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Integrating Current and Emerging MS Therapies into Practice

Integrating Current and Emerging MS Therapies into Practice. Goals of MS Disease-Modifying Therapy. Delay disability progression Reduce the frequency of relapses Improve MRI measures of disease. Modern-Day Goals—Relapse Rate.

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Integrating Current and Emerging MS Therapies into Practice

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  1. Integrating Current and Emerging MS Therapies into Practice

  2. Goals of MSDisease-Modifying Therapy • Delay disability progression • Reduce the frequency of relapses • Improve MRI measures of disease

  3. Modern-Day Goals—Relapse Rate Annualized relapse rates (ARRs) in recently completed RRMS trials with glatiramer acetate (GA), interferon (IFN), and placebo (PBO) arms 1. Comi G, et al. Paper presented at: 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P07.194. 2. O'Connor P, et al. Lancet Neurol. 2009;8:889-897. 3. Giovannoni G, et al. N Engl J Med. 2010;362:416-426. 4. Comi G, et al. Ann Neurol. 2011;69:75-82. 5. Kappos L, et al. N Engl J Med. 2010;362:387-401. 6. Mikol DD, et al. Lancet Neurol. 2008;7:903-914. 7. O’Connor P, et al. Paper presented at: ECTRIMS; October 13­–16, 2010; Gothenburg, Sweden. Abstract 79. 8. Cohen JA, et al. N Engl J Med. 2010;362:402-415.

  4. Modern-Day Goals—Other Patients treated with IFN or GA in recent CIS and RRMS studies Abbreviations: CIS, clinically isolated syndrome; GA, glatiramer acetate; IFN, interferon; RRMS, relapsing-remitting MS. 1. O'Connor P, et al. Lancet Neurol. 2009;8:889-897. 2. Mikol DD, et al. Lancet Neurol. 2008;7:903-914. 3. Coles AJ, et al. N Engl J Med. 2008;359:1786-1801. 4. Kappos L, et al. Lancet Neurol. 2009;8:987-997.

  5. Timeline of Approved and Emerging MS Therapies 5 Alemtuzumab IFN β-1b SC Natalizumab Daclizumab IFN β-1a IM IFN β-1b SC Ocrelizumab Glatiramer acetate Fumarate (BG12) Fingolimod Laquinimod* Mitoxantrone Teriflunomide IFN β-1a SC 1995 2000 2005 2009 2010 2011 2012 Approval Date Estimated Launch Date *In 20-F report filed 2/17/12: Teva will not file an NDA with the FDA for laquinimod for RRMS at this time; development continues, however.1 Approved Therapies Phase III Completed In Phase III Abbreviations: NDA, new drug application; RRMS, relapsing-remitting MS. 1. TEVA Pharmaceutical Industries Ltd. Form 20-F. February 17, 2012. Accessed 3/1/12 at http://ir.tevapharm.com/phoenix.zhtml?c=73925&p=irol-sec. Graphic courtesy of Dr. Mark J. Tullman.

  6. What’s New?Interferon Beta • BEYOND trial data analysis shows negative impact of neutralizing antibodies on MRI measures, but no negative impact on clinical measures1 • 21-year follow-up from start of phase III enrollment shows significant survival benefit vs placebo2 • Meta-analysis finds limited benefits in secondary-progressive MS3 • 5-year follow-up shows modest beneficial effect on clinical variables and brain atrophy in primary-progressive MS4 1. Goodin DS, et al. MultScler. 2012;18:181-195. 2. Goodin D, et al. Paper presented at ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P940. 3. La Mantia L, et al. Cochrane Database Syst Rev. 2012;1:CD005181. 4. Tur C, et al. Arch Neurol. 2011;68:1421-1427.

  7. What’s New?Glatiramer Acetate • Long-term follow-up of patients with mean MS duration of 22 years receiving continuous glatiramer acetate for up to 15 years shows long-term efficacy and safety1 • Reduced relapse rates, decreased disability progression, decreased transition to secondary-progressive MS • No long-term safety issues • 5-year brain MRI study showed less progression of brain atrophy with glatiramervs interferon2 • Preliminary analysis of Coptimize study shows significant reduction in annualized relapse rate after switching to glatiramer acetate3 • Induces in vivo expansion of immunosuppressive CD4+ T-cells4 1. Ford C, et al. MultScler. 2010;16:342-350. 2. Khan O, et al. J Neurol Sci. 2012;312:7-12. 3. Ziemssen T, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P510. 4. Ryzhkova A, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P799.

  8. What’s New?Fingolimod • TRANSFORMS subgroup analysis: brain volume reduction with fingolimod not accounted for by inflammatory lesion activity or new disease activity during 1st year of treatment1 • Data from safety study extension shows sustained low level of disease activity over 5 years2 • July 2011, fingolimod label expanded to include reduction in MRI gadolinium-enhancing lesions3 • December 2011, FDA announced safety evaluation of a patient who died within 24 hours of taking first dose; exact cause of death has not been established4 • January 2012, Novartis announced a total of 31 deaths worldwide are being investigated: 11 "deaths of potential interest" plus 20 other deaths in 30,000+ patients treated since 20035 1. Barkhof F, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P907. 2. Montalbán S, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P978. 3. FDA letter. July 20, 2011. Accessed 3/5/12 at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/022527s002ltr.pdf. 4. FDA. Safety announcement. December 20, 2011. Accessed 3/6/12 at: http://www.fda.gov/Drugs/DrugSafety/ucm284240.htm. 5. Novartis webcast, January 25, 2012. Accessed 3/8/12 at: http://www.novartis.com/investors/ event-calendar/index.shtml#2012-01-25_full-year-results.

  9. What’s New?Natalizumab • Long-term outcomes from AFFIRM in patients free of disease activity after 2 years presented at ECTRIMS1 • Patients treated with natalizumab had higher magnetization transfer ratio volume in normal-appearing brain tissue compared with patients treated with IFN or healthy controls at years 1 and 22 • FDA approves STRATIFY JCV antibody ELISA test3 • Pathologic and radiologic characteristics of immune reconstitution inflammatory syndrome described4 1. Rudick R, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P513. 2. Zivadinov R, et al. MultScler. 2011 Dec 22. [Epub ahead of print]. 3. FDA. News release. 1/20/12. Accessed 3/20/12 at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm288471.htm. 4. Metz I, et al. ActaNeuropathol. 2012;123:235-245.

  10. What’s New?Mitoxantrone • Mitoxantrone found to exert cytotoxic and immunomodulatory effects on central nervous system (CNS) microglia, major CNS antigen-presenting cells that play a key role in MS pathogenesis1 • 5-year prospective safety study from French cohort (N = 802) reported2 • 0.1% acute congestive heart failure • 4.9% asymptomatic left ventricular ejection fraction reduction under 50% • 0.25% therapy-related leukemia • 17.3% persistent age-dependent amenorrhea in women treated before age 45 years 1. Li JM, et al. ImmunopharmacolImmunotoxicol. 2012;34:36-41. 2. Le Page E, et al. MultScler. 2011;17:867-875.

  11. Fumarate (BG-12)–DEFINE, Phase III • BG-12 240 mg BID and TID vs placebo for 2 years(N = 1234 RRMS) • All primary and secondary endpoints met • Compared with placebo, BG-12 BID and TID • Reduced the relapse rate by 49% and 50%, respectively (P <.0001) • Reduced annualized relapse rate by 53% and 48%, respectively (P <.001) • Reduced 12-week disability progression by 38% (P <.01) and 34%, respectively (P <.05) Gold R, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 95.

  12. Laquinimod–ALLEGRO, Phase III • Laquinimod 0.6 mg/d vs placebo for 24 months (N = 1106 RRMS) • Achieved primary end point showing annualized relapse rate significantly reduced by 23% (P = .002) • Achieved secondary endpoints • Expanded Disability Status Scale progression of disability significantly reduced by 36% (P = .01) • Mean cumulative number Gad-enhancing lesions significantly reduced by 37% (P <.001) • Mean cumulative number new or enlarging T2 lesions significantly reduced by 30% (P <.001) Comi G, et al. N Engl J Med. 2012;366:1000-1009.

  13. Laquinimod–BRAVO, Phase III Laquinimod 0.6 mg/d vs placebo vs IFN β-1a for 24 months (N = 1331 RRMS) Compared with placebo, laquinimod Did not statistically reduce unadjusted annualized relapse rate (ARR) (P = .075) Reduced adjusted ARR by 22% (P = .026) Reduced disability progression by 33.5% (P = .044) Reduced brain atrophy by 27.5% (P <.0001) Compared with placebo, interferon β-1a Significantly reduced ARR by 29% (P = .002) Did not significantly reduce disability progression or brain atrophy Vollmer TL, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 148.

  14. Teriflunomide–Phase III TEMSO Data • Teriflunomide 7 mg/d or 14 mg/d vs placebo for 2 years (N = 1088 RRMS) • Achieved primary endpoint showing ARR significantly reduced by 31.2% at 7 mg and by 31.5% at 14 mg (P <.001 for both) • Achieved key secondary endpoint showing 12-week disability progression significantly reduced by 24% (P = .08) at 7 mg and by 30% (P = .03) for 14 mg • Was superior for a range of MRI endpoints • Significantly reduced total lesion volume by 39.4% at 7 mg and by 67.4% at 14 mg (P = .03) • Significantly reduced number of Gad-enhancing lesions by 57% at 7 mg and by 80% at 14 mg (P <.001) O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.

  15. Alemtuzumab–CAMMS223 Phase II Trial • Alemtuzumab 12 mg or 24 mg vs IFN β-1a for 3 years (N = 334 early RRMS)1 • Achieved primary endpoints (both doses combined)1 • Significantly reduced relapse rate by 74% (P <.001) • Significantly reduced risk of sustained disability by 71% (P <.001) • Achieved secondary MRI endpoints (both doses combined)1 • Significantly reduced lesion burden (P = .005) • Significantly reduced reduction in brain volume (P = .05) • Treatment effect durable through 5 years2 1. Coles, AJ. N Engl J Med.2008;359:1786-1801. 2. Twyman C, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract PD6.003.

  16. Alemtuzumab–CARE-MS I Phase III Trial • Alemtuzumabvs IFN β-1a for 2 years (N = 581 treatment-naive RRMS)1 • Compared with IFN β-1a, alemtuzumab (primary endpoints)1,2 • Significantly reduced ARR by 54% (P <.0001) • Did not significantly reduce sustained accumulation of disability (11% vs 8%; P = .22) • Other outcomes1,2 • Percentage relapse-free: 78% alemtuzumab, 59% IFN (P <.0001) • Percentage with new/enlarging T2 lesions: 49% alemtuzumab, 58% IFN (P = .035) • Mean change in Expanded Disability Status Scale disability score: 0.14 for both alemtuzumab and IFN • Percentage with new T1 hypointense lesions: 24% alemtuzumab, 31% IFN(P = .05) • Brain atrophy: -0.87% alemtuzumab, -1.49% IFN (P <.0001) • Safety1,2 • 0.8% immune thrombocytopenia, 18% thyroiditis 1. Coles A, et al. Paper presented at: ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 151. 2. Gever J. MedPage Today. October 22, 2011. Accessed 3/12/12 at: http://www.medpagetoday.com/MeetingCoverage/ECTRIMS/29173.

  17. Daclizumab–CHOICE and SELECT Phase II • CHOICE phase II trial1 • 3 arms: 2 doses of daclizumab and placebo added to IFN (N = 230 RRMS) • No significant difference in relapse rate • Decrease in new MRI lesions with higher dose vs IFN alone • 5% serious infections with daclizumab, all resolved with standard therapy • SELECT phase IIb trial2 • Daclizumabmonotherapy 150 mg vs 300 mg vs placebo (N = 600 RRMS) • Compared with placebo, daclizumab • Significantly reduced ARR • Significantly reduced proportion of patients who relapsed • Reduced new or enlarging Gad+ lesions between weeks 8 and 24 • Adverse effects included increase in serious infections (2%) 1. Wynn D, et al. Lancet Neurol. 2010;9:381-390. 2. Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 149.

  18. Ocrelizumab–Phase II Data • Ocrelizumab (OCR) 600 mg and 2000 mg vs IFN β-1a vs placebo (N = 220 RRMS)1 • At week 24, Gad-enhancing lesions reduced by 89% and 96% with OCR 600 mg and 2000 mg, respectively, compared with placebo1 • At week 24, ARR reduced by 80% and 73% with OCR 600 mg and 2000 mg1, respectively, compared with placebo • Adverse effects1 • Serious infection rates were similar across groups • 41-year-old woman treated with ocrelizumab 2000 mg died at week 14 of systemic inflammatory response syndrome • Deaths in rheumatoid arthritis and systemic lupus erythematosustrials suspends development in those settings2 1. Kappos L, et al. Lancet. 2011;378:1779-1787. 2. Reid, K. Reuters. March 8, 2010. Accessed 3/12/12 at: http://www.reuters.com/article/2010/03/08/roche-idUSLDE62705720100308.

  19. Risk Stratification by Baseline Brain MRI 20-Year Clinical Status Abbreviations: CDMS, clinically definite MS; EDSS, Expanded Disability Status Scale.Fisniku LK et al. Brain. 2008;131:808-817. Graphics courtesy of Dr. Mark J. Tullman.

  20. Factors in Selecting a Disease-Modifying Therapy • Efficacy • Safety/tolerance • Convenience • Patient preference • Cost • Escalation vs induction • Window of opportunity • Risk mitigation

  21. Anti-JCV antibody status1,2 Negative Positive Prior immunosuppressive use No Yes ≤0.10/100095% CI: 0–0.593 Risk Mitigation–Estimated Incidence of PML in Natalizumab-Treated Patients by Risk Factors Abbreviations: JCV, JC virus; IS, immunosuppressant; PML, progressive multifocal leukoencephalopathy. 1. Tysabri. [package insert]. South San Francisco, CA: Biogen Idec Inc; 2012. 2. FDA Drug Safety Communication. January 20, 2012. Accessed 2/23/12 at http://www.fda.gov/Drugs/DrugSafety/ucm288186.htm. 3. Bloomgren G, ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P995. Graphics courtesy of Dr. Mark J. Tullman.

  22. Monitoring for Interferon-β–Specific Safety Issues See prescribing information for complete details. 1. Avonex [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. 2. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2010. 3. Extavia [PI]. East Hanover, NJ: Novartis Pharmaceutical Corporation; 2009. 4. Rebif [PI]. Rockland, MA: EMD Serono, Inc.; 2011.

  23. Monitoring for Glatiramer Acetate-Specific Safety Issues See prescribing information for complete details. Copaxone [PI]. Kansas City, MO: Teva Neuroscience, Inc.; 2009.

  24. Monitoring for Fingolimod-Specific Safety Issues See prescribing information for complete details. Abbreviations: ECG, electrocardiogram; EMEA, European Medicines Agency; HIV, human immunodeficiency virus. 1. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011. 2. Robert P. Lisak, MD. Written communication. 3/6/12. 3. FDA. Safety announcement. December 20, 2011. Accessed 3/6/12 at: http://www.fda.gov/Drugs/DrugSafety/ucm284240.htm. 4. EMA. Press release. January 12, 2012. Accessed 3/15/12 at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/01/WC500120703.pdf.

  25. Monitoring for Natalizumab-Specific Safety Issues See prescribing information for complete details. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.

  26. Monitoring for Mitoxantrone-Specific Safety Issues See prescribing information for complete details. Abbreviations: ECG, electrocardiogram; LVEF, left ventricular ejection fraction; MUGA, multiple gate acquisition scan. Mitoxantrone [PI]. Irvine, CA: TevaParenteral Medicines, Inc.; 2011.

  27. Making Switching Decisions Monitoring outcomes Decide whether to switch Decide when to switch Agent-specificfactors Decide how to switch Patient-specific factors

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