exhibited with active RRMS who were treatment naïve and had an inadequate significant improvements from baseline in their Symbol Digit response to prior therapy, respectively. Modalities Test cognitive scores. Similarly, patients exhibited significant improvements from baseline in their MSIS-29 physical score and In a recently completed 4-year extension study of these trials, patients quality-of-life scores. In addition, patients also showed improvements originally treated with alemtuzumab could receive as-needed from baseline in work capacity in terms of hours missed from work due alemtuzumab retreatment at 12 mg/day on 3 consecutive days at least to MS and daily activities affected by MS. 12 months after their previous course or a different disease-modifying therapy if they suffered a relapse or had two new spots on their MRI. Post Hoc Analysis of ASCEND Trial of Natalizumab in Patients With SPMS1 In addition, patients initially treated with subcutaneous interferon β-1a in the core CARE-MS I and CARE-MS II studies discontinued that therapy P = .020 Natalizumab and initiated alemtuzumab 12 mg for two courses—baseline 5 days and 24.5 25 Placebo 12 months later 3 days—in the extension study. They could also receive 20 19.18 as-needed alemtuzumab retreatment—12 mg/day on 3 consecutive 15 days at least 12 months after their previous course—or another disease- 10 P = .006 modifying therapy, if they suffered a relapse or new MRI activity. 5 2.58 Median AUC 0 -5 -1.59 Patients completing at least 48 months of the CARE-MS extension study a T25FW 9HPT could enroll in TOPAZ, a 5-year phase 3b/4 study, to further evaluate the a Average hand. 1. Giovannoni G et al. MSParis2017. Abstract 131. durable efficacy and long-term safety of alemtuzumab.

8 Go online to complete the post-test and evaluation for CME credit www.peerview.com/SQK900 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

So, let’s begin by looking at the data from TOPAZ from the CARE-MS I TOPAZ Phase 3b/4 Study: Year 7 Results for Patients Originally Cohort. Three hundred and forty-nine patients originally treated with Treated With Alemtuzumab in CARE-MS II alemtuzumab in CARE-MS I entered the extension. Three hundred and Year 0-2 Year 7 Outcome twenty-one remained on study until the end of year 6 and then entered CARE-MS II TOPAZ ARR1 0.28 (0-2 y) 0.14 TOPAZ, of whom 299 completed year 7. Improved or stable EDSS, %1 85 (2 y) 73 NEDA, %1 58 (2 y) 60 Alemtuzumab demonstrated durable clinical efficacy in patients No NEL, %2 76 (2 y) 67 with active RRMS who were treatment naïve. The majority of patients No new GEL, %2 91 (2 y) 90 maintained a low annualized relapse rate, showed stabilized or No new non-enhancing T1-hypointense lesions, %2 93 (2 y) 88 2 improved disability, and achieved NEDA each year. Alemtuzumab also BV loss (median yearly BPF change), % -0.22 (2 y) -0.14 No additional treatment after 2 initial courses of alemtuzumab, %1,2 47 resulted in a durable suppression of MRI disease activity over 7 years in the CARE-MS I patients. A durable reduction in brain volume loss 1. Singer B et al. MSParis2017. Abstract P736. 2. Pelletier D et al. MSParis2017. Abstract P741. was also observed with alemtuzumab treatment. Fifty-nine percent of patients had no additional treatment course after the two initial courses So let’s turn our attention to the data of TOPAZ from the CARE-MS II of alemtuzumab through year 7. cohort. Three hundred and ninety-three patients originally treated with alemtuzumab in CARE-MS II entered the extension. Three hundred and Alemtuzumab had a consistent safety profile through year 7, and the thirty-eight remained on study until the end of year 6, and 336 enrolled overall incidence of AEs decreased over time. in TOPAZ, of whom 317 completed year 7.

TOPAZ Phase 3b/4 Study: Year 5 Results for Patients Originally Alemtuzumab demonstrated durable clinical efficacy in patients Treated With SubQ IFN β-1a in CARE-MS I with active RRMS who had inadequate response to prior therapy. The

Alemtuzumab Year 5 majority of patients maintained a low annualized relapse rate, showing Outcome CARE-MS I Extension TOPAZ stabilized or improved disability, and achieved NEDA in each year. ARR1 0.11 (0-2 y) 0.09 Alemtuzumab also resulted in a durable suppression of MRI disease Improved or stable EDSS, %1 88.7 (1 y) 76.8 NEDA, %1 71 (2 y) 56 activity over 7 years in patients with active RRMS who had inadequate No NEL, %2 82 (2 y) 67 responses to prior therapy. A durable reduction in brain volume No new GEL, %2 96 (2 y) 89 loss—0.19% or less annually—was seen from year 3 through year 7. No new non-enhancing T1-hypointense lesions, %2 95 (2 y) 83 Forty-seven percent of patients had no additional treatment after the 2 BV loss (median yearly BPF change), % -0.15 (2 y) -0.13 two initial courses of alemtuzumab through year 7. No additional treatment after 2 initial courses of alemtuzumab, %1,2 71

1. Oreja-Guevara C et al. MSParis2017. Abstract P1190. 2. Rovira A et al. MSParis2017. Abstract P728. Alemtuzumab had a consistent safety profile through year 7, and the overall incidence of AEs decreased over time. Now let’s look at the data from TOPAZ from the cohort of patients who were treated with subcutaneous interferon β-1a over 2 years during the TOPAZ Phase 3b/4 Study: Year 5 Results for Patients Originally CARE-MS I core study. One hundred and thirty-nine patients who were Treated With SubQ IFN β-1a in CARE-MS II originally treated with subcutaneous interferon β-1a in the CARE-MS Alemtuzumab Year 5 Outcome I initiated alemtuzumab in the extension study. Of these patients, 122 CARE-MS II Extension TOPAZ ARR1 0.15 (0-2 y) 0.18 remained on study and then entered TOPAZ, of whom 118 completed Improved or stable EDSS, %1 73.8 (1 y) 67.0 year 5. NEDA, %1 66 (2 y) 55 No NEL, %2 81 (2 y) 67 Alemtuzumab demonstrated durable clinical efficacy over 5 years No new GEL, %2 92 (2 y) 85 in patients with active RRMS who were previously treated with No new non-enhancing T1-hypointense lesions, %2 93 (2 y) 88 2 subcutaneous interferon β-1a during CARE-MS I. The majority of BV loss (median yearly BPF change), % -0.04 (2 y) -0.08 No additional treatment after 2 initial courses of alemtuzumab, %1,2 61 patients maintained a low annualized relapse rate, showed stabilization or improvement of disability, and achieved NEDA in each year after 1. Van Wijmeersch B al. MSParis2017. Abstract P1194. 2. Pelletier D et al. MSParis2017. Abstract P724. initiation of alemtuzumab. Alemtuzumab also resulted in a durable suppression of MRI disease activity over 5 years in patients who were Now let’s look at the data of TOPAZ from the cohort of patients who previously treated with subcutaneous interferon β-1a during CARE-MS I. were treated with subcutaneous interferon β-1a over the 2 years of Seventy-one percent of patients had no additional treatment after the 2 CARE-MS II core study. initial courses of alemtuzumab through year 5. Alemtuzumab demonstrated durable clinical efficacy over 5 years Alemtuzumab has a consistent safety profile through year 5 in patients in patients with active RRMS who were previously treated with previously treated with subcutaneous interferon β-1a, and the overall subcutaneous interferon β-1a during CARE-MS II. The majority of incidence of AEs decreased over time. patients also maintained a low annualized relapse rate, showed stabilization or improved disability and achieved NEDA each year

9 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris after initiating alemtuzumab. Alemtuzumab also resulted in a durable DECIDE and EXTEND Trials: Sustained Efficacy1 suppression of MRI disease activity over 5 years in patients who were previously treated with subcutaneous interferon β-1a during CARE-MS Effects on clinical outcomes, MRI II. Alemtuzumab also durably slowed brain volume loss in the absence outcomes, and PBVC were of continuous treatment in patients who were previously treated with maintained during prolonged daclizumab treatment (up to 6 years) subcutaneous interferon β-1a during CARE-MS II. in the EXTEND study, and patients on IM IFN β-1a in DECIDE who switched to daclizumab in EXTEND showed improved outcomes with daclizumab Alemtuzumab had a consistent safety profile through year 5 in patients over up to 3 years previously treated with interferon -1a, and the overall incidence of AEs β In DECIDE/EXTEND, incidence of AEs evaluated at 1-year intervals remained decreased over time. stable and consistent with previous observations; autoimmune hemolytic anemia identified as new safety risk2 These findings are consistent in demonstrating greater improvements 1. Kappos L et al. MSParis2017. Abstract P731. 2. Cohan S et al. MSParis2017. Abstract 206. in outcomes based on alemtuzumab versus subcutaneous interferon β-1a over the 2 years of CARE-MS I, and durable improvements in Additional data on daclizumab show the effects of clinical outcomes alemtuzumab arm over 5 years in the absence of continuous treatment. and brain volume change were maintained during prolonged daclizumab treatment up to 6 years in the EXTEND study, and patients who switched from interferon β-1a in DECIDE to daclizumab in EXTEND DECIDE Trial: Subgroup Analysis1 showed improved outcomes over a 3-year period on daclizumab NEDA Status Wk 24-96 By Subgroup for Daclizumab and IM IFN β-1a treatment.

In the DECIDE/EXTEND combined treatment period in which some patients received daclizumab for greater than 5 years, the incidence of AEs remained stable when evaluated at 1-year intervals. Despite the addition of autoimmune hemolytic anemia as a new safety risk, the safety profile remained consistent with previous observations and, together with EXTEND efficacy data, supports a continued favorable

a Highly active disease activity defined as ≥2 relapses long-term risk/benefit profile of daclizumab in relapsing MS. in year before randomization and ≥1 GEL at BL on MRI. 1. Giovannoni G et al. MSParis2017. Abstract P695. Pooled Data From OPERA I and OPERA II Trials: Moving on, let’s look at some updates on daclizumab. In the DECIDE Ocrelizumab vs SubQ IFN β-1a in Patients With Relapsing MS trial, significantly more patients treated with daclizumab 150 mg Visual Outcome1 Ocrelizumab IFN β-1a achieved NEDA as compared to intramuscular interferon β-1a over 2 Mean ∆ from BL in # letters correctly identified on LCLA at 1.355 0.012 years, with the benefits being more pronounced between weeks 24 2.5% contrast (ITT population, 96 wk) P = .03 and 96. Mean ∆ from BL in # letters correctly identified on LCLA at 3.440 -0.470 2.5% contrast (visual impairment at BL subgroup, 96 wk) P < .001

In the 7th Joint ECTRIMS-ACTRIMS meeting in Paris, Giovannoni and Pooled data from the OPERA trials also showed • Ocrelizumab reduces disability progression independent of relapse activity in patients with colleagues examined the influence of baseline characteristics on relapsing MS2 • Treatment benefit of ocrelizumab vs IFN β-1a, as measured by either ARR3 or proportion of achieving NEDA in patients receiving daclizumab versus intramuscular patients reaching NEDA status,4 was maintained across all subgroups and strata interferon β-1a in DECIDE. The results of the analysis demonstrated 1. Balcer L et al. MSParis2017. Abstract 192. 2. Kappos L et al. MSParis2017. Abstract P654. that daclizumab has greater benefit on achieving NEDA versus 3. Papeix C et al. MSParis2017. Abstract P687. 4. Turner B et al. MSParis2017. Abstract P688. intramuscular interferon β-1a across clinically important subgroups, with a higher odds of achieving NEDA being observed for lower EDSS Now let’s shift our focus on to ocrelizumab. Several updates from and lower MRI burden at baseline. the OPERA I and OPERA II trials, which compared ocrelizumab with subcutaneous interferon β-1a in patients with relapsing MS, were presented at the 7th Joint ECTRIMS-ACTRIMS meeting in Paris.

For example, pooled data from the OPERA I and II studies showed ocrelizumab was associated with improved visual outcomes as assessed by low-contrast letter acuity tested in patients with relapsing MS, particularly in those with visual impairment at baseline, compared to interferon β-1a. Pooled data from the OPERA trials also showed that ocrelizumab reduces disability progression independent from relapse activity in patients with relapsing MS.

10 Go online to complete the post-test and evaluation for CME credit www.peerview.com/SQK900 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

Moreover, subgroup analyses showed the treatment benefits of ocrelizumab versus interferon β-1a—as measured by annualized relapse rate and the proportion of patients achieving NEDA status— were maintained across all subgroups and strata, and were consistent with the findings of the overall pooled OPERA I and OPERA II populations.

Updates From ORATORIO Trial: Ocrelizumab in Patients With PPMS

Time to Onset of CDP During Double-Blind and Extended Controlled Periods1 12-Week Confirmed 24-Week Confirmed

↓ risk of progression of upper extremity disability Safety profile in MS all-exposure population with ocrelizumab vs placebo in patients with consistent with controlled treatment period in relapsing MS and PPMS populations3 PPMS, as measured by 9-hole peg test2 • Rate of malignancies in ocrelizumab-treated patients within range reported in epidemiological data and clinical trials 1. Wolinsky J et al. MSParis2017. Abstract 1234. 2. Fox EJ et al. MSParis2017. Abstract P1236. 3. Hauser RL et al. MSParis2017. Abstract P659.

Looking at updates from the ORATORIO trial, we saw the significant and clinically meaningful benefit of reducing disability progression seen with ocrelizumab in patients with primary progressive MS persists and is durable with ongoing treatment. Ocrelizumab treatment lowered the risk of progression of upper extremity disability, as measured by the nine-hole peg test, compared with placebo in patients with PPMS.

Lastly, the updated safety profile in the ocrelizumab MS all-exposure population is generally consistent with that seen during the controlled treatment period in the relapsing MS and PPMS populations. Importantly, the rate of malignancies in ocrelizumab-treated patients remained within the range reported in epidemiologic data and clinical trials of MS.

As I review data on monoclonal antibodies in MS, I’m impressed by an evolution in our very expectations of what we get out of these drugs. Years ago, we talked about reducing the frequency of attacks or reducing the disability progression or reducing the number of spots on an MRI. These days, we’re talking about no evidence of disease activity, confirmed disability improvements, and normalization of brain volume. This is an exciting time to be treating MS.

11 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

Data on Emerging Therapies for MS In SUNBEAM, patients were randomized 1:1:1 to receive once-daily oral ozanimod 0.5 mg or 1 mg, or weekly interferon β-1a for 12 months.

Phase 3 RADIANCE Part B: Ozanimod vs IM IFN β-1a The results of this trial showed that, compared to interferon β-1a, both in Patients With Relapsing MS1 doses of ozanimod significantly reduced annualized relapse rates, the

Ozanimod 0.5 mg number of new or enlarged T2 lesions, and the number of gadolinium- 60 e Ozanimod 1.0 mg d 53 enhanced lesions. Significant reductions were seen in cortical gray b 47 50 b 42 38 c volume loss and thalamic volume loss for both doses of ozanimod, and 1a, % 40 34 - b b β a 25 27 30 21 for total brain volume loss in the 1 mg dose only. 20

IM IFN 10 Net Reduction vs vs Reduction Net 0 Unfortunately, no significant difference in the time to 3-month ARR NEL GEL Normalized BV Loss • In general, ozanimod was very well tolerated confirmed disability progression was noted with either ozanimod dose – No patients had a 2nd degree or higher AV block – Infection risk comparable to with IFN β-1a as compared to interferon β-1a in the pooled analysis of the RADIANCE – ALT increases were transient and generally resolved without study drug discontinuation Part B and SUNBEAM trials. a P = .0167; b P < .0001; c P = .0001; d P = .003; e P = .0006. 1. Cohen JA et al. MSParis2017. Abstract 280. The safety profile of ozanimod observed in SUNBEAM was similar to Dr. Boster: Now let’s evaluate data on a few emerging therapies under that observed in RADIANCE Part B. investigation for the treatment of relapsing MS. EVOLVE-MS-1: Global, Open-Label, Phase 3 Study Ozanimod is an oral selective sphingosine 1-phosphate receptor of Long-Term Safety of ALKS 8700 in RRMS modulator in development for relapsing MS. At the 7th Joint ECTRIMS-

ACTRIMS Meeting in Paris, the results of the phase 3 RADIANCE Part Preliminary data from this ongoing trial showed ALKS 8700 (462 mg, B and SUNBEAM trials, which compared ozanimod to interferon β-1a twice daily PO) is generally well tolerated, with a low rate of GI AEs and no serious GI AEs observed during the month of treatment1 intramuscular, were presented. Both studies were randomized, double- blinded, double-dummy, active-controlled, parallel-group studies in patients with relapsing MS. Long-term results from this study and the EVOLVE-MS-2 trial will provide safety and tolerability data on the use of ALKS-8700 in patients with RRMS2 In RADIANCE Part B, patients were randomly assigned 1:1:1 to receive once-daily oral ozanimod 0.5 mg or 1 mg, or weekly intramuscular interferon β-1a for a period of 24 months. The primary outcome was 1. Naismith R et al. MSParis2017. Abstract P1170. 2. Naismith R et al. MSParis2017. Abstract P708. annualized relapse rate at 24 months. ALKS 8700 is a prodrug of monomethyl fumarate—MMF—that is The results of this trial showed that, compared to intramuscular rapidly converted to MMF, the active metabolite in dimethyl fumarate interferon β-1a, both doses of ozanimod significantly reduced that’s being developed for the treatment of RRMS. annualized relapse rate, the number of new and enlarged T2 lesions, and the number of gadolinium-enhanced lesions. Significantly reduced EVOLVE-MS-1 is a global, interventional, open-label, phase 3 study brain volume loss, cortical gray volume loss, and thalamic volume loss evaluating the long-term safety of ALKS 8700 in about 930 patients with was also observed. RRMS.

In general, ozanimod was very well tolerated. No subjects had a Preliminary data from the ongoing trial presented in Paris showed that second-degree or higher AV block. The infection risk with ozanimod ALKS 8700 is generally well tolerated, with a low rate of GI AEs, and was comparable to interferon β-1a. no serious GI AEs were observed during the first month of treatment. Long-term results from this study and the EVOLVE-MS-2 trial will SUNBEAM Trial: Ozanimod vs IM IFN β-1a in Patients provide safety and tolerability data on the use of ALKS 8700 in patients With Relapsing MS1 with RRMS.

100 Ozanimod 0.5 mg

80 b Ozanimod 1.0 mg 63

1a, % b b - 60 48 48 β a d b 40 31 c 34 33 25 17.8

IM IFN 20 12

Net Reduction vs Net Reduction vs 5.0 0 e ARR NEL GEL Whole BV Loss 3 mo-CDP • Similar to RADIANCE Part B, ozanimod was very well tolerated – No patients had a 2nd degree or higher AV block – Infection risk comparable to with IFN β-1a – ALT increases were transient and generally resolved without study drug discontinuation a P = .0013; b P < .0001; c P = .0032; d P = .0182. e Pooled analysis of RADIANCE Part B and SUNBEAM. 1. Comi G et al. MSParis2017. Abstract 232.

12 Go online to complete the post-test and evaluation for CME credit www.peerview.com/SQK900 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

CLARITY Subgroup and Post Hoc Analyses: The SYNERGY trial was a phase 2, 72-week, parallel-group, dose-ranging Oral Cladribine in RRMS study designed to assess the efficacy and safety of the anti-LINGO • In a subgroup analysis of CLARITY, cladribine produced statistically significant monoclonal antibody opicinumab versus placebo in relapsing forms effects vs placebo on GEL, active T2 lesions, and cumulative combined-unique lesions in patients with high disease activity1 of MS when used concurrently with interferon β-1a intramuscular. A • In addition, a post hoc analysis showed that compared with the overall CLARITY statistically linear dose response was not observed with opicinumab study population, high disease activity subgroups had higher odds of achieving NEDA with cladribine vs placebo2 versus placebo. An analysis showed an inverted U-shape opicinumab • Data from CLARITY, its extension study, and the PREMIERE registry showed that dose response, with more favorable outcomes in the 10 and 30 mg/kg lymphocyte recovery begins soon after treatment with cladribine in year 1 and year 2 in patients with MS3 dose groups. • In addition, data from an integrated safety analysis of oral cladribine clinical trials showed severe lymphopenia resulted in an increased frequency of infections, but did not have any differential effect on the type of infectious AEs4 However, a post-hoc analysis presented in Paris identified a potential patient subpopulation who may benefit from opicinumab treatment. 1. Giovannoni G et al. MSParis2017. Abstract P1164. 2. Giovannoni G et al. MSParis2017. Abstract P1143. 3. Soelberg-Sorenson P et al. MSParis2017. Abstract P655. 4. Cook S et al. MSParis 2017. Abstract P1142. The consistency of findings across clinical and MRI endpoints in this subpopulation together suggest that opicinumab could be developed The efficacy of cladribine tablets 3.5 mg/kg—cumulative dose given in as an add-on therapy to disease-modifying therapies. short courses annually for 2 years—has been demonstrated in patients with early MS in the ORACLE-MS study and in patients with RRMS in Updates on Siponimod: New Data From EXPAND Study the CLARITY study, which was maintained in the CLARITY extension in Patients With SPMS study. The most common AEs in CLARITY and its extension were Adjusted Mean Differences in ∆ From BL vs Placebo1 lymphopenia. MRI Endpoint Per-Protocol-Analysis Set Full-Analysis Set T2LV at mo 12, mm3 -613 -634 A large number of posters on cladribine were recently presented at the T2LV at mo 24, mm3 -778 -830 7th Joint ECTRIMS-ACTRIMS meeting. For example, a subgroup analysis PBVC at mo 12, % 0.175 0.221 PBVC at mo 24, % 0.128 0.277 of CLARITY showed cladribine produced statistically significant effects versus placebo on gadolinium-enhanced lesions, active T2 lesions, • In addition, an exploratory multistate model indicated siponimod reduces risk of CDP independently from on-study relapses2 and cumulative combined-unique lesions in patients with high disease activity.

1. Fox R et al. MSParis2017. Abstract 129. 2. Kappos L et al. MSParis2017. Abstract P782. In addition, a post-hoc analysis showed that, compared to the overall CLARITY study population, the high disease activity subgroup had Now let’s discuss some therapies that are currently under investigation higher odds of achieving NEDA with cladribine versus placebo. for the treatment of progressive forms of MS.

Moreover, data from CLARITY, its extension study, and the PREMIERE The EXPAND study demonstrated that siponimod, a selective registry shows that lymphocyte recovery begins soon after treatment modulator of sphingosine 1-phosphate receptor types 1 and 5, with cladribine tablets in year 1 and year 2 in patients with MS. significantly delayed confirmed disability progression in patients with SPMS. In addition, data from the integrated safety analysis of cladribine tablets clinical trials showed severe lymphopenia resulted in an increased Additional data from the trial presented at the 7th Joint ECTRIMS- frequency of infections, but did not have any differential effect on the ACTRIMS meeting showed siponimod significantly reduced MRI type of infectious AEs. activity and slowed brain volume loss in patients with SPMS already at month 12, and effects were sustained at month 24. In addition, an SYNERGY Trial Post Hoc Analysis: Predictors of Opicinumab exploratory, multistate model indicated that siponimod reduces the Treatment Effect and Identification of Efficacy Subpopulation1 risk of confirmed disability progression independently from on-study

Improved Disability Worsening Disability BL characteristics relapses. predictive of greater and more durable treatment response to opicinumab: 1. Shorter disease duration (≤20 years) 2. Baseline MTR values in pre-existing T2 lesions, which may be consistent with relative myelin loss 3. Baseline DTI-RD values in pre-existing T2 The post hoc subpopulation also showed increased MTR values lesions, which may be and reduced DTI-RD values in pre-existing T2 lesions and reduced consistent with relative brain atrophy in the opicinumab 10 mg/kg group vs placebo group, structural integrity when compared with the SYNERGY efficacy population

1. Sheikh S et al. MSParis2017. Abstract P718.

Now let’s discuss some emerging monoclonal antibodies for the treatment of relapsing MS.

13 Potential Clinical Implications of the Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

MD1003 in Progressive MS: Most AEs with GLD52 were mild infusion- or administration-related 24-Month Brain MRI Results of MS-SPI Trial1 reactions. The absence of severe serious infusion- or administration- • At 12 months, decreases in WBV and GMV measures were observed in related AEs with or without steroid premedication was consistent with MD1003 arm vs placebo arm an improved tolerability profile. – Differences statistically significant for WBV and GMV % change – No differences observed for WMV % change Further studies will characterize lymphocyte repopulation and the • At 24 months, change from BL in WBV, GMV, and WMV were relatively constant in the MD1003 group that continued on treatment, compared potential of GLD52 to rebalance the immune system. with month 12 – Placebo group experienced a decrease across all volumetric measures Only a few years back, 1993, the very first MS disease-modifying therapy when switched to MD1003 at month 12  maintained for 12 months  At 24 months, similar decreases observed in placebo/MD1003 and hit the market. Look where we are now. There has never been a better MD1003/MD1003 groups time to be beating up on MS than today. And we have just seen an 1. Arnold D et al. MSParis2017. Abstract 130. exciting wave of new therapies, which we’ll be testing over the next several years. It’s a great time to be fighting against MS. Now let’s discuss MD1003. MS-SPI was a 12-month, randomized, double-blind, placebo-controlled trial studying the effects of Conclusions MD1003—high-dose biotin—in patients with progressive, non- clinically active MS. In this open-label extension, all patients received • Recently presented data continue to add to our breadth of knowledge on the MD1003. efficacy and safety of conventional injectable DMTs for relapsing MS • New analyses of recent clinical trials and their extension studies provide new insight into the long-term efficacy and safety of approved oral DMTs, as well as In the MSParis2017 meeting, the results of the brain volumetric their impact on patient-report outcomes MRI follow-up substudy showed volumetric analyses performed • Late-breaking data on approved monoclonal antibodies provide additional independently and blindly by two different reading centers indicated understanding of their potential benefits with respect to their effectiveness in early disease, durable efficacy, and safety a decrease in the loss of brain volume and gray matter volume in the • A number of emerging DMTs are in various stages of development for treatment MD1003 arm as compared to placebo. A decrease in the loss of these of relapsing or progressive forms of MS; it has not yet been determined how volumes was also observed in the placebo group switching to MD1003. these potential advances might fit into the current treatment landscape No difference between groups was observed at month 24, after the placebo arm had been switched to active treatment. Recently presented data continue to add to our breadth of knowledge GLD52: Assessment of T- and B-Lymphocyte Depletion From a on the efficacy and safety of conventional injectable DMTs for relapsing Single Ascending-Dose Trial in Patients With Progressive MS1 MS. New analyses of recent clinical trials and their extension studies GLD52: next-generation humanized anti-CD52 mAb being assessed for treatment of MS; provide new insights into the long-term efficacy and safety of approved targets an epitope that is distinct but overlapping with that targeted by alemtuzumab oral disease-modifying therapies.

Late-breaking data on approved monoclonal antibodies provide additional understanding in the potential benefits of these therapies with respect to their effectiveness in early disease, durable efficacy and safety in patients with MS.

There are also a number of emerging disease-modifying therapies in 1. Margolin DH et al. MSParis2017. Abstract P682. various stages of development for the treatment of either relapsing or progressive forms of MS. It has not yet been determined how these And finally, GLD52 is a next-generation, humanized, anti-CD52 potential advances might fit into the current treatment landscape. monoclonal antibody being assessed for the treatment of MS. GLD52 targets an epitope that is distinct but overlapping with the epitopes That ends our discussion for today. I hope you found it informative and targeted by alemtuzumab. useful in your practice. I encourage you to download the slides and practice aids from this activity, which include summaries of additional At the 7th Joint ECTRIMS-ACTRIMS meeting, data from a randomized, data not discussed during this presentation. Thank you. single-ascending-dose trial in patients with progressive MS was presented. The results of this study showed both IV and subcutaneous Narrator: This activity has been jointly provided by Medical Learning GLD52 induced robust, dose-dependent T- and B-lymphocyte Institute, Inc. and PVI, PeerView Institute for Medical Education. depletion in a pattern similar to that of alemtuzumab.

14 Go online to complete the post-test and evaluation for CME credit www.peerview.com/SQK900 Potential Clinical Implications of the CME Latest Data on Approved and Emerging Disease-Modifying Therapies for Multiple Sclerosis: A Recap From Paris

Expert commentary is based on data presented at the 7th Joint Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS)*

*PeerView is an independent publisher of conference news and medical education programs.

This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. This activity is supported by educational grants from Biogen and Sanofi Genzyme.

New and improved source www.peerview.com/SQK900 for free CME/CE