1. © 2014 Direct One Communications, Inc. All rights reserved. 1 A New Era of Therapy in Multiple Sclerosis: Balancing the Options and Challenges Ahead Jennifer L. Orthmann-Murphy, MD, PhD Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania A REPORT FROM THE 29TH CONGRESS OF THE EUROPEAN COMMITTEE FOR TREATMENT AND RESEARCH IN MULTIPLE SCLEROSIS (ECTRIMS 2013)

2. © 2014 Direct One Communications, Inc. All rights reserved. 2 Introduction Disease-modifying therapy for patients with relapsing remitting multiple sclerosis (RRMS) has become increasingly complicated with the recent explosion in approved immunomodulatory drugs. It is not yet known which medication is best for which patient, at which point in the disease process. Based upon nearly two decades of experience with beta interferons, it is clear that early intervention modifies the disease course, but no current treatment has been shown to prevent or reverse disability accumulation in the long term.

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Timeline of Development of Interferon Beta Adapted, with permission, from a presentation by Peter A. Calabresi, MD, at ECTRIMS 2013

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 First-Line Therapy for RRMS

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 Targeted Immunomodulation

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Milestones in Development of Natalizumab Adapted, with permission, from Rudick R et al, JAMA Neurol 2013;70:172

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Risk Stratification for PML in MS Patients Treated with Natalizumab Adapted, with permission, from Bloomgren G et al, N Engl J Med 2012;366:1870

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Are We Ready for a Treatment Algorithm? It is clear from the available evidence that we should diagnose and treat multiple sclerosis early. The revised 2010 McDonald criteria enable earlier diagnosis of RRMS and intervention. However, newly diagnosed patients may be more like patients in early clinical trials with clinically isolated syndrome, rather than RRMS. Patients with a poor prognosis need to be singled out for more aggressive intervention. Polman CH et al, Ann Neurol 2011;69:292

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Factors Linked to a Higher Risk of More Aggressive Disease at Diagnosis Relapse severity » One or more moderate or severe attacks » Corticosteroids and/or hospitalization needed » Activities of daily living severely affected » More than one functional system affected » Severe motor/cerebellum/brainstem involvement Incomplete recovery from relapse Older age Fox EJ, Rhoades RW, Curr Opin Neurol 2012;25:S11

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 Factors Linked to a Higher Risk of More Aggressive Disease at Diagnosis Magnetic resonance imaging findings » Two or more gadolinium-enhancing/new T2 lesions » Two or more T1 hypointense lesions » Two or more spinal cord lesions » Brain atrophy Male gender African-American ethnicity Fox EJ, Rhoades RW, Curr Opin Neurol 2012;25:S11

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 Are We Ready for a Treatment Algorithm? Currently available disease-modifying agents for treating RRMS may be ranked as: » First-line therapies (interferon beta or glatiramer acetate) versus second-line therapies (all others) » Low, medium, or highly effective agents Clinician and patient need to identify treatment goals (relapse reduction, MRI burden prevention, disease freedom) and balance patient preference (risk stratification).

12. © 2014 Direct One Communications, Inc. All rights reserved. 12 Identifying Treatment Nonresponders It is critical to identify early whether an intervention is not working. The modified Rio Score is an evidence-based algorithm that incorporates three tools: » Expanded Disability Status Scale (EDSS) score » Accumulation of MRI lesion burden, and » Clinical reports of relapses Biomarkers of response to therapy (eg, brain atrophy on imaging; cerebrospinal fluid and serum markers) as well as consistent tools for identifying physical and cognitive changes over time are needed. Sormani MP, De Stefano N, Nat Rev Neurol 2013;9:504

13. © 2014 Direct One Communications, Inc. All rights reserved. 13 The Future: Remyelination LINGO-1 is expressed by neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) and is a negative regulator of both oligodendrocyte differentiation and myelination. Anti–LINGO-1 antibody led to OPC differentiation, improving remyelination and functional recovery in several murine models of demyelination. In a phase 1 study, IV administration of the antibody was safe and could access the CSF of healthy controls and patients with RRMS or secondary progressive MS at levels that were deemed likely to be efficacious. Two phase 2 trials currently are underway. Adapted from a presentation by Alfred Sandrock, MD, at ECTRIMS 2013