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1 Introduction Fred D. Lublin, MD Saunders Family Professor of Neurology Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Mount.

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Presentation on theme: "1 Introduction Fred D. Lublin, MD Saunders Family Professor of Neurology Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Mount."— Presentation transcript:

1 1 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

2 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 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 4 Increased Importance of Risk Mitigation with New MS Therapies Promise of Enhanced Efficacy Greater Tolerability and Safety Issues

5 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 6 Risk Mitigation: Where We Are Now Risk Mitigation: Where We Are Going Faculty Panel Discussion Webcast Agenda

7 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 8 Risk Evaluation and Mitigation Strategies (REMS) The FDA Amendments Act of 2007 authorized the FDA to require an REMS, as needed for certain drugs 1 –To ensure that a drug's benefits outweighs its risks 1 –Driven primarily to ensure that patients and providers are better informed prior to starting therapy 2 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 concerns 2 1. FDA. Approved Risk Evaluation and Mitigation Strategies (REMS). Accessed 1/15/13 at: 350.htm. 2. Hollingsworth K, et al. Popul Health Manag Oct 31. [Epub ahead of print].

9 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 Accessed 1/17/13 at:

10 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 Accessed 1/17/13 at:

11 11 REMS vs Safety Warnings or Cautions for Currently Approved DMTs Fingolimod and natalizumab are the only currently approved DMTs required to have an REMS 1 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: 50.htm.

12 12 IFN β-1a SC 1 IFN β-1a IM 2 IFN β-1b SC 3 IFN β-1b SC 4 Hepatic injuryXXXX Depression, suicideXXXX Anaphylaxis, Other allergic reactions XXXX Decreased blood countXXX Injection-site necrosisXXX Congestive heart failureXX Flu-like complexXX Albumin viral transmission riskX*†X Thyroid dysfunctionX Autoimmune disorderX 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.; Avonex [PI]. Cambridge, MA: Biogen Idec MA Inc.; Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

13 13 Interferon-βs—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS) No REMS required Pretreatment Screening* ContraindicationsHypersensitivity to components 1-4 Risk factorsCongestive heart failure: pre-existing significant cardiac disease 2,3 Thyroid dysfunction: pre-existing thyroid disease 4 Seizures: pre-existing seizures 1 1. Rebif [PI]. Rockland, MA: EMD Serono, Inc.; Avonex [PI]. Cambridge, MA: Biogen Idec MA Inc.; Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; *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.

14 14 Interferon-βs—Risk Mitigation On-Treatment Monitoring* Periodic labsComplete blood count (CBC) with white blood cell (WBC) differential and platelets 1-4 Blood chemistries, including liver function tests 1-4 Thyroid function tests in patients with thyroid disease 4 OngoingMonitor cardiac condition in patients with cardiac disease 2,3 Monitor for depression, suicidal ideation, and/or psychosis 1-4 Monitor patients for seizures 1-3 Monitor for infection Rebif [PI]. Rockland, MA: EMD Serono, Inc.; Avonex [PI]. Cambridge, MA: Biogen Idec MA Inc.; Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; *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.

15 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 16 Glatiramer Acetate—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS) No REMS required On-Treatment Monitoring* No routine safety monitoring required Pretreatment Screening* ContraindicationsKnown hypersensitivity to glatiramer acetate or mannitol Risk factorsNone Copaxone [PI]. Kansas City, MO: Teva Neuroscience, Inc.; *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.

17 17 Natalizumab—Warnings and Precautions Progressive multifocal leukoencephalopathy (PML) 1 –Black-box warning 1 –323 cases of PML have been reported as of January 2, Hypersensitivity reactions 1 Immunosuppression/infection 1 Hepatoxicity 1 1. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; Biogen Idec. Tysabri Update. January 2013.

18 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: ders/UCM pdf.

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

20 20 PML Risk Mitigation–Estimated Incidence in Natalizumab-Treated Patients by Risk Factors Anti-JCV Antibody Status NegativePositive 1 Prior Immunosuppressive Use ≤0.09/ NoYes Natalizumab Exposure No Prior IS UsePrior IS Use 1–24 mo <1/10002/ –48 mo 4/100011/1000 Abbreviations: IS, immunosuppressant; PML, progressive multifocal leukoencephalopathy. 1. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; Bloomgren G, et al. N Engl J Med. 2012;366:

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

22 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:

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

24 24 Natalizumab—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS) 1 Communication toolsMedication guide Elements To Assure Safe Use (ETASU) TOUCH program requirements Pretreatment Screening* 2 ContraindicationsPML; component hypersensitivity Risk factorsAnti-JC virus positive; immunosuppressant use; long duration of therapy 1. Tysabri (natalizumab) Risk Evaluation and Mitigation Strategy. 1/2012. Accessed 1/15/13 at: s/UCM pdf. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; *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.

25 25 Natalizumab—Risk Mitigation On-Treatment Monitoring* 1,2 Periodic labsComplete blood count Liver function tests OngoingMonitor for signs/symptoms of infection Monitor for signs/symptoms of PML Monitor for signs/symptoms of liver dysfunction *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: s/UCM pdf. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.

26 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:

27 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 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: rs/UCM pdf.

29 29 Fingolimod—Cardiac Risk Decreased heart rate, potential arrhythmia 1 –Via action on cardiac S1P receptors 2 Peak effects within 6 hours of first dose, and again between 12 and 20 hours postdose 3 Concern for fatal arrhythmia –1 death in US, within 24 hours of first dose 3 –10 deaths in Europe 4 1. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Kappos L, et al. N Engl J Med. 2010;362: FDA. Drug Safety Communication. 5/14/2012. Accessed 1/16/13 at: 4. EMA. Press release. 1/2/2012. Accessed 1/16/13 at: 425.jsp&mid=WC0b01ac058004d5c1.

30 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:

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

32 32 Fingolimod—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS) 1 Communication toolsCommunication plan Pretreatment Screening* 2 ContraindicationsCertain pre-existing cardiac conditions, treatment with Class I or III anti-arrhythmic Risk factorsCertain cardiac conditions and drugs; active/chronic infection; immunosuppressive therapy; varicella zoster seronegative status; diabetes mellitus (macular edema); fetal risk in women of child-bearing potential *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: ers/UCM pdf. 2. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

33 33 Fingolimod—Risk Mitigation On-Treatment Monitoring* 1,2 At 1st doseHourly pulse and blood pressure for 6 hours after EKG before dose and after observation period Overnight inpatient monitoring as indicated Periodic labsComplete blood count with differential and platelets Liver function tests Hepatitis panel screen at baseline OngoingMonitor cardiac function Monitor for signs/symptoms of infection Monitor visual acuity with ophthalmologic evaluation Monitor for signs/symptoms of respiratory effect Monitor for continued contraception *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: ers/UCM pdf. 2. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

34 34 Teriflunomide—Mechanism of Action Immunomodulatory agent, anti-inflammatory properties Inhibits dihydro-orotate dehydrogenase –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 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 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 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 38 Risk Evaluation and Mitigation Strategy (REMS) No REMS required at this time Pretreatment Screening ContraindicationsSevere hepatic impairment, pregnancy, current leflunomide treatment Risk factorsConcomitant use of other hepatoxic drugs; active/chronic infection; immunosuppression; concomitant neurotoxics and diabetes mellitus (neuropathy); hypertension Teriflunomide—Risk Mitigation Aubagio [PI]. Cambridge, MA: Genzyme Corporation; *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. *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.

39 39 On-Treatment Monitoring* Periodic labsComplete blood count Blood chemistries, including liver function tests, kidney function tests, and potassium OngoingMonitor for signs/symptoms of liver dysfunction Monitor for signs/symptoms of infection Monitor blood pressure Monitor for respiratory effects Monitor for skin reactions Monitor for symptoms of peripheral neuropathy Monitor for continued contraception, if applicable Teriflunomide—Risk Mitigation Aubagio [PI]. Cambridge, MA: Genzyme Corporation; *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.

40 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 41 Panel Discussion I: Physicians’ Perspectives of Risk Mitigation of Current Therapies Moderator Fred D. Lublin, MD Panel Anne H. Cross, MD Andrew H. Goodman, MD

42 42 Risk Mitigation: Where We Are Going Anne H. Cross, MD Professor of Neurology Washington University School of Medicine St. Louis, Missouri

43 43 AgentMS Type Mechanisms of Action *Alemtuzumab, IVRRMSAnti-CD52 (depletes T- and B-cells and monocytes) *Dimethyl fumarate (BG- 12), oral RRMS Activates Nrf2, prevents oxidative stress Daclizumab, IVRRMSAnti-CD25 (increases CD56+ natural killer cells) Laquinimod, oralRRMSTh2 shift Ocrelizumab, IVRRMS, PPMS Anti-CD20 (depletes B-cells) *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: Graphic courtesy of Anne H. Cross, MD. 5 MS Pipeline MS Drugs in Phase III What Are Their Risks and Benefits?

44 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 45 Alemtuzumab—Overview Monoclonal antibody to CD52 1 Humanized IgG1 1 –Cell lysis via antibody-dependent cellular cytolysis 1 CD52 –12 amino acid glycosylated surface protein on T- and B-cells, natural killer cells, monocytes, and some dendritic cells 1-3 –Role of CD52 not fully known 1 1. Hu Y, et al. Immunology. 2009;128: Saidha S, et al. Ann N Y Acad Sci. 2012;1247: Buggins AG, et al. Blood. 2002;100:

46 46 Alemtuzumab (ALZ)—Phase III Studies Both studies 1,2 –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 I 1 –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 II 2 –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: Coles AJ, et al. Lancet. 2012;380:

47 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 48 Alemtuzumab Risks—Infusion Reactions, Infection Infusion reactions 1,2 –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 rate 1,2 –Most infections mild/moderate –Herpetic infections 16% vs 2%–4% for IFN-β 1. Cohen JA, et al. Lancet. 2012;380: Coles AJ, et al. Lancet. 2012;380:

49 49 Alemtuzumab Risks—Cancer CARE-MS I 1 –Thyroid 2 CARE-MS II 2 –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: Coles AJ, et al. Lancet. 2012;380:

50 50 Alemtuzumab Risks—Secondary Autoimmunity Immune thrombocytopenic purpura –3% in CAMMS223 phase II extension, 1 fatality 1 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 factor 3 but is also risk factor for MS 4 Higher serum IL-21 5,6 and CCL21 5 may predict future autoimmunity Abbreviation: Glomerular basement membrane. 1. Coles AJ, et al. Neurology. 2012;78: Clatworthy MR, et al. N Engl J Med. 2008;359: Phelps RG, et al. Kidney Int. 1999;56: Lincoln MR, et al. Proc Natl Acad Sci USA. 2009;106: Jones JL, et al. J Clin Invest. 2009;119: Jones JL, et al. Mult Scler J. 2011:17(suppl 10):S459.

51 51 Alemtuzumab Risks—Prolonged Alterations of Lymphocytes Hill-Cawthorne GA, et al. J Neurol Neurosurg Psychiatry. 2012;83: Follow-up of initial 37 MS patients receiving single dosing of alemtuzumab in 1990s Median time to recover to lower limit of normal range after single dose –35 months for CD4+ T-cells –20 months for CD8+ T-cells –7.1 months for B-cells CD4+ and CD8+ T-cells did not recover to baseline in most patients

52 52 Alemtuzumab—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS)* Communication toolsLikely to include medication guide, patient package insert, and communication plan Elements To Assure Safe Use (ETASU) May require special training to prescribe and deliver/infuse, and recommended monitoring On-Treatment Monitoring* During infusionMonitor for infusion reactions Periodic labsCBC with differential and platelet count Thyroid, liver, and renal functions tests OngoingMonitor for signs/symptoms of infection *All of the above is projected based on clinical trial protocols and expert opinion and cannot be known with certainty without FDA approval, REMS documents, and product label. Written communication with A. Cross, MD. January Abbreviations: CBC, complete blood count; ITP, immune thrombocytopenic purpura. Pretreatment Screening* ContraindicationsActive infection, active neoplastic disease Risk factorsHistory of ITP, other autoimmune diseases

53 53 Dimethyl Fumarate (BG-12)— Overview Activates nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional pathway 1 Nrf2 antioxidant response pathway regulates phase 2 detoxifying enzymes crucial to countering oxidative stress 1 Not considered immunosuppressive 240 mg BID or TID, oral 1. Linker RA, et al. Brain. 2011;134:

54 54 Dimethyl Fumarate—Phase III Summary Percent Reductions Compared with Placebo in DEFINE and CONFIRM DEFINE 1 BID CONFIRM 2 BID DEFINE 1 TID CONFIRM 2 TID ARR53%↓44%↓48%↓51%↓ % with relapse49%↓34%↓50%↓45%↓ Disability progression 38%↓21%↓34%↓ 24%↓ New/enlarging T2 lesions 85%↓71%↓74%↓73%↓ New T1 lesions 57%↓ 65 %↓ New Gd+ lesions90%↓73%↓ DEFINE, n= 1234; CONFIRM, n=1417; BG-12 at dose of 240 mg in both studies. Abbreviation: ARR, annualized response rate. 1. Gold R, et al. N Engl J Med. 2012;367: Fox RJ, et al. N Engl J Med. 2012;367: Graphic courtesy of Anne H. Cross, MD.

55 55 Dimethyl Fumarate—For Which Patient Types Might This Drug Be Appropriate? Patients seeking an oral medication but who have contraindications to the current oral medications Patients with MS and psoriasis –Fumaric acid esters used in Europe to treat psoriasis 1 1. Meissner M, et al. J Dtsch Dermatol Ges. 2012;10:

56 56 Dimethyl Fumarate Risks—General Adverse Events Common adverse events –Flushing in >25% in both DEFINE and CONFIRM 1,2 –Gastrointestinal effects >35% in CONFIRM 2 Adverse events leading to drug discontinuation –Similar to placebo in both DEFINE and CONFIRM 1,2 Mean lymphocyte count decreases by 25–30% over year 1, then plateaued 3 Hepatic transaminases increase first 6 months 3 1. Gold R, et al. N Engl J Med. 2012;367: Fox RJ, et al. N Engl J Med. 2012;367: Selmaj K, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 484.

57 57 Dimethyl Fumarate Risks—General Adverse Events Infections –Infections: greater in the BG-12 arms in CONFIRM 1 –Serious infections: no different vs placebo in both DEFINE 2 and CONFIRM 1 –Opportunistic infections: none in either study 1,2 Malignancies –No malignancies in the BG-12 groups in CONFIRM 1 –No increased rate of malignancies with BG-12 in DEFINE 2 1. Fox RJ, et al. N Engl J Med. 2012;367: Gold R, et al. N Engl J Med. 2012;367:

58 58 Dimethyl Fumarate—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS)* Unlikely to require an REMS On-Treatment Monitoring* Periodic labs, at least during year 1 CBC with differential and platelet count Liver transaminases Pretreatment Screening* ContraindicationsNone known Risk factorsActive or frequent infection, low WBC, GERD *All of the above is projected based on clinical trial protocols and expert opinion and cannot be known with certainty without FDA approval, REMS documents, and product label. Written communication with A. Cross, MD. January Abbreviations: CBC, complete blood count; GERD, gastroesophageal reflux disease; WBC, white blood cell count.

59 59 Daclizumab—Overview Humanized monoclonal antibody to IL-2 receptor alpha sub-unit 1 Formerly FDA-approved to limit transplant rejection, but removed from US market by manufacturer in (not due to safety concerns) Mechanisms of action not fully understood 3 Increases CD56 bright natural killer cell subset 3 Phase II 4,5 (SELECT/SELECTION) and III 6 MS studies of daclizumab “High Yield Process” (HYP) ongoing 1. Saidha S, et al. Ann N Y Acad Sci. 2012;1247: FDA. Dear Healthcare Professional letter. 9/2009. Accessed 1/24/13 at: 3. Stüve O, et al. Lancet Neurol. 2010;9: Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract ClinicalTrials.gov ID: NCT

60 60 RRMS and SPMS patients failing IFN-β alone N = 230 CHOICE, Phase II—Daclizumab vs Placebo + IFN-β for 24 Weeks Low-dose DAC = 1 mg/kg q4wk; high-dose DAC = 2 mg/kg q2wk. Abbreviation: DAC, daclizumab. Wynn D, et al. Lancet Neurol. 2010;9: Mean New or Enlarging Gd+ Lesions (Adjusted) P =.51 P =.004 n = 77n = 78n = 75

61 61 Daclizumab—For Which Patient Types Might This Drug Be Appropriate Patients who do not want to self-inject frequently Patients with aggressive MS and prior therapy –Suboptimal response –Intolerance Patients who may be candidates for combination therapy –Add-on daclizumab reduced disease activity in patients on interferon-β 1 1. Wynn D, et al. Lancet Neurol. 2010;9:

62 62 Daclizumab Risks—Infection and Other Serious Adverse Events Serious adverse events in CHOICE –13% vs 5% with IFN β-1a + placebo Infections in CHOICE –Most frequent grade 3 adverse events were infections and infestations (7% vs 3%) –No opportunistic infections Wynn D, et al. Lancet Neurol. 2010;9:

63 63 Daclizumab Risks—Autoimmune Complications Autoimmune complications in SELECTION* 1 –1 death from autoimmune hepatitis, 300-mg dose –Reports of autoimmune complications in 2 others Deaths –No deaths in CHOICE 2 –1 death in SELECT (psoas abscess complication) 3 –1 death in SELECTION (autoimmune hepatitis) 1 *Phase II trial of daclizumab “High Yield Process” (HYP). 1. Giovannoni G, et al. Paper presented at: ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract Wynn D, et al. Lancet Neurol. 2010;9: Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 149.

64 64 Daclizumab—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS)* Communication toolsLikely to include medication guide, patient package insert, and communication plan Elements To Assure Safe Use (ETASU) May require education/restrictions for prescribers, due to potential serious autoimmunity risk On-Treatment Monitoring* Periodic labsLiver function tests OngoingMonitor for signs/symptoms of infection Pretreatment Screening* ContraindicationsActive infection Risk factorsHistory of autoimmune hepatitis or other autoimmune diseases, frequent infections *All of the above is projected based on clinical trial protocols and expert opinion and cannot be known with certainty without FDA approval, REMS documents, and product label. Written communication with A. Cross, MD. January 2013.

65 65 Laquinimod—Overview Oral synthetic chemical 1 Structure based on linomide 1 –Linomide previously under study and appeared effective in RRMS and SPMS 2 –Linomide phase III trial halted due to cardiopulmonary toxicity, pancreatitis, death 2 –Laquinimod developed by chemical modification of linomide to reduce toxicity and improve potency 3 Penetrates intact blood-brain barrier and into CNS tissues 4 –May act in both the periphery and in the CNS itself 1. Thöne J, et al. Am J Pathol. 2012;180: Noseworthy JH, et al. Neurology. 2000;54: Jönsson S, et al. J Med Chem. 2004;47: Brück W, Wegner C. J Neurol Sci. 2011;306:

66 66 Laquinimod—Phase III Summary ALLEGRO (n = 1106) 1 –Reduced ARR by 23% compared with placebo –Reduced proportion with progression by 36% BRAVO (n = 1331) 2 –Reduced ARR by 17.6% compared with placebo, unadjusted (P =.075) Reduced ARR by 21.6%, adjusted (P =.026) –Reduced 3-month confirmed disability progression by 33.5% (P =.04) CONCERTO 3 –Planned study to assess higher dose of 1.2 mg vs 0.6 mg/day; estimated completion Comi G, et al. N Engl J Med. 2012;366: Vollmer TL, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract ClinicalTrials.gov ID: NCT

67 67 Laquinimod—For Which Patient Types Might This Drug Be Appropriate? Patients seeking an oral medication who have contraindications to the current oral medications Patients with secondary-progressive MS, because studies of linomide, its precursor, showed suggestions of efficacy in SPMS 1 1. Karussis DM, et al. Neurology. 1996;47:

68 68 Laquinimod Risks—General Adverse Events in ALLEGRO Common adverse events –Back pain in 16.4% vs 9.0% for placebo –Abdominal pain in 5.8% vs 2.9% for placebo –Cough in 7.5% vs 4.5% for placebo Transient elevations in ALT to >3 x ULN in 5% vs 2% for placebo Abbreviations: ALT, alanine aminotransaminase; ULN, upper limit of normal. 1. Comi G, t al. N Engl J Med. 2012;366:

69 69 Laquinimod Risks—General Adverse Events in ALLEGRO Proportion with serious adverse events 11.1% vs 9.5% for placebo 1 –Appendicitis 5 cases vs 1 –Cancer 8 cases vs 6 No deaths reported in the laquinimod group 1 Total discontinuations due to adverse events 7.8% vs 5% for placebo 2 1. Comi G, et al. N Engl J Med. 2012;366: Supplementary Appendix for Comi G, et al. N Engl J Med. 2012;366:

70 70 Laquinimod—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS)* Unlikely to require an REMS On-Treatment Monitoring* Periodic labsLiver function tests, particularly during first months Pretreatment Screening* ContraindicationsActive hepatic or pancreatic disease Risk factorsNot known *All of the above is projected based on clinical trial protocols and expert opinion and cannot be known with certainty without FDA approval, REMS documents, and product label. Written communication with A. Cross, MD. January 2013.

71 71 Ocrelizumab—Overview 1. Kappos L, et al. Lancet. 2011;378: ClinicalTrials.gov ID: NCT ClinicalTrials.gov ID: NCT ClinicalTrials.gov ID: NCT Fully humanized monoclonal antibody anti-CD20 1 Depletes B lymphocytes primarily through increased antibody-dependent cell-mediated cytolysis 1 Similar to rituximab, not identical 1 –Rituximab chimeric, ocrelizumab fully humanized Ongoing phase III studies –OPERA I 2 and II 3 – relapsing-remitting MS –ORATORIO 4 – primary-progressive MS

72 72 Ocrelizumab 600 mg Placebo Annualized relapse rate Mean Gd+ lesions Mean new/enlarging T2 lesions Kappos L, et al. Lancet. 2011;378: Graphic courtesy of Anne H. Cross, MD. Phase II—Ocrelizumab vs Placebo vs IFN β-1a IM for 24 Weeks 2 infusions (300 mg x 2) 2 weeks apart Ocrelizumab 600 mg reduced: –ARR by 80% –Number of Gd+ lesions by 89%

73 73 Ocrelizumab—For Which Patient Types Might This Drug Be Appropriate Patients who want a long-acting medication –Ocrelizumab is given every 6 months Patients with aggressive MS and prior therapy –Suboptimal response –Intolerance Patients with very aggressive MS not responding to or not wishing to take natalizumab –Or with positive anti-JC virus serology putting them at risk for PML on natalizumab

74 74 Ocrelizumab Risks—Opportunistic Infections No opportunistic infections in MS trials 1,2 But increased serious and opportunistic infections, including deaths, in phase III trials for rheumatoid arthritis (RA) 3 –RA trials were discontinued –Increased infections in RA trials driven by sites in Asia and higher dose 1 1. Kappos L, et al. Lancet. 2011;378: Hauser S, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract S Roche. Press release. March 8, Accessed 1/24/13 at:

75 75 Ocrelizumab Risks—Progressive Multifocal Leukoencephalopathy (PML) With rituximab: –At least 2 cases of PML seen in systemic lupus erythematosus patients –2 cases of PML in lymphoma who also had MS –0 cases in MS alone These cases are with rituximab – one cannot extrapolate this risk to ocrelizumab FDA. Information for Healthcare Professionals: Rituximab. December Accessed 1/24/13 at: htm.

76 76 Ocrelizumab—Risk Mitigation Risk Evaluation and Mitigation Strategy (REMS)* Communication toolsLikely to include medication guide, patient package insert, and communication plan Elements To Assure Safe Use (ETASU) May require education/restrictions on prescribers due to possible risk of serious infections, including PML On-Treatment Monitoring* OngoingMonitor for signs/symptoms of infection Pretreatment Screening* ContraindicationsActive infection, immunoglobulin deficiency syndromes Risk factorsAntibodies to JC virus (possible) *All of the above is projected based on clinical trial protocols and expert opinion and cannot be known with certainty without FDA approval, REMS documents, and product label. Written communication with A. Cross, MD. January 2013.

77 77 For More Information on Clinical Trial Data of These Emerging Therapies, Please See Dr. Cross’s Recent MS Grand Rounds Webcast. “New and Emerging Therapies in MS: Is it Time to Change the Status Quo?” Emerging-Therapies-MS-Is-it-Time-to-Change-Status.cfm?jn= Emerging-Therapies-MS-Is-it-Time-to-Change-Status.cfm?jn=

78 78 Conclusion Several new MS DMTs are in the near pipeline All have different mechanisms of action from each other and from currently approved DMTs Risks, adverse events, and contraindications not fully known yet Choices for DMTs will be wider in future –Allowing treatment of patients with suboptimal response to, intolerance of, or contraindication for existing DMTs

79 79 Panel Discussion II: Physicians’ Perspectives of Risk Mitigation of Emerging Therapies Moderator Fred D. Lublin, MD Panel Anne H. Cross, MD Andrew H. Goodman, MD

80 80 Conclusion Fred D. Lublin, MD

81 81 Practical Action for Neurologists in Current Practice to Mitigate Risk Awareness –Risks –Product labels, including safety profiles –REMS plans, if relevant –FDA postmarketing safety updates Education –Practitioners –Patients –Goals Awareness of adverse effects of new medications Compliance with programs (REMS or other)

82 82 Practical Action for Neurologists in Current Practice to Mitigate Risk Communication of risks and benefits –Practitioners –Patients –Goals Open discussion of risk/benefit and treatment goals with patient Assess patient tolerance for risk Compliance with administration and monitoring requirements Partnering with MS centers

83 83 Involving Patients in the Risk:Benefit Analysis Open discussion Individualized treatment goals Tolerance for risk Informed consent

84 84 Key Questions Related to Balancing Efficacy and Safety in the Future What is the short-term future? What is the long-term future? How will we define inadequate response? –What risks will be associated with evolving treatment goals? –What about the patient’s perspective? What role will biomarkers play in selecting therapy and assessing individual risk? What are the unmet needs?

85 85 Conclusions 9 approved agents MS treatment arena becoming more exciting and complex Pipeline of interesting molecules –Potential to make our patients’ lives better –Will require us to be more vigilant about risks


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