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Practitioner’s Edge is a registered service mark of Integrity Continuing Education, Inc.© 2014 Integrity Continuing Education, Inc.
Sponsored by Integrity Continuing Education
Improving Management Strategies for Patients With Multiple Sclerosis:
An Evaluation of Current Practice
Supported by an educational
grant from Novartis
2
Elizabeth Crabtree, MD
Associate Professor of Neurology Director of Patient Education and Support University of California San Francisco MS Center San Francisco, California
3
Faculty Disclosures
4
• Apply the most recent evidence-based criteria toward the diagnosis of multiple sclerosis (MS)
• Implement management strategies that are personalized to the individual needs of patients with MS
• Describe the risks and benefits of all approved therapies for the management of patients with MS
• Monitor response to therapy as recommended by current treatment guidelines, so that changes in a patient’s treatment plan can be implemented if necessary
Learning Objectives
Multiple Sclerosis Overviewand Unmet Needs
5
6
Chronic inflammatory, neuroimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS)
Characterized by macroscopic and microscopic injury to gray and white matter
Common manifestations are optic neuritis, partial transverse myelitis, and brain stem or cerebellar syndrome
Progressive disability occurs over time
Exact etiology is unknown
Multiple Sclerosis Overview
7
• Affects ~400,000 people1
• Major cause of nontraumatic disability2
• Disease sequelae
– Multiple symptoms
– Disability (cognitive, motor, vocational)
– Psychological stress3
• $8,528 to $54,244 per patient/year in direct plusindirect costs4
Prevalence and Burden of MS in the United States
1. Tullman MJ. Am J Manag Care. 2013;19(2, suppl):S15-S20; 2. Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10;3. Kalb R. J Neurol Sci. 2007;256(suppl 1):S29-S33; 4. Adelman G, et al. J Med Econ. 2013;16(5):639-647.
8
Relapsing Remitting (RRMS)Unpredictable
exacerbations of new symptoms or worsening of old
symptoms
Initial onset in 85% of cases
Secondary Progressive (SPMS)
Initially relapsing remitting course
that finally becomes
progressive
Usually the natural course
following RRMS
Progressive
Relapsing (PRMS)
Progressive from onset and is
characterized by intermittent
relapses
Rare
Primary Progressive (PPMS)
Progressive disease from the
onset without relapses
Observed in 10% to 15% of
cases
Clinical Courses of MS
Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10.
9
• Delay in diagnosis and misdiagnosis
• Lack of biomarkers for disease activity
• No curative or reparative/restorative therapy
• Patient compliance with therapeutic protocols
Unmet Needs in MS
Pathophysiology of MS
10
11
• Immune-mediated mechanisms damage CNS tissue
• Inflammatory response (early vs later, gray vs white matter)
− B-cell, follicle-like structures in cortical areas
• Environmental factors (vitamin D, smoking, ultraviolet light)
• Infectious factors (Epstein-Barr virus)
• Genetic factors (eg, multiple non-MHC susceptibility genes)
− No family history: 1/750 for developing MS
− Family history (parent or sibling): 1/40 for developing MS
− 1st-degree relative (2%-3% chance; sibling > parent)
Underlying Pathophysiology of MS
Handel AE, et al. Mult Scler Rel Disord. 2012;1(1):39-42; National MS Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/genetics/index.aspx.
MHC, major histocompatibility complex.
12
• Focal demyelinated plaques disseminated in CNS
• Easily visualized in the white matter, but extensive gray matter involvement especially in early MS
• Predilection for optic nerves, subpial, spinal cord, brain stem, cerebellum and juxtacortical, and periventricular white matter regions
• Variable degrees of inflammation, gliosis, and neurodegeneration
Observed Changes in the CNS in MS
Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.
13
Patients with early RRMS showed significantly lower SDGM, but not cortical volumes compared with patients with CIS
Evidence that significant SDGM atrophy (not cortical) occurs rapidly during first 4 years in treatment-naïve patients
Confirms that selective regional, but not global, atrophy occurs from clinical onset to conversion to clinically definite MS
Evidence for Gray Matter Involvement
Bergsland N, et al. AJNR Am J Neuroradiol. 2012;33:1573–1578.
SDGM, subcortical deep gray matter; CIS, clinically isolated syndrome.
14
Immune-mediated Axonal Injury Mechanisms
Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12.
Transection leads to degeneration of the distal end of the axon and the proximal end forms an ovoid due to accumulation of transported organelles
Immune-mediated processes lead to axonal transection
15
Cortical Demyelination Patterns
Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12.
16
• Common and may represent an early and/or initial target of MS disease process
• May represent the pathologic substrate of cognitive impairment and seizures in RRMS
• Highly inflammatory and suggests that neuronal and axonal injury in early cortical demyelination occur on a background of inflammation
• Meningeal inflammation is present in early MS and topographically associated with cortical lesions
– Infiltrates are composed of T cells, B cells, and macrophages
Cortical Demyelinated Lesions in Early MS: New Insights
Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.
17
MRI of Cortical Onset MS
Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.
MRI, magnetic resonance imaging.
18
• Very prominent
• Less inflammatory than white matter lesions
− Lack inflammatory infiltrates, complement deposition, and breakdown of blood-brain barrier
• Characterized by meningeal inflammatory aggregates (B cell follicle-like structures) in primary as well as secondary progressive MS
• Associated with increased rate of clinical progression
Cortical Demyelinated Lesions in Progressive MS: New Insights
Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921; Popescu BF, Lucchinetti CF. BMC Neurol. 2012;12:11; Howell OW, et al. Brain. 2011;134(Pt 9):2755-2771; Choi SR, et al. Brain. 2012;135(Pt 10):2925-2937.
19
Cortical Demyelination in SPMS
Howell OW, et al. Brain. 2011;134(Pt 9):2755-2771.
20
New Data on Cortical Pathology and SPMS
Calabrese M, et al. Ann Neurol. 2013;74(1):76-83.
21
Other Studies on Cortical Demyelinating Lesions
• New MRI techniques for visualization (DIR, PSIR, T1-weighted 3D FSPGR) and early diagnosis
• Correlation between gray matter pathology and patient disability and cognitive impairment
• Effect of disease-modifying therapy on gray matter pathology
• Increased cortical demyelinating lesions can indicate evolution of RRMS to SPMS
DIR, double inversion recovery; PSIR, phase-sensitive inversion recovery; 3D, three-dimensional;FSPGR, fast spoiled gradient echo.
Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.
Diagnosis of MS
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23
Exclusion of hereditary, psychological, and other
CNS disorders
Supplemented by paraclinical tests, including MRI, evaluation of cerebrospinal fluid (CSF)
Clinical evaluation of history, symptoms, signs, relapses, and disability progression
Recommendations for Diagnosis of MS
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
24
No clinical findings are unique to MS Difficulty in patient characterization and
physician interpretation of symptoms Numerous differential diagnoses of MS-like
symptoms Imaging is not always specific and there may be
an overreliance on MRI Confounding comorbidities Unpredictable MS clinical courses
Challenges in the Diagnosis of MS
Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922–943.
25
• Typically affects young adults (aged 20-45 years)
• Patient demonstrates signs and symptoms suggestive of CNS demyelination
• Attacks last for at least 24 hours and reach a peak within 2 to 3 weeks
• No indication of fever, infection, or encephalopathy
• Many qualify for definitive diagnosis based on 2010 International Panel diagnostic criteria
Clinically Isolated Syndrome
Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922–943; Lo CP, et al. J Neurol Neurosurg Psychiatry. 2009;80(10):1107-1109.
26
Medical history and neurological examination
usually indicating CIS
MRI to confirm presence of macroscopic
lesions
CSF analysis
Blood tests for ruling out differential diagnoses
Steps Toward the Diagnosis of MS
Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.
27
Core Requirement: Objective demonstration of dissemination of CNS lesions in both space (DIS)
and time (DIT) by MRI
Revised criteria simplify DIS and DIT for MS diagnosis
Correct interpretation of clinical signs is critical
(Patient-reported symptoms or objectively observed signs typical
of an acute inflammatory demyelinating event, duration of at least 24 hours, in the absence of
fever or infection)
Alternative diagnoses need to be considered and excluded
McDonald Criteria: 2010 Revision*
*Please see detailed 2010 Revised McDonald Criteria to confirm a diagnosis of MS in your handout. Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
28
Important Considerations in Revised 2010 McDonald Criteria
• Allows diagnosis of MS in patients with CIS
• Exclusion of neuromyelitis optica (NMO) and NMO spectrum disorders
• Diagnosis of PPMS
• Applicability in pediatric, Asian, and Latin American populations
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
29
Pediatric MS
• >95% of pediatric patients with MS have an initial relapsing-remitting disease course
• PPMS is exceptional
• ~80% of pediatric cases, and nearly all adolescent-onset cases, present with attacks typical for adult CIS, with a similar or greater total T2 lesion burden
• MS must be differentiated from acute disseminated encephalomyelitis (ADEM) or NMO
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
30
Confirmation by:
– ≥2 non–ADEM-like attacks following a first ADEM-like attack
OR
– 1 non-ADEM attack followed by accrual of clinically silent lesions
Serial clinical and MRI observations are requiredto confirm a diagnosis of MS in children
Accurate diagnosis of pediatric MS is critical
Criteria for Diagnosis of MS in Pediatric Patients
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
31
• DIS can be demonstrated by:− ≥1 T2 lesion in at least 2 of 4 regions of the CNS*
− Development of further attack implicating different CNS site
− In patients with brain stem or spinal cord syndromes, symptomatic MRI lesions are excluded from the criteria and do not contribute to lesion count
• DIT can be demonstrated by:− Simultaneous presence of asymptomatic gadolinium
(Gd)-enhancing and nonenhancing lesions at any time
− A new T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective of the timing with baseline scan
− The development of a second clinical attack
Revised MRI Criteria for DIS and DIT
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
*Periventricular, juxtacortical, infratentorial, or spinal cord.
32
• How have these revised criteria affected your evaluation of clinical and MRI findings toward a diagnosis of MS?
• Do you use these criteria to make a diagnosis of MS?
• If not, what do you use?
• How many of your patients may have been diagnosed with MS prior to 2010 using the revised criteria?
Clinical Questions
Imaging in MS
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MS Lesions on MRI
Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.
35
MS Lesions on MRI (cont’d)
Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.
CSF Findings
36
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• CSF findings such as ≥2 oligoclonal bands or elevated IgG index can support:
− Inflammatory demyelinating nature of the underlying condition
− Evaluation of alternative diagnoses
− Prediction of confirmed diagnosis of MS
− PPMS
Supportive Role for CSF Findingsin MS Diagnosis
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
IgG, immunoglobulin G.
Case Study #1: Kim, 25-year-old Female
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• Do you agree with how her physician treated her?
• Careful history and physical/neurologic exam− Funduscopic exam− Referral to neuroophthalmologist
• What tests do you order?− Blood work− Brain MRI (with/without contrast, with orbit views)− Spinal MRI (cervical, thoracic, and lumbar)− Lumbar puncture
• Does she meet 2010 criteria for CIS?
• Would you have recommended treatment at the initial visit if her symptoms were still present?
• Approach to counseling on the risk for MS?
Clinical Questions
40
• Depending on level of clinical suspicion, perform tests to exclude:– Autoimmune/demyelinating disorders
– Collagen vascular disease and other rheumatologic conditions
– Infections (ie, Lyme disease, syphilis, HTLV-1, HIV)
– Endocrine abnormalities (eg, thyroid disease)
– Vitamin B12 deficiency
– Sarcoidosis
• Order specific tests? – NMO antibody test
– Cadasil gene test
– Very long chain fatty acids
– Other?
• Kim’s blood work is normal
• Diagnosis: CIS
Case Study #1, Kim, 25-year-old Female: Blood Work
HTLV-1, human T-lymphotropic virus, type 1; HIV, human immunodefiency virus.
Management of Patients with MS
41
42
Proposed Algorithm
Modified from original in Río J, et al. Nat Rev Neurol. 2009;5(10):553-560.
Relapse and/orobserved progression
Consider changein therapy
Treatment with disease-modifyingagents commences
MRI and clinical assessments at 6 to 12 months
Negative MRI result
Relapses and/ordisease progression
Active MRI result
Consider change of therapy
Periodic clinical andMRI assessment
Close clinical and MRI monitoring
No relapses and no disease progression
43
• 10 DMTs to choose from after diagnosis is confirmed
• None are curative
• No “one size fits all” empiric treatment (given variability and unpredictability of MS)
• Disease, drug, patient factors
• Prior experience, availability, cost
• Risk-benefit ratio
Choosing a Disease-modifying Therapy (DMT)
Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.
44
Current disease activity and disability
Disease prognostic profile
Patient lifestyle and expected longevity
Preference for route of treatment administration
Patient's ability to self-treat
Need for therapy to be delivered by a healthcare professional
Reproductive status
Other expectations
Important Considerations Before Making Therapeutic Decisions
Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10.
45
• First-line option involves glucocorticoids• Glucocorticoids may speed up recovery time frame
• Most common regimen – 1000-mg IV methylprednisolone daily for 5 days
without an oral taper– Excellent bioavailability– High-dose oral could be substituted
• Second-line options involve corticotropin gel, plasma exchange, IVIG
Recommendations for Treatment of Acute MS Exacerbations
Goodin DS, et al. Neurology. 2002;58:169-178.
IV, intravenous; IVIG, intravenous immunoglobulin.
46
First-line Agents Second-line Agents
Interferon beta-1aInterferon beta-1bGlatiramer acetate
Oral therapies:FingolimodTeriflunomideDimethyl fumarate
MitoxantroneNatalizumab
Oral therapies:Fingolimod
DMTs Approved for RRMS
Río J, et al. Curr Opin Neurol. 2011;24(3):230-237; Coyle PK. CNS Drugs. 2013;27(4):239-247.
47ClinicalTrials website. www.clinicaltrials.gov. Accessed December 2, 2013.
Safety and efficacy of Siponimod (BAF312) versus placebo for variable treatment durations in patients with SPMS
Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe)
Study of Tcelna (Imilecleucel-T) in Secondary Progressive Multiple Sclerosis (Abili-T)
Masitinib for the treatment of patients with PPMS or relapse-free SPMS
Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis
Current Trials in SPMS
Overview of AvailableAgents for MS
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49
PR
ISM
S
OW
IMS
EV
IDE
NC
E
CA
MM
S22
3
RE
GA
RD
MS
CR
G
EV
IDE
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TR
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BR
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0.0
0.2
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0.87
0.77
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0.340.30
0.670.64
0.33
0.27
0.84
0.36
An
nu
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Ra
te
Relapse Response Rate to Interferons
Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.
INTERFERONS
INF β-1a subcutaneous
‘94 ‘07
INF β-1a intramuscular
‘93 ‘11
INF β-1b
‘88 ‘07
50
• Glatiramer acetate vs placebo• 2-year relapse rate (1.19 vs 1.68)• Reduced disability (22%)• Significant reduction in the number of new T1
Gd-enhancing lesions over 9 months
Study 1 (N=50)Study 2 (N=251)Study 3 (N=239)
(RRMS)
• Results similar to IFNβ-1a for time to first relapse, relapse rates, disease progression, or number and change in volume of T2 active or Gd+ lesions
REGARD trial(RRMS)
• Results similar to IFNβ-1b for relapse risk, disease progression, or MRI measures of lesion burden
BEYOND trial(RRMS)
Clinical Evidence for Glatiramer Acetate
Mikol DD, et al. Lancet Neurol. 2008;7(10):903-914; O'Connor P, et al. Lancet Neurol. 2009;8(10):889-897; McGraw CA, et al. Neurotherapeutics. 2013;10(1):2-18.
IFN, interferon.
51
Relapse Response Rate to Therapies
GLATIRAMER ACETATE
Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.
Johnson REGARD BEYOND CONFIRM0.0
0.2
0.4
0.6
0.8
0.59
0.290.34
0.29
An
nu
ali
zed
Re
lap
se
Ra
te
1991 2011
52
• 3, 6 mg of IV natalizumab per kg of body weight every 28 days compared with placebo
• Fewer inflammatory brain lesions and fewer relapses over a 6-month period
Study 1 (RRMS or relapsing
SPMS)
• 300 mg of natalizumab every 4 weeks compared with placebo for over 2 years
• 68% ↓ in rate of clinical relapse• 83% ↓ in new or enlarging hyperintense
lesions• 92% fewer Gd-enhancing lesions over 2 years• 42% ↓ in risk of sustained disability
progression
Study 2(RRMS)
Clinical Evidence for Natalizumab(mAb against leukocyte integrin α4)
Miller DH, et al. N Engl J Med. 2003;348(1):15-23; Polman CH, et al. N Engl J Med. 2006;354(9):899-910; Río J, et al. Curr Opin Neurol. 2011;24(3):230-237.
mAb, monoclonal antibody.
Newer Oral Therapies
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Would you switch to a new therapy that was oral or injectable and was associated with mild or severe risk and vigilance?
Survey of Patients Taking Self-injected DMT: Route of Administration
Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.
New Oral TherapyMild Risk/Vigilance
New Oral TherapySevere Risk/Vigi-
lance
New TherapyMild Risk/Vigilance
New TherapySevere Risk/Vigi-
lance
0
20
40
60
80
10092
31
78
28
97
59
84
63
Disease and DMT <5 years (n=100) Disease and DMT ≥5 years (n=100)
% P
ati
en
ts R
es
po
nd
ing
Ye
s
55
• Oral dimethyl fumarate 240 mg 2 or 3 times daily compared with placebo over 2 years
• Significantly reduced annualized relapse rates (ARRs; 0.22, 0.20, placebo 0.4) and new or enlarging T2–weighted hyperintense lesions
• Trend towards decreased disability compared with placebo
CONFIRM trial (RRMS)
• Oral dimethyl fumarate 240 mg 2 or 3 times daily compared with placebo over 2 years
• Reduction in relapse rates (27%, 26% vs 46%), ARRs (0.17, 0.19 vs 0.36), ↓number of Gd-enhancing lesions and of new or enlarging T2-weighted hyperintense lesions, and ↓progression of disability (16%-18%) compared with placebo (27%)
DEFINE trial(RRMS)
• Results similar to glatiramer acetate in CONFIRM trial• Long-term benefits unclearLong term
Clinical Evidence for Dimethyl Fumarate
Fox RJ, et al. N Engl J Med. 2012;367:1087-1097; Gold R, et al. N Engl J Med. 2012;367:1098-1107; Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.
56
Indicated for relapsing forms of MS• May cause lymphopenia and flushing• Recent complete blood cell count (< 6 months) before starting treatment
and annually or as clinically indicated• Liver function tests• Administration with food may decrease flushing (ASA but watch GI effects)• Withholding treatment should be considered in patients with severe
infectionsDosing: 240 mg twice-a-day, oral
Warnings and Precautions
Practice Recommendations for Dimethyl Fumarate
National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/warnings-safety-management/index.aspx.
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• Oral fingolimod at a dose of 0.5 mg or 1.25 mg daily compared with placebo over 2 years
• Reduced ARRs (0.18, 0.16 vs 0.4)• Statistically significant reductions in both the risk of
sustained disability progression (hazard ratio, 0.70 and 0.68, respectively; P=.02 vs placebo, for both comparisons)
• Superior MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, Gd-enhancing lesions, and brain-volume loss; P<.001 for all comparisons at 24 months)
FREEDOMS trial(RRMS)
• Compared oral fingolimod (1.25 or 0.5 mg) with IFNβ-1a daily over 1 year
• ↓ ARR (0.2, 0.16 vs 0.33) and reduced MRI lesions• Effect on disability progression was unclear
TRANSFORM MS trial
(RRMS)
• Survey showed that more than 80% of patients reported the first dose of fingolimod was moderately/very/extremely manageable, convenient, and easy to take.
• 4-year data show that continued fingolimod treatment improved brain volume loss
Long term
Clinical Evidence for Fingolimod
Kappos L, et al. N Engl J Med. 2010;362(5):387-401; Cohen JA, et al. N Engl J Med. 2010;362(5):402-415; Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991; Hanson KA, et al. Patient Prefer Adherence. 2013;7:309-318.
58
Adherence with Fingolimod Therapy
Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print]
Naïve disease-modifying therapy users1.0
0.9
0.8
0.7
0.6
0.5
0.4Pro
bab
ilit
y o
f S
tayi
ng
on
In
dex
Med
ica
tio
n
5 25 45 65 85 105 125 145 165 185 205 225 245 265 285 305 325 345 365
DaysFingolimodSubcutaneous interferon beta-1a
Interferon beta-1bGlatiramer acetate
Intramuscular interferon beta-1a
59
Adherence with Fingolimod Therapy (cont’d)
Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print]
Experienced disease-modifying therapy users1.0
0.9
0.8
0.7
0.6
0.5
0.4Pro
bab
ilit
y o
f S
tayi
ng
on
In
dex
Med
ica
tio
n
1 31 61 91 121 151 181 211 241 271 301 331 361
DaysFingolimodSubcutaneous interferon beta-1a
Interferon beta-1bGlatiramer acetate
Intramuscular interferon beta-1a
60
Indicated for relapsing forms of MS• Infection; macular edema; dose-dependent decreased pulmonary function; elevated
serum hepatic transaminases; hypertension• Screening white blood cell count (WBC), serum transaminase determination, serum
bilirubin determination, serum varicella zoster antibody testing (in patients with no history of chicken pox), baseline electrocardiogram, and ophthalmologic evaluation; baseline pulse/blood pressure prior to first dose and observation of all patients for 6 hours after the first dose for signs and symptoms of bradycardia; ophthalmologic evaluation after 3 to 4 months of treatment and in the event of new visual symptoms
• Withholding treatment in patients with severe infections• Women of childbearing age should use effective contraception during and for 2 months
after stopping therapy• Cardiac contraindication
Dosing: 0.5 mg once daily (qd), oral
Warnings and Precautions
Practice Recommendations for Fingolimod
Singer BA. Ther Adv Neurol Disord. 2013;6(4):269-275; National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/warnings-safety-management/index.aspx.
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• Teriflunomide (7/14 mg po qd) vs placebo over 108-week treatment period
• 31% reduction in ARRs• 67% reduction in MRI lesion volume• 30% reduction in disability progression
TEMSO trial(RRMS)
• Teriflunomide (7/14 mg po qd) vs placebo over 48 weeks
• 36% reduction in annual relapse rates• 32% reduction in disability progression
TOWER trial(RRMS)
• History not well established to date• However, have long history of leflunomide use
in rheumatoid arthritis (black boxed warnings for leflunomide)
Long term
Clinical Evidence for Teriflunomide
O’Connor, et al. N Engl J Med. 2011;365(14):1293-303; Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205.
po, by mouth.
62
• Oral teriflunomide 7 or 14 mg or subcutaneous IFNβ-1a 44 µg
• No difference in time to failure was observed• No difference in ARR between teriflunomide
14 mg and IFNβ-1a (0.26 vs 0.22)
TENERE trial (RRMS)
Comparison of Teriflunomide with IFNβ-1a
Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205; Vermersch et al. Mult Scler. 2013 Oct 14. [Epub ahead of print].
63
Indicated for relapsing forms of MS• Infection; elevated serum hepatic transaminases (“black boxed” warning); fetal death
and malformations (“black boxed” warning); skin reactions; blood pressure increase; respiratory effects
• Screen for tuberculosis• Pre-treatment: evaluation for infection, pregnancy, renal failure, peripheral neuropathy,
interstitial pulmonary disease and hypertension; WBC, serum transaminase determination, and serum bilirubin determination
• During treatment: blood pressure monitoring; serum transaminase determinations, renal function
• Women of childbearing age should not be started on therapy until pregnancy is excluded and confirmation of reliable contraception (category X)Dosing: 7 mg or 14 mg; qd oral
Warnings and Precautions
Practice Recommendations for Teriflunomide
National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/warnings-safety-management/index.aspx.
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• Superior efficacy
• Ease of administration
• Good tolerability
• Long-term safety data
• Differs from patient to patient (therefore must be individualized based on risk-benefit ratio)
Ideal Therapy
Fox EJ, et al. Curr Opin Neurol. 2012;25(suppl):S11-S19.
65
Agent Mode of ActionRoute of Administration
Promising Outcomes
Current Status
Glatiramer acetate
Immunomodulatory agent
Subcutaneous Results available on double-dose (20 vs 40 mg) administration
Under FDA review
Laquinimod Immunomodulatory agent
Oral ALLEGRO and BRAVO trials—modest outcomes in annual relapse rates
Ongoing phase 3 trial
Alemtuzumab Humanized monoclonal antibody against CD52
Intravenous CARE-MS I and II trials—reduced annual relapse rate
Under FDA review
Pegylated interferon
PEG-IFN beta-1a Subcutaneous Phase 3 trial—reduced annual relapse rate
Ongoing phase 3 trials
Investigational Agents
Tullman MJ. Am J Manag Care. 2013;19(2, suppl):S21-27; Peru al J, Khan O. Curr Treat Options Neurol. 2012;14(3):256-263; Castro-Borrero et al. Ther Adv Neurol Disord. 2012;5(4):205-220; Clinicaltrials website. www.clinicaltrials.gov. Accessed December 2, 2013.
FDA, US Food and Drug Administration.
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Agent Mode of Action Route of Administration
Promising Outcomes
Current Status
Daclizumab Humanized monoclonal antibody against IL2-R
Subcutaneous SELECT trial—reduction in annual relapse rate
Ongoing phase 3 trials
Ocrelizumab Recombinant human anti-CD20 monoclonal antibody
Intravenous infusion
Phase 2 trial—reduction in annual relapse rate
Ongoing phase 3 trials
BAF312 Selective modulator of sphingosine 1-phosphate receptor types 1 and type 5
Oral BOLD trial—reduction in active lesions
Ongoing phase 3 trials
Masitinib Tyrosine kinase inhibitor
Oral Promising in PPMS and SPMS
Ongoing phase 2b/3 trials
Investigational Agents (cont’d)
Tullman MJ. Am J Manag Care. 2013;19(2,suppl):S21-S27; Peru al J, Khan O. Curr Treat Options Neurol. 2012;14(3):256-263; Castro-Borrero et al. Ther Adv Neurol Disord. 2012;5(4):205-220.
Case Study #2: Carl, 40-year-old Male
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New Imaging Results—New Strategy for Treatment?
• T2-weighted image• Recent scans show
multiple new lesions• What are the next steps
for this patient?
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For this patient with changes on imagery, what is your management strategy:• Do you switch medications? If so, to what?• What criteria do you use to make this decision?• How many relapses are enough in 1 year to consider
switching therapies?• How do you monitor disease status/progression following
a relapse?− Set new baseline MRI at time of relapse
− Frequency of MRI?
• Image results—one new enhancing lesion
Case Discussion
Considerations for Switching Medications
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Proposed Algorithm
Modified from original in Río J, et al. Curr Opin Neurol. 2011;24(3):230-237.
Relapse and/orobserved progression
Consider changein therapy
Treatment with disease-modifyingagents commences
MRI and clinical assessments at 6 to 12 months
Negative MRI result
Relapses and/ordisease progression
Active MRI result
Consider change of therapy
Periodic clinical andMRI assessment
Close clinical and MRI monitoring
No relapses and no disease progression
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Indication Category Example
Intolerable side effects
Adverse reactions Injection site reaction, infusion reaction, infections
Persistent symptoms Flu-like symptoms, headache, nausea
Significant and persistentlaboratory abnormality Increased liver enzymes, low WBC
Detection of antibodies
JC (John Cunningham) virus antibody positivity Pertinent for natalizumab use
Persistent neutralizing antibodies
Pertinent for natalizumab and IFNβ (high-titer antibodies)
Unacceptable breakthrough activity
Clinical activityRelapses, disability, cognitive status, transition to progressive disease
Neuroimaging activity Brain MRI, spinal cord MRIabnormalities
Indications for Switching Therapies
Coyle PK. CNS Drugs. 2013;27(4):239-247.
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•African American, Hispanic, older age (≥35 years), male gender•Clinical and MRI features
Baseline prognostic
factors
Tolerability history
Careful analysis of breakthrough disease activity
Considerations for Switching Therapies
Coyle PK. CNS Drugs. 2013;27(4):239-247.
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•Switch between approved first-line agents
Side effects or poor adherence
•Switch from first- to second-line agent (natalizumab)
Poor prognosis or significant
breakthrough activity
•Switch to off-label use, investigational gents
Failed therapy with approved DMTs or
restricted
Switching Recommendations
Coyle PK. CNS Drugs. 2013;27(4):239-247.
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• Natalizumab to fingolimod– JC virus antibody–negative patients
• Few weeks
– JC virus antibody–positive patients • 4 to 8 weeks after MRI for progressive multifocal
leukoencephalopathy lesions
• Fingolimod to natalizumab– JC virus antibody–negative patients
• Few weeks
– JC virus antibody–positive patients • Until WBC count improves
Washout Considerations
Coyle PK. CNS Drugs. 2013;27(4):239-247.
Individualized Treatment and Patient Education Are Necessary
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Patient’s adherence to monitoring or drug regimen
Individualized treatment
Roadmap for Individualized Treatment
Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.
Increasinglycomplex
environment
Treatmentstrategy
Economicfactors
Patient’s treatment
goals
Patient’s risk/benefit tolerance
Other
Patient’s disease profile
and characteristics
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• Pharmacological and nonpharmacological management of symptoms such as:
– Fatigue, spasticity, bladder problems, bowel problems, cognitive dysfunction, pain, paroxysmal symptoms, sexual dysfunction, tremor, heat intolerance, and optic neuritis
• Rehabilitation (physical and occupational therapy)
• Surgery as indicated to alleviate symptoms
Supportive Treatments
National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/symptom-management/index.aspx.
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• Encourage patients to discuss diagnosis, voice concerns, and share feelings about treatment progress
• Help patients access information
• Recognize opportunities to discuss treatment strategies
• Manage adverse events
• Facilitate optimal monitoring of disease progression
• Improving patient concordance
Patient Education
Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.
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• Improve quality of life by relieving symptoms caused by exacerbations and reduce number of events
• Reduce MRI activity
• Delay/prevent the onset of SPMS
• Slow or stop the course of disease progression
• Minimize treatment-associated adverse events
Treatment Goals
Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.
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• Updated diagnostic criteria to facilitate early and accurate diagnosis of MS
• Unbiased communication of clinical evidence to support decision making and to accommodate patient preferences
• Effective strategies to monitor therapeutic progressand switch therapies
• Individualizing treatment goals and interventions for patients with MS
Summary
Questions & Answers
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Thank You!
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Revised 2010 McDonald Criteria to Confirm Diagnosis of MS—
Reference Slides
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Clinical Attacks
Lesions Additional Criteria for Diagnosis
1 Objective clinical evidenceof 1 lesion
DIS, demonstrated by:• 1 T2 lesion in at least 2 MS-typical CNS regionsOR• Await further clinical attack implicating a different CNS site AND DIT, demonstrated by:• Simultaneous asymptomatic contrast-enhancing
and non-enhancing lesions at any time OR
• New T2 and/or contrast-enhancing lesions(s) on follow-up MRI, irrespective of its timing OR• Await a second clinical attack
Revised 2010 McDonald Criteria to Confirm Diagnosis of MS
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
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Clinical Attacks
Lesions Additional Criteria for Diagnosis
1 Objective clinical evidenceof 2 or more lesions
DIT, demonstrated by:• Simultaneous asymptomatic
contrast-enhancing and non-enhancing lesions at any time
OR• New T2 and/or contrast-enhancing
lesions(s) on follow-up MRI, irrespective of its timing
OR• Await a second clinical attack
Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d)
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
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Clinical Attacks
Lesions Additional Criteria for Diagnosis
2 or more Objective clinical evidenceof 2 or more lesions orobjective clinical evidenceof 1 lesion with reasonablehistorical evidence of a prior attack
None. Clinical evidence alone will suffice; additional evidence desirable but must be consistent with MS
2 or more Objective clinical evidenceof 1 lesion
DIS, demonstrated by: • 1 T2 lesion in at least 2 MS-
typical CNS regions (periventricular, juxtacortical, infratentorial, spinal cord)
OR• Await further clinical attack
implicating a different CNS site
Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d)
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
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Clinical Attacks Lesions Additional Criteria for Diagnosis
0 (progressionfrom onset)
One year of disease progression (retrospective or prospective) AND at least 2 out of 3 criteria:• DIS in the brain based on ≥1 T2 lesion in
periventricular, juxtacortical, or infratentorial regions
• DIS in the spinal cord based on ≥2 T2 lesions
• Positive CSF
Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d)
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.