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
Feb 23, 2016
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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 MedicineNew York, New York
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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
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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
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Increased Importance of Risk Mitigation with New MS Therapies
Promise of Enhanced Efficacy
Greater Tolerability and Safety Issues
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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
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Risk Mitigation: Where We Are Now
Risk Mitigation: Where We Are Going
Faculty Panel Discussion
Faculty Panel Discussion
Webcast Agenda
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Risk Mitigation: Where We Are Now Andrew D. Goodman, MD, FAAN
Professor of NeurologyDirector, Multiple Sclerosis Center
Chief, Neuroimmunology UnitDepartment of Neurology
University of Rochester Medical CenterRochester, NY
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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].
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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.
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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.
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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.
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IFN β-1a SC1
IFN β-1a IM2
IFN β-1b SC3
IFN β-1b SC4
Hepatic injury X X X X
Depression, suicide X X X X
Anaphylaxis,Other allergic reactions
X X X X
Decreased blood count X X X
Injection-site necrosis X X X
Congestive heart failure X X
Flu-like complex X X
Albumin viral transmission risk X * † X
Thyroid dysfunction X
Autoimmune disorder X
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.
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Interferon-βs—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)No REMS required
Pretreatment Screening*Contraindications Hypersensitivity to components1-4
Risk factors • Congestive heart failure: pre-existing significant cardiac disease2,3
• Thyroid dysfunction: pre-existing thyroid disease4
• Seizures: pre-existing seizures1
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.
*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.
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Interferon-βs—Risk MitigationOn-Treatment Monitoring*Periodic labs • Complete blood count (CBC) with white blood cell
(WBC) differential and platelets1-4
• Blood chemistries, including liver function tests1-4
• Thyroid function tests in patients with thyroid disease4
Ongoing • Monitor cardiac condition in patients with cardiac disease2,3
• Monitor for depression, suicidal ideation, and/or psychosis1-4
• Monitor patients for seizures1-3
• Monitor for infection2-4
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.
*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.
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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.
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Glatiramer Acetate—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)No REMS required
On-Treatment Monitoring*No routine safety monitoring required
Pretreatment Screening*Contraindications Known hypersensitivity to glatiramer acetate
or mannitolRisk factors None
Copaxone [PI]. Kansas City, MO: Teva Neuroscience, Inc.; 2012.
*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.
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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.
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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.
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TOUCH Program REMS mandates that natalizumab is available
only through TOUCH program Requirements for:
– Prescribers– Pharmacies and infusion centers– Patients
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PML Risk Mitigation–Estimated Incidence in Natalizumab-Treated Patients by Risk Factors
Anti-JCV Antibody Status
Negative Positive1
Prior Immunosuppressive Use
≤0.09/10002
No Yes
NatalizumabExposure No Prior IS Use Prior IS Use
1–24 mo <1/1000 2/1000
25–48 mo 4/1000 11/1000
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.
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Natalizumab PML—Diagnosis
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
Any new symptom or MRI lesion in a patient on natalizumab should raise concern for PML
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.
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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.
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JC Viral DNA (PCR) Assays on CSF
Commercial assay– eg, Focus Diagnostics: lower limit of quantitation
50 copies/mL1 JCV PCR-negative natalizumab PML2
– 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.
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Natalizumab—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)1
Communication tools Medication guideElements To Assure Safe Use (ETASU)
TOUCH program requirements
Pretreatment Screening*2
Contraindications PML; component hypersensitivityRisk factors Anti-JC virus positive;
immunosuppressant use; long duration of therapy
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.
*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.
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Natalizumab—Risk Mitigation
On-Treatment Monitoring*1,2
Periodic labs • Complete blood count• Liver function tests
Ongoing • Monitor 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: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM288126.pdf. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.
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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.
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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.
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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.
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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.
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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 pointesFDA. Drug Safety Communication. 5/14/2012. Accessed 1/16/13 at: http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm.
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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.
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Fingolimod—Risk MitigationRisk Evaluation and Mitigation Strategy (REMS)1
Communication tools Communication plan
Pretreatment Screening*2
Contraindications Certain pre-existing cardiac conditions, treatment with Class I or III anti-arrhythmic
Risk factors Certain 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: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM227965.pdf. 2. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
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Fingolimod—Risk MitigationOn-Treatment Monitoring*1,2
At 1st dose • Hourly pulse and blood pressure for 6 hours after • EKG before dose and after observation period• Overnight inpatient monitoring as indicated
Periodic labs • Complete blood count with differential and platelets• Liver function tests• Hepatitis panel screen at baseline
Ongoing • Monitor 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: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM227965.pdf. 2. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
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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.
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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.
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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.
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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.
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Risk Evaluation and Mitigation Strategy (REMS)No REMS required at this time
Pretreatment ScreeningContraindications Severe hepatic impairment, pregnancy,
current leflunomide treatmentRisk factors Concomitant 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; 2012.
*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.
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On-Treatment Monitoring*Periodic labs • Complete blood count
• Blood chemistries, including liver function tests, kidney function tests, and potassium
Ongoing • Monitor 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; 2012.
*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.
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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
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Panel Discussion I:Physicians’ Perspectives of
Risk Mitigation of Current Therapies
ModeratorFred D. Lublin, MD
PanelAnne H. Cross, MD
Andrew H. Goodman, MD
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Risk Mitigation: Where We Are Going
Anne H. Cross, MD Professor of Neurology
Washington University School of MedicineSt. Louis, Missouri
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Agent MS Type
Mechanisms of Action
*Alemtuzumab, IV RRMS Anti-CD52 (depletes T- and B-cells and monocytes)
*Dimethyl fumarate (BG-12), oral
RRMS Activates Nrf2, prevents oxidative stress
Daclizumab, IV RRMS Anti-CD25 (increases CD56+ natural killer cells)
Laquinimod, oral RRMS Th2 shift Ocrelizumab, IV RRMS,
PPMSAnti-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;1247:117-137. Graphic courtesy of Anne H. Cross, MD.
5 MS Pipeline MS Drugs in Phase III What Are Their Risks and Benefits?
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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
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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.
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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.
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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
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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.
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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.
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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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Alemtuzumab Risks—Prolonged Alterations of Lymphocytes
Hill-Cawthorne GA, et al. J Neurol Neurosurg Psychiatry. 2012;83:298-304.
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
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Alemtuzumab—Risk MitigationRisk Evaluation and Mitigation Strategy (REMS)*Communication tools Likely to include medication guide, patient
package insert, and communication planElements To Assure Safe Use (ETASU)
May require special training to prescribe and deliver/infuse, and recommended monitoring
On-Treatment Monitoring*During infusion Monitor for infusion reactionsPeriodic labs • CBC with differential and platelet count
• Thyroid, liver, and renal functions testsOngoing Monitor 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 2013.Abbreviations: CBC, complete blood count; ITP, immune thrombocytopenic purpura.
Pretreatment Screening*Contraindications Active infection, active neoplastic diseaseRisk factors History of ITP, other autoimmune diseases
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Dimethyl Fumarate (BG-12)—Overview
Activates nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional pathway1
Nrf2 antioxidant response pathway regulates phase 2 detoxifying enzymes crucial to countering oxidative stress1
Not considered immunosuppressive 240 mg BID or TID, oral
1. Linker RA, et al. Brain. 2011;134:678-692.
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Dimethyl Fumarate—Phase III Summary Percent Reductions Compared with Placebo in
DEFINE and CONFIRM
DEFINE1 BID
CONFIRM2 BID
DEFINE1 TID
CONFIRM2 TID
ARR 53%↓ 44%↓ 48%↓ 51%↓% with relapse 49%↓ 34%↓ 50%↓ 45%↓Disability progression
38%↓ 21%↓ 34%↓ 24%↓
New/enlarging T2 lesions
85%↓ 71%↓ 74%↓ 73%↓
New T1 lesions 57%↓ 65 %↓New Gd+ lesions 90%↓ 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;367:1098-1107. 2. Fox RJ, et al. N Engl J Med. 2012;367:1087-1097. Graphic courtesy of Anne H. Cross, MD.
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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
psoriasis1
1. Meissner M, et al. J Dtsch Dermatol Ges. 2012;10:793-801.
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Dimethyl Fumarate Risks—General Adverse Events
Common adverse events– Flushing in >25% in both DEFINE and CONFIRM1,2
– Gastrointestinal effects >35% in CONFIRM2
Adverse events leading to drug discontinuation – Similar to placebo in both DEFINE and CONFIRM1,2
Mean lymphocyte count decreases by 25–30% over year 1, then plateaued3
Hepatic transaminases increase first 6 months3
1. Gold R, et al. N Engl J Med. 2012;367:1098-1107. 2. Fox RJ, et al. N Engl J Med. 2012;367:1087-1097. 3. Selmaj K, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 484.
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Dimethyl Fumarate Risks—General Adverse Events
Infections – Infections: greater in the BG-12 arms in CONFIRM1
– Serious infections: no different vs placebo in both DEFINE2 and CONFIRM1
– Opportunistic infections: none in either study1,2
Malignancies – No malignancies in the BG-12 groups in CONFIRM1
– No increased rate of malignancies with BG-12 in DEFINE2
1. Fox RJ, et al. N Engl J Med. 2012;367:1087-1097. 2. Gold R, et al. N Engl J Med. 2012;367:1098-1107.
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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*Contraindications None knownRisk factors Active 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 2013.Abbreviations: CBC, complete blood count; GERD, gastroesophageal reflux disease; WBC, white blood cell count.
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Daclizumab—Overview
Humanized monoclonal antibody to IL-2 receptor alpha sub-unit1
Formerly FDA-approved to limit transplant rejection, but removed from US market by manufacturer in 20092 (not due to safety concerns)
Mechanisms of action not fully understood3
Increases CD56bright natural killer cell subset3
Phase II4,5 (SELECT/SELECTION) and III6 MS studies of daclizumab “High Yield Process” (HYP) ongoing
1. Saidha S, et al. Ann N Y Acad Sci. 2012;1247:117-137. 2. FDA. Dear Healthcare Professional letter. 9/2009. Accessed 1/24/13 at: http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM194907.pdf. 3. Stüve O, et al. Lancet Neurol. 2010;9:337-338. 4. Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 149. 5. Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 169. 6. ClinicalTrials.gov ID: NCT01064401.
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Series10
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5 4.75
3.58
1.32
Placebo + IFNLow-dose DAC + IFNHigh-dose DAC + IFN
RRMS and SPMS patients failing
IFN-β aloneN = 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;9:381-390.
Mea
n N
ew o
r Enl
argi
ng
Gd+
Les
ions
(Adj
uste
d)P = .51
P = .004
n = 77 n = 78 n = 75
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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-β1
1. Wynn D, et al. Lancet Neurol. 2010;9:381-390.
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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;9:381-390.
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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 CHOICE2
– 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 169. 2. Wynn D, et al. Lancet Neurol. 2010;9:381-390. 3. Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 149.
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Daclizumab—Risk MitigationRisk Evaluation and Mitigation Strategy (REMS)*Communication tools Likely to include medication guide, patient
package insert, and communication planElements To Assure Safe Use (ETASU)
May require education/restrictions for prescribers, due to potential serious autoimmunity risk
On-Treatment Monitoring*Periodic labs Liver function testsOngoing Monitor for signs/symptoms of infection
Pretreatment Screening*Contraindications Active infection Risk factors History 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.
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Laquinimod—Overview Oral synthetic chemical1
Structure based on linomide1
– Linomide previously under study and appeared effective in RRMS and SPMS2
– Linomide phase III trial halted due to cardiopulmonary toxicity, pancreatitis, death2
– Laquinimod developed by chemical modification of linomide to reduce toxicity and improve potency3
Penetrates intact blood-brain barrier and into CNS tissues4
– May act in both the periphery and in the CNS itself1. Thöne J, et al. Am J Pathol. 2012;180:267-274. 2. Noseworthy JH, et al. Neurology. 2000;54:1726-1733. 3. Jönsson S, et al. J Med Chem. 2004;47:2075-2088. 4. Brück W, Wegner C. J Neurol Sci. 2011;306:173-179.
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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)
CONCERTO3
– Planned study to assess higher dose of 1.2 mg vs 0.6 mg/day; estimated completion 2018
1. Comi G, et al. N Engl J Med. 2012;366:1000-1009. 2. Vollmer TL, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 148. 3. ClinicalTrials.gov ID: NCT01707992.
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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 SPMS1
1. Karussis DM, et al. Neurology. 1996;47:341-346.
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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;366:1000-1009.
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Laquinimod Risks—General Adverse Events in ALLEGRO
Proportion with serious adverse events 11.1% vs 9.5% for placebo1
– Appendicitis 5 cases vs 1– Cancer 8 cases vs 6
No deaths reported in the laquinimod group1
Total discontinuations due to adverse events 7.8% vs 5% for placebo2
1. Comi G, et al. N Engl J Med. 2012;366:1000-1009. 2. Supplementary Appendix for Comi G, et al. N Engl J Med. 2012;366:1000-1009.
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Laquinimod—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)*Unlikely to require an REMS
On-Treatment Monitoring*Periodic labs • Liver function tests, particularly during
first months
Pretreatment Screening*Contraindications Active hepatic or pancreatic diseaseRisk factors Not 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.
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Ocrelizumab—Overview
1. Kappos L, et al. Lancet. 2011;378:1779-1787. 2. ClinicalTrials.gov ID: NCT01247324. 3. ClinicalTrials.gov ID: NCT01412333. 4. ClinicalTrials.gov ID: NCT01194570.
Fully humanized monoclonal antibody anti-CD201
Depletes B lymphocytes primarily through increased antibody-dependent cell-mediated cytolysis1
Similar to rituximab, not identical1 – Rituximab chimeric, ocrelizumab fully humanized
Ongoing phase III studies– OPERA I2 and II3 – relapsing-remitting MS– ORATORIO4 – primary-progressive MS
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Ocrelizumab 600 mg
Placebo
Annualized relapse rate 0.13 0.64Mean Gd+ lesions 0.6 5.5Mean new/enlarging T2 lesions
0.0 1.4
Kappos L, et al. Lancet. 2011;378:1779-1787. 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%
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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
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Ocrelizumab Risks—Opportunistic Infections
No opportunistic infections in MS trials1,2
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 dose1
1. Kappos L, et al. Lancet. 2011;378:1779-1787. 2. Hauser S, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract S30.006. 3. Roche. Press release. March 8, 2010. Accessed 1/24/13 at: http://www.roche.com/media/media_releases/med-cor-2010-03-08.htm.
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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 2006. Accessed 1/24/13 at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126519.htm.
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Ocrelizumab—Risk MitigationRisk Evaluation and Mitigation Strategy (REMS)*Communication tools Likely to include medication guide, patient
package insert, and communication planElements To Assure Safe Use (ETASU)
May require education/restrictions on prescribers due to possible risk of serious infections, including PML
On-Treatment Monitoring*Ongoing Monitor for signs/symptoms of infection
Pretreatment Screening*Contraindications Active infection, immunoglobulin deficiency
syndromes Risk factors Antibodies 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.
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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?”
http://www.projectsinknowledge.com/neurology/multiple-sclerosis/New-Emerging-Therapies-MS-Is-it-Time-to-Change-Status.cfm?jn=2121.04
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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
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Panel Discussion II:Physicians’ Perspectives of
Risk Mitigation of Emerging Therapies
ModeratorFred D. Lublin, MD
PanelAnne H. Cross, MD
Andrew H. Goodman, MD
80
Conclusion
Fred D. Lublin, MD
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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)
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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
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Involving Patients in the Risk:Benefit Analysis
Open discussion Individualized treatment goals Tolerance for risk Informed consent
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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?
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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