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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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, FAANProfessor of Neurology

Director, Multiple Sclerosis CenterChief, Neuroimmunology Unit

Department of NeurologyUniversity of Rochester Medical Center

Rochester, 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 mannitol

Risk 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 guide

Elements To Assure Safe Use (ETASU)

TOUCH program requirements

Pretreatment Screening*2

Contraindications PML; component hypersensitivity

Risk 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 Mitigation

Risk 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


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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


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Risk Evaluation and Mitigation Strategy (REMS)No REMS required at this time

Pretreatment ScreeningContraindications Severe hepatic impairment, pregnancy,

current leflunomide treatment

Risk factors Concomitant use of other hepatoxic drugs; active/chronic infection; immunosuppression; concomitant neurotoxics and diabetes mellitus (neuropathy); hypertension

Teriflunomide—Risk Mitigation


*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.


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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



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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, 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;1247:117-137. 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 plan


May require special training to prescribe and deliver/infuse, and recommended monitoring

On-Treatment Monitoring*During infusion Monitor for infusion reactions

Periodic labs • CBC with differential and platelet count• Thyroid, liver, and renal functions tests

Ongoing 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 disease

Risk 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.

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*Contraindications None known

Risk 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.

59

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.

60

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.

Me

an

New

or

En

larg

ing

G

d+

Les

ion

s (

Ad

jus

ted

)

P = .51P = .004

n = 77 n = 78 n = 75

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-β1

1. Wynn D, et al. Lancet Neurol. 2010;9:381-390.

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;9:381-390.

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 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.

64

Daclizumab—Risk MitigationRisk Evaluation and Mitigation Strategy (REMS)*Communication tools Likely to include medication guide, patient



May require education/restrictions for prescribers, due to potential serious autoimmunity risk

On-Treatment Monitoring*Periodic labs Liver function tests

Ongoing 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.

65

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.

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)

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.

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 SPMS1

1. Karussis DM, et al. Neurology. 1996;47:341-346.

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;366:1000-1009.

69

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.

70

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 disease

Risk factors Not known


71

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

72

Ocrelizumab 600 mg

Placebo

Annualized relapse rate 0.13 0.64

Mean Gd+ lesions 0.6 5.5

Mean 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%

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

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.

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 2006. Accessed 1/24/13 at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126519.htm.

76

Ocrelizumab—Risk MitigationRisk Evaluation and Mitigation Strategy (REMS)*Communication tools Likely to include medication guide, patient



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)


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?”

http://www.projectsinknowledge.com/neurology/multiple-sclerosis/New-Emerging-Therapies-MS-Is-it-Time-to-Change-Status.cfm?jn=2121.04



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

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

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

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

Involving Patients in the Risk:Benefit Analysis

Open discussion Individualized treatment goals Tolerance for risk Informed consent

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

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

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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