Achieving Therapeutic Goals with Current Treatments

1. Achieving Therapeutic Goals with Current Treatments

2. ARS Polling Which of the following is not recommended as a first-line treatment for a patient with relapsing-remitting MS? • Interferon beta-1b 250 mcg SC QOD • Natalizumab 300 mg IV monthly infusion • Glatiramer acetate 20 mg SC QD • Interferon beta-1a 44 mcg SC TIW or 30 mcg IM weekly

3. Therapeutic Goals in MS In the absence of a cure for MS, current goals of disease modifying therapy are to Prevent disability Prevent relapses Prevent development of new or enhancing lesions on MRI Additional goals in the management of MS are to Relieve symptoms Maintain well-being Optimize quality of life

4. Treating Acute Relapse IV corticosteroids = standard of care Methylprednisolone 500 to 1000 mg/d IV for 3 to 5 days May be followed by oral steroid taper High-dose oral steroids may be acceptable alternative Phase III randomized OMEGA trial currently comparing oral and IV steroids Plasmapheresis and IVIG for refractory relapse

5. Therapeutic Targets in MS

6. FDA-ApprovedDisease-Modifying Agents First line: • Interferon beta • Interferon beta-1b 250 mcg SC QOD (two brands) • Interferon beta-1a 44 mcg SC TIW • Interferon beta-1a 30 mcg IM weekly • Glatiramer acetate • 20 mg SC QD Second line: • Mitoxantrone • 12 mg/m2 over 5 to 15 min q3mo; lifetime max, 144 mg/m2 • Natalizumab • 300 mg IV monthly infusion

7. Current First-Line MS Therapies Interferon beta-1a, interferon beta-1b, glatiramer acetate Interferons are FDA approved for relapsing forms of MS Glatiramer acetate is FDA approved for RRMS Similar efficacy for relapse rate reduction ~ 30% Generally very safe and well tolerated All require self-injection

8. Mechanisms of Action for Interferons Reduction of proinflammatory cytokine secretion Promotion of anti-inflammatory cytokine secretion Stabilization of blood-brain barrier Enhancement of regulatory T cell activity Downregulation of antigen presentation to T cells

9. Mechanisms of Action for Glatiramer Acetate Competitive inhibition of antigen presentation (myelin basic protein) to autoreactive T cells Activates regulatory T cells Promotes Th1 to Th2 cytokine shift

10. Head-to-Head StudyEVIDENCE (IFN beta-1a) Trial,48 Weeks Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times per week. Pantich H, et al. Neurology. 2002;59:1496-1506.

11. Head-to-Head StudyINCOMIN (IFN beta-1b vs beta-1a)Trial, 104 Weeks Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously. Durelli L, et al. Lancet.2002;359:1453-1460.

12. Head-to-Head StudyREGARD (Glatiramer Acetate vs IFN beta-1a), 96 weeks Abbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per week. Mikol DD, et al. Lancet Neurol. 2008;7:903-914.

13. Head-to-Head StudiesBECOME and BEYOND (Glatiramer Acetate vs IFN beta-1b) Abbreviations: GA, glatiramer acetate; QD, once daily; IFN, interferon; SC, subcutaneously; QOD, every other day; NS, not significant. 1. Cadavid D, et al. Neurology. 2009;72:1976-1983. 2. O’Connor P, et al. Lancet Neurol. 2009;8:889-897.

14. Head-to-Head StudiesBottom Line Higher-dose subcutaneous interferons are more effective than lower-dose intramuscular interferon High-dose subcutaneous interferon formulations and glatiramer acetate probably all offer comparable efficacy

15. Side Effects of Interferons Side effects include flu-like symptoms, injection site reactions/necrosis (SC), liver enzyme elevations, lymphopenia, depression Pregnancy category C Warnings: depression/suicide, decreased peripheral blood counts, hepatic injury, seizures, cardiomyopathy/CHF, autoimmune disease Laboratory tests: periodic CBC with differential, liver function profile, thyroid function Avonex [package insert]. Cambridge, MA: Biogen Idec; 2006. Betaseron [package insert] Montville, NJ: Bayer HealthCare Pharmaceuticals; 2009. Extavia [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals; 2009. Rebif [package insert]. Rockland, MA: EMD Serono; 2009.

16. Neutralizing Antibodies • Interferon therapies are associated with production of neutralizing antibodies (NAbs) to the interferon beta molecule1 • NAbs may reduce radiographic and clinical effectiveness of interferon treatment • NAb testing • Sometimes used when deciding whether to switch from one interferon to another (usually IM to SC) in a patient with suboptimal response • There are no guidelines on when to test, which test to use, how many tests are needed, or which cutoff titer to apply1 Probability of NAbs (%) Data from prescribing information. 1. Goodin DS, et al. Neurology. 2007;68:977-984.

17. Side Effects of Glatiramer Acetate Injection-site reactions, vasodilation, rash, dyspnea, chest pain Pregnancy category B Warnings: Immediate postinjection reaction, chest pain, lipoatrophy, skin necrosis Postinjection reaction (flushing, chest pain, palpitations, anxiety, dyspnea, constriction of throat, urticaria) is self-limited; no treatment required No lab testing required Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; 2009.

18. Side Effect Management Tips

19. Time window for early treatment Timing of Therapy May Be Key to Preventing Disability First Demyelinating Event Secondary Progressive Pre-clinical Relapsing-Remitting Transitional First Clinical Attack Axonal loss Clinical threshold Demyelination Inflammation Time (years)

20. Rationale for Early Treatment • Time is ticking… • What is lost by delaying early therapy is not regained by starting later

21. Treating CIS Treating CIS vs waiting until patient has clinically definite MS (CDMS) Decrease progression to CDMS Decrease rate of disability progression Reduced lesion load on MRI Fewer and less severe relapses Most clinicians advocate early treatment BUT not all CIS will develop MS

22. Placebo-Controlled Trials of Disease-Modifying Therapy in CIS 1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Comi G, et al. Lancet. 2001;357:1576-1582. 3. Kappos L, et al. Neurology. 2006;67:1242-1249. 4. Comi G, et al. Lancet. 2009;374:1503-1511.

23. FDA Approved for CIS Interferon beta-1a 30 mcg IM QW Interferon beta-1b 250 mcg SC QOD Glatiramer acetate 20 mg SC daily Interferon beta-1a 44 mcg SC TIW is sometimes used off-label

24. Second-Line MS TherapiesNatalizumab • Inhibits cell adhesion and leukocyte migration across BBB • AFFIRM trial1 of natalizumab vs placebo in RRMS • 42% reduction in risk of sustained progression of disability in 2 years (P <.001) • 68% reduction in clinical relapse at 1 year (P <.001) • 83% reduction in new or enlarging T2 lesions over 2 years (P <.001) • 92% reduction in Gd-enhancing lesions at 1 and 2 years (P <.001) 1. Polman CH, et al. N Engl J Med. 2006;354:899-910.

25. Second-Line TherapiesNatalizumab • FDA approved for relapsing MS • Due to risk of PML, natalizumab is generally reserved for patients who have not responded to or tolerated alternate therapies • PML (JC virus of brain) leads to severe disability or death; no known treatment • Available only through very restricted distribution program (TOUCH Prescribing Program) • Other warnings: hepatotoxicity, hypersensitivity reactions, immunosuppression Tysabri [package insert]. Cambridge, MA: Biogen Idec; 2009.

26. Mitoxantrone Antineoplastic in anthracenedione class FDA approved for SPMS, PRMS, worsening RRMS Causes cross-links and strand breaks in DNA; inhibits B cell, T cell, and macrophage proliferation Due to serious side effects, reserve for patients with rapidly advancing MS despite other disease-modifying therapies Cardiomyopathy (LVEF elevations in up to 18%; CHF) Secondary acute myelogenous leukemia (0.25%) Elevated liver enzyme and glucose levels Requires frequent monitoring (CBC, liver function tests, LVEF, ECG) Administration should be performed by an oncologist Novantrone [package insert]. Rockland, MA: EMD Serono, and Melville, NY: OSI Pharmaceuticals; 2009.

27. Starting an MS Patient on a Disease-Modifying Agent Obtain starter kit from local representative If you do not know your local representative, phone the company’s 800 number Complete physician portion of Enrollment Form and have patient complete the patient portion Fax form back to manufacturer Starter kit will contain educational materials and tools for patient Company will verify patient’s insurance benefits Company will supply medication and send nurse to the patient’s home for training on self-injection and proper needle disposal The nurse may be an added resource for patients to call with questions about the product or self-injection Titrate interferon dose as indicated on the Enrollment Form

28. Monitoring Follow up 4−6 weeks after initiating therapy Assess injection technique and tolerability If stable on therapy, re-evaluate every 3−6 months Laboratory testing for interferon CBC and liver enzyme levels 4–6 weeks after starting treatment, 3 months later, then every 6 months No laboratory testing needed for glatiramer acetate Continue on therapy indefinitely unless clear lack of benefit, intolerable side effects, or better treatment becomes available

29. Assess Adherence!Most Patients Who Discontinue Do So in First 2 Years Cohort of patients who stopped therapy Rio J, et al. Mult Scler. 2005;11:306-309.

30. Assess Adherence by Asking • Patients typically will not tell you they have been nonadherent if you do not ask • Ask in nonjudgmental manner that assumes they have missed some doses • For example: How many injections do you think you have missed in the past 2 months? • Being asked helps motivate patients to adhere • Assess barriers by asking: What prevents you from taking your medication? • NOT: Why aren’t you taking it? (Avoid casting blame)

31. Address Barriers to Adherence Difficulty self injecting Adverse events Unrealistic expectations of therapy (symptom relief) Lack of acceptance of MS diagnosis and need for treatment Financial considerations “Treatment fatigue” Depression Cognitive deficits Impairment in fine motor skills Changes to family and support circumstances

32. Suboptimal Treatment Response Worsening clinical status Radiologic changes (MRI) New Gd enhancement and/or new or enlarging T2 lesions are signs of disease activity No consensus as to when such findings warrant change in treatment Interpret in context of whole clinical picture If found on repeat scans, even if patient is clinically stable, probably warrants change in therapy Remember: comparison of serial MRI scans requires consistent use of standardized MRI protocol (CMSC protocol)

33. Suboptimal ResponsePotential Causes • Nonadherence • Pharmacogenomics: responsiveness to IFN β related to genetics1 • Variable pathologies with differing responses to immune therapies • NAbs • MS subtype (disease modifying agents do not work in PPMS) 1. Byun E, et al. Arch Neurol. 2008;65:337-344.

34. Refer or Consult a Neurologist When diagnosis is in doubt If a consult is desired regarding selection of initial therapy For patients with poor response or toleration of first-line therapies When considering use of natalizumab or mitoxantrone

35. ResourcesMS Centers in Oregon OHSU Multiple Sclerosis Center 3181 SW Sam Jackson Park Rd, Portland, OR 97239 503-494-7321 Providence Multiple Sclerosis Center 9427 SW Barnes Rd, Suite 595, Portland, OR 97225 503-216-1060 VA Medical Center–Portland 3710 SW US Veterans Hospital Rd (153), Portland, OR 97239 503-220-8262 x 57260

36. ResourcesMS Centers in Washington State Cascadia Multiple Sclerosis Center 11 Bellwether Way, Suite 210, Bellingham, WA 98225 360-752-9919 Evergreen Neuroscience Institute MS Center 12040 NE 128th St, MS #118, Kirkland, WA 98034 425-899-5350 Rockwood Multiple Sclerosis Center 400 East Fifth Ave, Spokane, WA 99202 509-838-2531 Swedish Neuroscience Institute 550 17th Ave, Suite 540, Seattle, WA 98122 206-386-3880

37. ResourcesMS Centers in Washington State VA MS Center of Excellence–West (VAMC Seattle) 1660 S Columbian Way, Seattle, WA 98108 206-277-4688 Virginia Mason Multiple Sclerosis Center 1100 9th Ave, Seattle, WA 98101 206-223-6600 Western MS Center at University of Washington Medical Center/MSRRTC 1959 NE Pacific St, Seattle, WA 98195 206-598-3344

38. ResourcesMS Center in Idaho Idaho Falls Multiple Sclerosis Center 2353 Coronado, Idaho Falls, ID 83404 208-552-4823 Stephen G. Vincent, MD, and Bradford L. Talcott, MD, PhD

39. ARS Polling Which of the following is not recommended as a first-line treatment for a patient with relapsing-remitting MS? • Interferon beta-1b 250 mcg SC QOD • Natalizumab 300 mg IV monthly infusion • Glatiramer acetate 20 mg SC QD • Interferon beta-1a 44 mcg SC TIW or 30 mcg IM weekly

40. Conclusions Current MS therapies can reduce relapse rates and disability progression Interferon beta or glatiramer acetate is first line It is best to start treatment as early as possible Patient education is essential when starting treatment Rationale for treatment, injection technique, side effect management, importance of adherence After starting treatment, monitor for response, tolerability, and adherence