1. © 2014 Direct One Communications, Inc. All rights reserved. 1 Controversies in the Treatment of Multiple Sclerosis Sara S. Qureshi, MD The University of Texas Southwestern Medical School, Dallas, Texas A REPORT FROM THE 28 TH ANNUAL MEETING OF THE CONSORTIUM OF MULTIPLE SCLEROSIS CENTERS AND THE 19 TH ANNUAL MEETING OF THE AMERICAS COMMITTEE FOR TREATMENT AND RESEARCH IN MULTIPLE SCLEROSIS

2. © 2014 Direct One Communications, Inc. All rights reserved. 2 Should DMTs Be Stopped in Patients With Secondary Progressive MS (SPMS)?

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Age at Onset and Time to Transition Patients who transitioned to SPMS several years ago and who have no evidence of relapses or MRI activity have not benefitted from continuing therapy. In 1998, a European study of alternate-day dosing with interferon  -1b versus placebo in patients with SPMS showed a significant delay in time to confirmed progression in the active treatment arm. Two years later, the North American Study Group released results on the use of two doses of interferon  -1b versus placebo; no treatment benefit was seen in terms of time to confirmed progression of disability. Kappos L et al. Neurology. 2001;57:1969; Goodkin DE et al. Neurology. 2000;54(suppl):2352.

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 Age at Onset and Time to Transition continued However, the European study involved younger patients who more recently were affected by MS and who had more quickly transitioned to SPMS. These studies had different outcomes probably because the study populations differed in time since onset of MS and progression to SPMS. Thus, the demographics of the patient population are an important consideration in interpreting studies of drug treatments for patients who have transitioned to SPMS, and disease-modufying therapies (DMTs) are more likely to work in younger patients with a more recent onset of MS and transition to SPMS. Kappos L et al. Neurology. 2001;57:1969; Goodkin DE et al. Neurology. 2000;54(suppl):2352.

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 Studies of Interferon  -1a in SPMS In 2001, the SPECTRIMS study group examined the effect of interferon  -1a in patients with SPMS. This multicenter study involved 22 centers in Europe, Canada, and Australia. The results failed to show a significant impact on time to sustained progression of disability. Subgroup analyses suggested a maximal benefit among women and patients still experiencing relapses when treatment was started. Thus, interferon  -1a treatment for such patients is reasonable. SPECTRIMS Study Group. Neurology. 2001;56:1496

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Studies of Interferon  -1a in SPMS continued In the IMPACT trial of interferon  -1a versus placebo, the primary outcome measure was the Multiple Sclerosis Functional Composite (MSFC), which consists of quantitative tests of ambulation, arm function, and cognition. The change in MSFC was significantly smaller in the active treatment arm; however, no significant effect on EDSS scores was observed in the IMPACT study. Thus, the EDSS may be not be a particularly sensitive measure of disability, and other large-scale studies are needed to explore the utility of the MFSC as an outcome measure in SPMS. Cutter GR et al. Brain. 1999;122:871; Schwid SR et al. Neurology. 2000;55:1901

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Mitoxantrone in Progressive MS A multicenter, randomized, double-blind, placebo- controlled study (MIMS trial) investigating the use of mitoxantrone in patients with SPMS and progressive relapsing MS showed significant treatment effects only at the higher dose (12 mg/m²) for: » Improvement in EDSS score » Improvement in ambulation index » Reduction in number of relapses treated with corticosteroids » Extension of time to first relapse » Improvement in standardized neurologic status However, these results need to be viewed with caution because of the heterogeneity of the study population. Hartung HP et al. Lancet. 2002;360:2018

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Conclusions Treatment should be continued in patients with SPPMS who are experiencing ongoing relapses or who show evidence of MRI activity. There is no convincing evidence that DMTs should be continued in SPMS patients whose disease has progressed for several years and who have no clinical or radiologic evidence of inflammation. More sensitive outcome measures than the EDSS score, such as the composite MSFC score, are needed for assessing disease activity in patients with SPMS. Larger systematic trials are needed to study the effects of continuing or stopping DMT in SPMS patients.

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 First-Line Oral or Parenteral DMTs in Relapsing MS?

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 The Case for Oral DMT Therapy Oral DMTs are preferable to injectable agents for first-line therapy in newly diagnosed RRMS patients based on clinical trial evidence of their: » Superior efficacy in terms of reduction in relapse rate, MRI activity, and disability » Better adherence to treatment » Patient preference In one retrospective study, RRMS patients started on fingolimod therapy were more compliant and less likely to discontinue treatment than were patients who started treatment using self-injected DMTs. They also tended to discontinue therapy later. Agashivala N et al. BMC Neurol. 2013,13:138

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 The Case for Oral DMT Therapy continued Use of injectable DMTs has been linked to flu-like symptoms, injection-site reactions, and lipoatrophy. Patients with RRMS should be treated on a case-by- case basis, with consideration for their unique characteristics and preferences. Oral DMTs often are the preferable therapeutic option for first-line treatment of RRMS in terms of adherence, side-effect profile, and cost.

12. © 2014 Direct One Communications, Inc. All rights reserved. 12 The Case Against Oral DMT Therapy Injectable DMTs are considered to be first-line agents by insurance companies, and a less-expensive generic form of glatiramer acetate may soon be available. Serious side effects rarely occur with the use of injectable DMTs. Some patients prefer receiving once-weekly injections of interferon  -1a to swallowing oral medications once or twice a day. Pegylated interferon needs to be injected not more than once every 14 days.

13. © 2014 Direct One Communications, Inc. All rights reserved. 13 The Case Against Oral DMT Therapy continued Oral agents, especially dimethyl fumarate, have serious tolerability issues—mainly flushing, rash, and gastrointestinal symptoms—that must be considered. Treatment with fingolimod has been associated with adverse cardiovascular effects, skin cancer, and macular edema. Teriflunomide therapy involves the risk of hepatic failure and requires the use of contraception if the patient is of child-bearing age. Given their proven safety, cost, availability, and side- effect profile, injectable DMTs remain good first-line agents for RRMS patients.

14. © 2014 Direct One Communications, Inc. All rights reserved. 14 Is Alemtuzumab Too Toxic for Use in Most MS Patients?

15. © 2014 Direct One Communications, Inc. All rights reserved. 15 Current Status of Alemtuzumab Alemtuzumab is a recombinant humanized monoclonal antibody that targets CD52, a cell- surface glycoprotein present on all T and B lymphocytes, monocytes, and eosinophils. It is currently approved in the United States for the treatment of B-cell chronic lymphocytic leukemia. Alemtuzumab is approved in Europe, Canada, Australia, and parts of Central and South America for the treatment of RRMS. It is currently under review by the FDA for the treatment of relapsing forms of MS.

16. © 2014 Direct One Communications, Inc. All rights reserved. 16 Efficacy of Alemtuzumab in RRMS In three randomized clinical trials, alemtuzumab significantly reduced the risk of clinical relapse by 49%–69% when compared with interferon  -1a. Alemtuzumab also appeared to reduce the risk of accumulation of significant disability when compared with interferon β-1a, but the evidence was less convincing than for the reduction in relapse rate. Treatment with alemtuzumab in the CAMMS-223 and CARE-MS II trials resulted in 71% and 42% fewer patients, respectively, who acquired fixed disabilities during each trial. Coles AJ et al. Neurology. 2012;78:1069; Cohen JA et al. Lancet. 2012;380:1819; Coles AJ et al. Lancet. 2012;380:1829

17. © 2014 Direct One Communications, Inc. All rights reserved. 17 Risks of Using Alemtuzumab Some of the adverse effects of alemtuzumab, such as severe infusion reactions and an increased risk of infection, malignancy, and other autoimmune diseases, could be life-threatening. Between 16% and 23% of alemtuzumab-treated patients with relapsing MS enrolled in the pivotal clinical trials developed thyroid disorders. One fatality due to immune thrombocytopenic purpura, two cases of Goodpasture’s syndrome, and one fatal case of Burkitt’s lymphoma, along with a clustering of thyroid cancer cases, were reported. Coles AJ et al. Neurology. 2012;78:1069; Cohen JA et al. Lancet. 2012;380:1819; Coles AJ et al. Lancet. 2012;380:1829

18. © 2014 Direct One Communications, Inc. All rights reserved. 18 Do the Benefits Outweigh the Risks? Based on its superior efficacy and acceptable safety profile in MS patients with aggressive disease, alemtuzumab could be considered a therapeutic alternative to natalizumab in patients with refractory MS, possibly as induction therapy. However, given the risk for serious and potentially fatal adverse effects, including an increased risk of malignancy (especially melanoma) and the severity of infusion reactions associated with the drug, the potential for harm may outweigh its benefits. The long half-life of alemtuzumab (mean, 6.1 days after repeated dosing) is a further complication. Menge T et al. Neurology. 2014;83:87; Hale G et al. Blood. 2004;104:948