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
1
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
2
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
3
Increased Importance of Risk
Mitigation with New MS Therapies
Promise of
Enhanced
Efficacy
Greater
Tolerability and
Safety Issues
4
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
5
Webcast Agenda
Risk Mitigation: Where We Are Now
Faculty Panel Discussion
Risk Mitigation: Where We Are Going
Faculty Panel Discussion
6
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
7
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/ucm111
8
350.htm. 2. Hollingsworth K, et al. Popul Health Manag. 2012 Oct 31. [Epub ahead of print].
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.
9
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.
10
REMS vs Safety Warnings or Cautions
for 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/ucm1113
11
50.htm.
Interferon(IFN)-βs—Prescribing
Information Safety Warnings/Precautions
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
X
X
X
X
X
Decreased blood count
Injection-site necrosis
X
Congestive heart failure
X
Flu-like complex
Albumin viral transmission risk
X
*
Thyroid dysfunction
Autoimmune disorder
X
X
X
†
X
X
X
*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.
12
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
*The above information is based on the product labels. Please refer to the product labels for full
prescribing information and screening/monitoring requirements. Additional screening/monitoring may be
needed based on individual patient clinical status and clinician discretion.
1. Rebif [PI]. Rockland, MA: EMD Serono, Inc.; 2012. 2. Avonex [PI]. Cambridge, MA: Biogen Idec
MA Inc.; 2012. 3. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2012. 4.
13
Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
Interferon-βs—Risk Mitigation
On-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
*The above information is based on the product labels. Please refer to the product labels for full
prescribing information and screening/monitoring requirements. Additional screening/monitoring may be
needed based on individual patient clinical status and clinician discretion.
1. Rebif [PI]. Rockland, MA: EMD Serono, Inc.; 2012. 2. Avonex [PI]. Cambridge, MA: Biogen Idec
MA Inc.; 2012. 3. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2012. 4.
14
Extavia [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
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.
15
Glatiramer Acetate—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)
No REMS required
Pretreatment Screening*
Contraindications
Known hypersensitivity to glatiramer acetate
or mannitol
Risk factors
None
On-Treatment Monitoring*
No routine safety monitoring required
*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.
16
Copaxone [PI]. Kansas City, MO: Teva Neuroscience, Inc.; 2012.
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.
17
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/PostmarketDrugSafetyInformationforPatientsandProvi
18
ders/UCM288126.pdf.
TOUCH Program

REMS mandates that natalizumab is available
only through TOUCH program

Requirements for:
– Prescribers
– Pharmacies and infusion centers
– Patients
19
PML Risk Mitigation–Estimated Incidence in
Natalizumab-Treated Patients by Risk Factors
Anti-JCV Antibody Status
Positive1
Negative
Prior Immunosuppressive Use
No
≤0.09/10002
Yes
Natalizumab
Exposure
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.
20
Natalizumab PML—Diagnosis
Any new symptom or MRI lesion in a patient on
natalizumab should raise concern for PML
Common symptoms1,2

Cognitive changes,
aphasia
Common locations3

Many are frontal, occipital

Can occur in any lobe

Personality/behavioral
changes

Brainstem and
cerebellum

Weakness


Seizures
Generally spares spinal
cord and optic nerves

Ataxia

Visual symptoms
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.
21
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.
“
22
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.
23
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
*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/PostmarketDrugSafetyInformationforPatientsandProvider
24
s/UCM288126.pdf. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.
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/PostmarketDrugSafetyInformationforPatientsandProvider
25
s/UCM288126.pdf. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.
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.
26
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.
27
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/PostmarketDrugSafetyInformationforPatientsandProvide
28
rs/UCM227965.pdf.
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:
29
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/01/news_detail_001
425.jsp&mid=WC0b01ac058004d5c1.
Fingolimod—Cardiac Risk

All patients monitored for 6 hours after 1st dose
–
–

Hourly pulse and blood pressure
EKG at beginning and end of dosing
Overnight inpatient cardiac monitoring for
patients with:
–
–
–
–
Severe bradycardia (<45 beats/minute) after 1st dose
Certain pre-existing conditions in whom bradycardia
may be poorly tolerated
QT interval prolongation prior to starting fingolimod
or during the monitoring period
Concurrent therapy with other drugs that:


Slow the heart rate or atrioventricular conduction
Prolong the QT interval and that can cause a serious and
life-threatening abnormal heart rhythm called Torsades de
pointes
FDA. Drug Safety Communication. 5/14/2012. Accessed 1/16/13 at:
http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm.
30
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
31
with A. Goodman, MD. January 2013. 3. Pelletier D, et al. N Engl J Med. 2012;366:339-347.
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/PostmarketDrugSafetyInformationforPatientsandProvid
32
ers/UCM227965.pdf. 2. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
Fingolimod—Risk Mitigation
On-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/PostmarketDrugSafetyInformationforPatientsandProvid33
ers/UCM227965.pdf. 2. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
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.
34
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.
35
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.
36
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.
37
Teriflunomide—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)
No REMS required at this time
Pretreatment Screening
Contraindications
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
*The above information is based on the product label. Please refer to the product label for full prescribing
information and screening/monitoring requirements. Additional screening/monitoring may be needed based
on individual patient clinical status and clinician discretion.
*The above screening/monitoring requirements are as reflected in prescribing information. Additional
screening/monitoring may be needed based on individual patient clinical status and clinician discretion.
38
Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.
Teriflunomide—Risk Mitigation
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
*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
Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.
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
40
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
41
Risk Mitigation:
Where We Are Going
Anne H. Cross, MD
Professor of Neurology
Washington University School of Medicine
St. Louis, Missouri
42
5 MS Pipeline MS Drugs in Phase III
What Are Their Risks and Benefits?
Agent
MS
Type
Mechanisms of Action
*Alemtuzumab, IV
RRMS
Anti-CD52 (depletes T- and
B-cells and monocytes)
*Dimethyl fumarate (BG12), 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.
43
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
44
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.
45
3. Buggins AG, et al. Blood. 2002;100:1715-1720.
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.
46
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
47
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.
48
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.
49
Alemtuzumab Risks—Secondary
Autoimmunity

Immune thrombocytopenic purpura
–

Thyroid autoimmunity
–


3% in CAMMS223 phase II extension, 1 fatality1
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;56:16381653. 4. Lincoln MR, et al. Proc Natl Acad Sci USA. 2009;106:7542-7547. 5. Jones JL, et al. J Clin Invest.
50
2009;119:2052-2061. 6. Jones JL, et al. Mult Scler J. 2011:17(suppl 10):S459.
Alemtuzumab Risks—Prolonged
Alterations of Lymphocytes

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
Hill-Cawthorne GA, et al. J Neurol Neurosurg Psychiatry. 2012;83:298-304.
51
Alemtuzumab—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)*
Communication tools
Likely 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
Pretreatment Screening*
Contraindications
Active infection, active neoplastic disease
Risk factors
History of ITP, other autoimmune diseases
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.
52
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.
53
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%↓
57%↓
New T1 lesions
New Gd+ lesions
90%↓
65 %↓
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.
54
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.
55
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.
56
3. Selmaj K, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 484.
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
57
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.
Dimethyl Fumarate—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)*
Unlikely to require an REMS
Pretreatment Screening*
Contraindications
None known
Risk factors
Active or frequent infection, low WBC, GERD
On-Treatment Monitoring*
Periodic labs, at least
during year 1
• CBC with differential and platelet count
• Liver transaminases
*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 58
cell count.
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,
59
2011; Amsterdam, Netherlands. Abstract 169.
6. ClinicalTrials.gov ID: NCT01064401.
CHOICE, Phase II—Daclizumab vs
Placebo + IFN-β for 24 Weeks
P = .51
Mean New or Enlarging
Gd+ Lesions (Adjusted)
5
P = .004
4.75
4.5
4
3.58
Placebo + IFN
Low-dose DAC + IFN
High-dose DAC + IFN
3.5
3
2.5
2
1.32
1.5
1
0.5
0
n = 77
n = 78
RRMS and SPMS
patients failing
IFN-β alone
N = 230
n = 75
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.
60
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.
61
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.
62
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
63
G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 149.
Daclizumab—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)*
Communication tools
Likely 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
Pretreatment Screening*
Contraindications
Active infection
Risk factors
History of autoimmune hepatitis or other
autoimmune diseases, frequent infections
On-Treatment Monitoring*
Periodic labs
Liver function 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.
64
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 itself
1. 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;306:17365
179.
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.
66
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.
67
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.
68
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.
69
Laquinimod—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)*
Unlikely to require an REMS
Pretreatment Screening*
Contraindications
Active hepatic or pancreatic disease
Risk factors
Not known
On-Treatment Monitoring*
Periodic labs
• Liver function tests, particularly during first
months
*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.
70
Ocrelizumab—Overview

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
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.
71
Phase II—Ocrelizumab vs Placebo
vs IFN β-1a IM for 24 Weeks
Annualized relapse rate
Mean Gd+ lesions
Mean new/enlarging T2
lesions


Ocrelizumab
600 mg
0.13
0.6
0.0
Placebo
0.64
5.5
1.4
2 infusions (300 mg x 2) 2 weeks apart
Ocrelizumab 600 mg reduced:
– ARR by 80%
– Number of Gd+ lesions by 89%
Kappos L, et al. Lancet. 2011;378:1779-1787. Graphic courtesy of Anne H. Cross, MD.
72
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
73
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.
74
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/ucm1
26519.htm.
75
Ocrelizumab—Risk Mitigation
Risk Evaluation and Mitigation Strategy (REMS)*
Communication tools
Likely 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
Pretreatment Screening*
Contraindications
Active infection, immunoglobulin deficiency
syndromes
Risk factors
Antibodies to JC virus (possible)
On-Treatment Monitoring*
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.
76
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/NewEmerging-Therapies-MS-Is-it-Time-to-Change-Status.cfm?jn=2121.04
77
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
78
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
79
Conclusion
Fred D. Lublin, MD
80
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)
81
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
82
Involving Patients in the
Risk:Benefit Analysis

Open discussion

Individualized treatment goals

Tolerance for risk

Informed consent
83
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?
84
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
85