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Introduction

Fred D. Lublin, MD Saunders Family Professor of Neurology Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Mount Sinai School of Medicine New York, New York. Introduction. Current MS Therapies. MS therapeutic era started in 1993

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Introduction

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  1. Fred D. Lublin, MD Saunders Family Professor of NeurologyDirector, The Corinne Goldsmith Dickinson Center for Multiple SclerosisMount Sinai School of MedicineNew York, New York Introduction

  2. Current MS Therapies • MS therapeutic era started in 1993 • Currently, 9 marketed agents representing 6 molecular entities • Long-term efficacy/safety data • No surprises • Changing relapse rate

  3. Introduction to Risk:Benefit Analysis • Newer safety issues • Evolving treatment goals • Data: safety vs efficacy • Clinical trials • Postmarketing • Comparative safety • FDA-mandated Risk Evaluation and Mitigation Strategies (REMS) for high-risk drugs • Patient preferences and risk factors • Patient involvement in decision making

  4. Increased Importance of Risk Mitigation with New MS Therapies Promise of EnhancedEfficacy Greater Tolerability and Safety Issues

  5. Identifying Patients Who Are Candidates for Older Vs Newer Therapies • How do we choose therapies? • Many patients do well on current therapies • How to define inadequate response • How to identify in advance those who will: • Do well on older therapies • Benefit from newer therapies with greater safety risk • Role of oral agents • Patient perspective – safety

  6. Webcast Agenda Risk Mitigation: Where We Are Now Faculty Panel Discussion Risk Mitigation: Where We Are Going Faculty Panel Discussion

  7. Risk Mitigation: Where We Are Now Andrew D. Goodman, MD, FAAN Professor of Neurology Director, Multiple Sclerosis Center Chief, Neuroimmunology Unit Department of Neurology University of Rochester Medical Center Rochester, NY

  8. Risk Evaluation and Mitigation Strategies (REMS) • The FDA Amendments Act of 2007 authorized the FDA to require an REMS, as needed for certain drugs1 • To ensure that a drug's benefits outweighs its risks1 • Driven primarily to ensure that patients and providers are better informed prior to starting therapy2 • An REMS is a “mandated strategy to manage a known or potentially serious risk”2 • FDA may require an REMS for new drugs and already approved drugs if warranted by safety concerns2 1. FDA. Approved Risk Evaluation and Mitigation Strategies (REMS). Accessed 1/15/13 at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm. 2. Hollingsworth K, et al. Popul Health Manag. 2012 Oct 31. [Epub ahead of print].

  9. REMS—Primary Components • Communication tools • Medication guide • Patient package insert • Communication plan to educate and inform healthcare providers • Elements to Assure Safe Use (ETASU) • Restrictions that allow safe use of potentially harmful or toxic drugs • Not all components are required for all REMS • Determined by FDA FDA. Food and Drug Administration Amendments Act of 2007. Accessed 1/17/13 at: http://www.gpo.gov:80/fdsys/pkg/PLAW-110publ85/html/PLAW-110publ85.htm.

  10. REMS Elements To Assure Safe Use (ETASU) Depending on the risk, an REMS may require any or all of the following: • Prescribers have specific training/experience or special certifications • Pharmacies, practitioners, or healthcare settings that dispense the drug be specially certified • Drug be dispensed only in certain healthcare settings • Drug be dispensed with evidence of safe-use conditions, such as laboratory test result • Each patient using the drug be subject to monitoring • Each patient using the drug be enrolled in a registry FDA. Food and Drug Administration Amendments Act of 2007. Accessed 1/17/13 at: http://www.gpo.gov:80/fdsys/pkg/PLAW-110publ85/html/PLAW-110publ85.htm.

  11. REMS vs Safety Warnings or Cautionsfor Currently Approved DMTs • Fingolimod and natalizumab are the only currently approved DMTs required to have an REMS1 • Glatiramer acetate, interferon-βs, mitoxantrone, and teriflunomide have safety warnings or precautions, as needed, but no REMS at this time 1. FDA. Approved Risk Evaluation and Mitigation Strategies (REMS). 12/31/2012. Accessed 1/15/13 at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

  12. Interferon(IFN)-βs—Prescribing Information Safety Warnings/Precautions *Powdered vial contains albumin; prefilled syringe and autoinjector are albumin free. †Also contains albumin but PI does not list albumin viral transmission risk as a warning or precaution.1. Rebif [PI]. Rockland, MA: EMD Serono, Inc.; 2012. 2. Avonex [PI]. Cambridge, MA: Biogen Idec MA Inc.; 2012. 3. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2012. 4. Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  13. Interferon-βs—Risk Mitigation *The above information is based on the product labels. Please refer to the product labels for full prescribing information and screening/monitoring requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. 1. Rebif [PI]. Rockland, MA: EMD Serono, Inc.; 2012. 2. Avonex [PI]. Cambridge, MA: Biogen Idec MA Inc.; 2012. 3. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2012. 4. Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  14. Interferon-βs—Risk Mitigation *The above information is based on the product labels. Please refer to the product labels for full prescribing information and screening/monitoring requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. 1. Rebif [PI]. Rockland, MA: EMD Serono, Inc.; 2012. 2. Avonex [PI]. Cambridge, MA: Biogen Idec MA Inc.; 2012. 3. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2012. 4. Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  15. Glatiramer Acetate—Warnings and Precautions • Immediate post-injection reaction • Flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and/or urticaria • Chest pain • Lipoatrophy and skin necrosis may occur • Potential to modify immune response Copaxone [PI]. Kansas City, MO: Teva Neuroscience, Inc.; 2012.

  16. Glatiramer Acetate—Risk Mitigation *The above information is based on the product label. Please refer to the product label for full prescribing information and screening/monitoring requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. Copaxone [PI]. Kansas City, MO: Teva Neuroscience, Inc.; 2012.

  17. Natalizumab—Warnings and Precautions • Progressive multifocal leukoencephalopathy (PML)1 • Black-box warning1 • 323 cases of PML have been reported as of January 2, 20132 • Hypersensitivity reactions1 • Immunosuppression/infection1 • Hepatoxicity1 1. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. 2. Biogen Idec. Tysabri Update. January 2013.

  18. Natalizumab—Goals of REMS • To inform about risk of progressive multifocal leukoencephalopathy (PML) and its risk factors • Long treatment duration • Anti-JCV antibody seropositivity • Prior immunosuppressant use • To warn against concurrent use with antineoplastic, immunosuppressant, or immunomodulating agents, and in patients who are immunocompromised • To promote early diagnosis of PML and timely discontinuation of natalizumab if PML is suspected Tysabri (natalizumab) Risk Evaluation and Mitigation Strategy. 1/2012. Accessed 1/15/13 at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM288126.pdf.

  19. TOUCH Program • REMS mandates that natalizumab is available only through TOUCH program • Requirements for: • Prescribers • Pharmacies and infusion centers • Patients

  20. Anti-JCV Antibody Status Negative Positive1 Prior Immunosuppressive Use No Yes ≤0.09/10002 PML Risk Mitigation–Estimated Incidence in Natalizumab-Treated Patients by Risk Factors Abbreviations: IS, immunosuppressant; PML, progressive multifocal leukoencephalopathy. 1. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. 2. Bloomgren G, et al. N Engl J Med. 2012;366:1870-1880.

  21. Natalizumab PML—Diagnosis • Any new symptom or MRI lesion in a patient on natalizumab should raise concern for PML Common symptoms1,2 • Cognitive changes, aphasia • Personality/behavioral changes • Weakness • Seizures • Ataxia • Visual symptoms Common locations3 • Many are frontal, occipital • Can occur in any lobe • Brainstem and cerebellum • Generally spares spinal cord and optic nerves 1. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. 2. Fox R. Cleve Clin J Med. 2011;78 (suppl2):S33-S37. 3. Written communication with A. Goodman, MD. January 2013.

  22. Natalizumab PML—Typical MRI Features “ • Subcortical white matter, including U-fibers • T2 hyperintense • T1 hypointense • Diffusion-restricted on diffusion-weighted imaging • May enhance (punctate) • Lesion border sharp towards gray matter and fuzzy toward white matter Yousry TA, et al. Ann Neurol. 2012;72:779-787.

  23. JC Viral DNA (PCR) Assays on CSF • Commercial assay • eg, Focus Diagnostics: lower limit of quantitation 50 copies/mL1 • JCV PCR-negative natalizumabPML2 • 1 report • CSF anti-JCV antibody titers • Brain biopsy • Note: Anti-JCV antibody tests should not be used to diagnose PML3 Abbreviation: CSF, cerebrospinal fluid. 1. Biogen Idec. PML Identification and Response brochure. Accessed 1/16/13 at: http://www.tysabrihcp.com/clinical-vigilance/pml-overview-hcp.xml. 2. Kuhle J, et al. Neurology. 2011;77:2010-2016. 3. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.

  24. Natalizumab—Risk Mitigation *The above information is based on the product label and REMS. Please refer to the product label for full prescribing information and screening/monitoring requirements and to the REMS for full TOUCH program requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. 1. Tysabri (natalizumab) Risk Evaluation and Mitigation Strategy. 1/2012. Accessed 1/15/13 at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM288126.pdf. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.

  25. Natalizumab—Risk Mitigation *The above information is based on the product label AND REMS. Please refer to the product label for full prescribing information and screening/monitoring requirements and to the REMS for full TOUCH program requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. 1. Tysabri (natalizumab) Risk Evaluation and Mitigation Strategy. 1/2012. Accessed 1/15/13 at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM288126.pdf. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.

  26. Fingolimod—Mechanism of Action • Sphingosine 1-phosphate (S1P) receptor modulator • Traps lymphocytes in lymph nodes • Presumed to reduce trafficking of activated lymphocytes into central nervous system Kappos L, et al. N Engl J Med. 2010;362:387-401.

  27. Fingolimod—Warnings and Precautions • Decrease in heart rate and/or atrioventricular conduction • Infection • Macular edema • Pulmonary dysfunction • Hepatotoxicity • Teratogenicity Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  28. Fingolimod—Goal of REMS • To inform healthcare providers about the serious risks of fingolimod • Risks include: • Bradyarrhythmia and atrioventricular block at treatment initiation • Infections • Macular edema • Respiratory effects • Hepatic effects • Fetal risk Gilenya (fingolimod) Risk Evaluation and Mitigation Strategy (REMS). Accessed 1/15/13 at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM227965.pdf.

  29. Fingolimod—Cardiac Risk • Decreased heart rate, potential arrhythmia1 • Via action on cardiac S1P receptors2 • Peak effects within 6 hours of first dose, and again between 12 and 20 hours postdose3 • Concern for fatal arrhythmia • 1 death in US, within 24 hours of first dose3 • 10 deaths in Europe4 1. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. 2. Kappos L, et al. N Engl J Med. 2010;362:387-401. 3. FDA. Drug Safety Communication. 5/14/2012. Accessed 1/16/13 at: http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm. 4. EMA. Press release. 1/2/2012. Accessed 1/16/13 at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/01/news_detail_001425.jsp&mid=WC0b01ac058004d5c1.

  30. Fingolimod—Cardiac Risk • All patients monitored for 6 hours after 1st dose • Hourly pulse and blood pressure • EKG at beginning and end of dosing • Overnight inpatient cardiac monitoring for patients with: • Severe bradycardia (<45 beats/minute) after 1st dose • Certain pre-existing conditions in whom bradycardia may be poorly tolerated • QT interval prolongation prior to starting fingolimod or during the monitoring period • Concurrent therapy with other drugs that: • Slow the heart rate or atrioventricular conduction • Prolong the QT interval and that can cause a serious and life-threatening abnormal heart rhythm called Torsades de pointes FDA. Drug Safety Communication. 5/14/2012. Accessed 1/16/13 at: http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm.

  31. Fingolimod—Infection Risk • Peripheral lymphopenia1 • Absolute lymphocyte count ≥300 cells/µL is generally tolerated2 • Discontinue if <200 cells/µL3 • 2 deaths due to herpetic infection1 • 1 disseminated primary varicella zoster • 1 herpes simplex encephalitis 1. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. 2. Written communication with A. Goodman, MD. January 2013. 3. Pelletier D, et al. N Engl J Med. 2012;366:339-347.

  32. Fingolimod—Risk Mitigation *The above information is based on the product label and REMS. Please refer to the product label and REMS-related communications for full prescribing information and screening/monitoring requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. 1. GILENYA (fingolimod) Risk Evaluation and Mitigation Strategy (REMS). Accessed 1/15/13 at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM227965.pdf. 2. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  33. Fingolimod—Risk Mitigation *The above information is based on the product label and REMS. Please refer to the product label and REMS-related communications for full prescribing information and screening/monitoring requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. 1. GILENYA (fingolimod) Risk Evaluation and Mitigation Strategy (REMS). Accessed 1/15/13 at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM227965.pdf. 2. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  34. Teriflunomide—Mechanism of Action • Immunomodulatory agent, anti-inflammatory properties • Inhibits dihydro-orotatedehydrogenase • Mitochondrial enzyme • Involved in de novo pyrimidine synthesis • Exact mechanism in MS is unknown • May work by reducing the number of activated lymphocytes in the central nervous system Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.

  35. Teriflunomide—Warnings and Precautions • Hepatotoxicity • Black-box warning • Teratogenicity • Black-box warning • Immunosuppression/infection • Peripheral neuropathy • Acute renal failure/hyperkalemia • Severe skin reaction • Blood pressure increase • Pulmonary dysfunction Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.

  36. Teriflunomide—Hepatotoxicity • Severe liver injury, including fatal liver failure, has been reported with leflunomide • Similar risk expected due to similar range of plasma concentrations • Concomitant use of other hepatotoxic drugs may increase the risk of severe liver injury • Contraindicated in patients with severe hepatic impairment • Pre-existing liver disease may increase risk of developing elevated serum transaminases .Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.

  37. Teriflunomide—Teratogenicity • May cause major birth defects if used during pregnancy (based on animal data) • Contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception • Exclude pregnancy before initiating • Pregnancy must be avoided during treatment • Or prior to the completion of an accelerated elimination procedure with cholestyramine treatment after teriflunomide treatment Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.

  38. Teriflunomide—Risk Mitigation *The above information is based on the product label. Please refer to the product label for full prescribing information and screening/monitoring requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. *The above screening/monitoring requirements are as reflected in prescribing information. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.

  39. Teriflunomide—Risk Mitigation *The above information is based on the product label. Please refer to the product label for full prescribing information and screening/monitoring requirements. Additional screening/monitoring may be needed based on individual patient clinical status and clinician discretion. Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.

  40. Conclusions • Risks of therapy and of disease inform risk:benefit assessment • Clinicians should be aware of all pertinent REMS and product label safety warnings and precautions • Critical need for: • Timely updates as safety signals emerge: rare events; delayed events • Biomarkers of prognosis and therapeutic response • Ultimately, better and hopefully “personalized” therapies for our patients

  41. ModeratorFred D. Lublin, MD PanelAnne H. Cross, MDAndrew H. Goodman, MD Panel Discussion I:Physicians’ Perspectives of Risk Mitigation of Current Therapies

  42. Anne H. Cross, MD Professor of NeurologyWashington University School of MedicineSt. Louis, Missouri Risk Mitigation: Where We Are Going

  43. 5 MS Pipeline MS Drugs in Phase III What Are Their Risks and Benefits? *Under review by FDA.Abbreviations: Nrf2, nuclear factor erythroid 2-related factor; PPMS, primary-progressive MS; RRMS, relapsing-remitting MS. Saidha S, et al. Ann N Y Acad Sci. 2012;1247:117-137. Graphic courtesy of Anne H. Cross, MD.

  44. For What Patient Types Might These Emerging Therapies Be Appropriate? • Patients with suboptimal response to current disease-modifying therapies (DMTs) • Patients who have been intolerant of current DMTs • Patients with needle phobia but contraindications to the current oral DMTs • Emerging oral drugs • Patients with very aggressive MS who are positive for anti-JCV antibodies • Alemtuzumab, daclizumab, or ocrelizumab

  45. Alemtuzumab—Overview • Monoclonal antibody to CD521 • Humanized IgG11 • Cell lysis via antibody-dependent cellular cytolysis1 • CD52 • 12 amino acid glycosylated surface protein on T- and B-cells, natural killer cells, monocytes, and some dendritic cells1-3 • Role of CD52 not fully known1 1. Hu Y, et al. Immunology. 2009;128:260-270. 2. Saidha S, et al. Ann N Y Acad Sci. 2012;1247:117-137. 3. Buggins AG, et al. Blood. 2002;100:1715-1720.

  46. Alemtuzumab (ALZ)—Phase III Studies • Both studies1,2 • ALZ IV vs IFN β-1a 44 µg TIW SC; rater blinded • 2 cycles of ALZ: x 5 days at time 0 and x 3 days at 1 year • CARE-MS I1 • ALZ 12 mg/day; naive RRMS patients • Reduced relapse rate at 2 years by 55% (P <.0001) • Did not meet endpoint of reducing sustained disability • CARE-MS II2 • ALZ 12 mg and 24 mg/day; RRMS patients with relapse on prior interferon or glatiramer • 12 mg reduced relapse rate at 2 years by 49% (P <.0001) • 12 mg reduced sustained disability by 42% (P = .008) 1. Cohen JA, et al. Lancet. 2012;380:1819-1828. 2. Coles AJ, et al. Lancet. 2012;380:1829-1839.

  47. Alemtuzumab—For Which Patient Types Might This Drug Be Appropriate? • Patients who want a long-acting medication • Alemtuzumab is given yearly • Patients with aggressive MS who have been intolerant of approved medications • Patients who are anti-JCV antibody positive and have very aggressive MS

  48. Alemtuzumab Risks—Infusion Reactions, Infection • Infusion reactions1,2 • Common, but not dangerous • Rate approximately 90% in both CARE-MS I and II • Typically, headache, rash, fever, flushing, hives, and chills • Only 3% serious • Infection rate1,2 • Most infections mild/moderate • Herpetic infections 16% vs 2%–4% for IFN-β 1. Cohen JA, et al. Lancet. 2012;380:1819-1828. 2. Coles AJ, et al. Lancet. 2012;380:1829-1839.

  49. Alemtuzumab Risks—Cancer • CARE-MS I1 • Thyroid 2 • CARE-MS II2 • ALZ 12 mg: thyroid 1, basal cell 1 • ALZ 24 mg: basal cell 1, colon 1, vulval 1 • IFN: basal cell 1 Abbreviations: ALZ, alemtuzumab; IFN, interferon. 1. Cohen JA, et al. Lancet. 2012;380:1819-1828. 2. Coles AJ, et al. Lancet. 2012;380:1829-1839.

  50. Alemtuzumab Risks—Secondary Autoimmunity • Immune thrombocytopenic purpura • 3% in CAMMS223 phase II extension, 1 fatality1 • Thyroid autoimmunity • May be as high as 30%1 • Goodpasture’s Disease (anti-GBM disease) • 2 reported cases (1 with MS)2 • HLA-DRB1*15 may be risk factor3 but is also risk factor for MS4 • Higher serum IL-215,6 and CCL215 may predict future autoimmunity Abbreviation: Glomerular basement membrane. 1. Coles AJ, et al. Neurology. 2012;78:1069-1078. 2. Clatworthy MR, et al. N Engl J Med. 2008;359:768-769. 3. Phelps RG, et al. Kidney Int. 1999;56:1638-1653. 4. Lincoln MR, et al. Proc Natl Acad Sci USA. 2009;106:7542-7547. 5. Jones JL, et al. J Clin Invest. 2009;119:2052-2061. 6. Jones JL, et al. Mult Scler J. 2011:17(suppl 10):S459.

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