Case Study #1 - American College of Physicians

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Improving Management Strategies for
Patients With Multiple Sclerosis:
An Evaluation of Current Practice
Sponsored by
Integrity Continuing Education
Supported by an educational
grant from Novartis
Practitioner’s Edge is a registered service mark of Integrity Continuing Education, Inc.
© 2014 Integrity Continuing Education, Inc.
Elizabeth Crabtree, MD
Associate Professor of Neurology Director
of Patient Education and Support
University of California San Francisco MS
Center San Francisco, California
2
Faculty Disclosures
3
Learning Objectives
• 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
4
Multiple Sclerosis Overview
and Unmet Needs
5
Multiple Sclerosis Overview
 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
6
Prevalence and Burden of MS in the
United States
• 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 plus
indirect costs4
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.
7
Clinical Courses of MS
Relapsing
Remitting
(RRMS)
Secondary
Progressive
(SPMS)
Progressive
Relapsing
(PRMS)
Primary
Progressive
(PPMS)
Unpredictable
exacerbations of
new symptoms or
worsening of old
symptoms
Initially relapsing
remitting course
that finally
becomes
progressive
Progressive from
onset and is
characterized by
intermittent
relapses
Progressive
disease from the
onset without
relapses
Initial onset in
85% of cases
Usually the
natural course
following RRMS
Rare
Observed in
10% to 15% of
cases
Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10.
8
Unmet Needs in MS
• Delay in diagnosis and misdiagnosis
• Lack of biomarkers for disease activity
• No curative or reparative/restorative therapy
• Patient compliance with therapeutic protocols
9
Pathophysiology of MS
10
Underlying Pathophysiology of MS
• 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)
MHC, major histocompatibility complex.
Handel​ AE, et al. Mult Scler Rel Disord. 2012;1(1):39-42; National MS Society. http://www.nationalmssociety.org/aboutmultiple-sclerosis/what-we-know-about-ms/who-gets-ms/genetics/index.aspx.
11
Observed Changes in the CNS in MS
• 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
Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.
12
Evidence for Gray Matter Involvement
 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
SDGM, subcortical deep gray matter; CIS, clinically isolated syndrome.
Bergsland N, et al. AJNR Am J Neuroradiol. 2012;33:1573–1578.
13
Immune-mediated Axonal Injury
Mechanisms
Immune-mediated
processes lead to
axonal transection
Transection leads to
degeneration of the
distal end of the axon
and the proximal end
forms an ovoid due to
accumulation of
transported organelles
Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12.
14
Cortical Demyelination Patterns
Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12.
15
Cortical Demyelinated Lesions in Early
MS: New Insights
• 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
Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.
16
MRI of Cortical Onset MS
MRI, magnetic resonance imaging.
Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.
17
Cortical Demyelinated Lesions in
Progressive MS: New Insights
• 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
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.
18
Cortical Demyelination in SPMS
Howell OW, et al. Brain. 2011;134(Pt 9):2755-2771.
19
New Data on Cortical Pathology and SPMS
Calabrese M, et al. Ann Neurol. 2013;74(1):76-83.
20
Other Studies on Cortical Demyelinating
Lesions
• New MRI techniques for visualization (DIR, PSIR, T1weighted 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.
21
Diagnosis of MS
22
Recommendations for Diagnosis of MS
Clinical evaluation of history, symptoms, signs,
relapses, and disability progression
Supplemented by paraclinical tests, including MRI,
evaluation of cerebrospinal fluid (CSF)
Exclusion of hereditary, psychological, and other
CNS disorders
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
23
Challenges in the Diagnosis of MS
 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
Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922–943.
24
Clinically Isolated Syndrome
• 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
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.
25
Steps Toward the Diagnosis of MS
Medical
history and
neurological
examination
usually
indicating CIS
MRI to confirm
presence of
macroscopic
lesions
Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.
CSF analysis
Blood tests for
ruling out
differential
diagnoses
26
McDonald Criteria: 2010 Revision*
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
*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.
27
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.
28
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.
29
Criteria for Diagnosis of MS in Pediatric
Patients
 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 required
to confirm a diagnosis of MS in children
 Accurate diagnosis of pediatric MS is critical
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
30
Revised MRI Criteria for DIS and DIT
• 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
*Periventricular, juxtacortical, infratentorial, or spinal cord.
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
31
Clinical Questions
• 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?
32
Imaging in MS
33
MS Lesions on MRI
Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.
34
MS Lesions on MRI (cont’d)
Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.
35
CSF Findings
36
Supportive Role for CSF Findings
in MS Diagnosis
• 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
IgG, immunoglobulin G.
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
37
Case Study #1:
Kim, 25-year-old Female
38
Clinical Questions
• 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?
39
Case Study #1, Kim, 25-year-old
Female: Blood Work
• 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
HTLV-1, human T-lymphotropic virus, type 1; HIV, human immunodefiency virus.
40
Management of Patients with MS
41
Proposed Algorithm
Treatment with disease-modifying
agents commences
MRI and clinical assessments
at 6 to 12 months
Relapse and/or
observed progression
Negative MRI result
Consider change
in therapy
Periodic clinical and
MRI assessment
Active MRI result
Relapses and/or
disease progression
No relapses and
no disease progression
Consider change
of therapy
Close clinical and
MRI monitoring
Modified from original in Río J, et al. Nat Rev Neurol. 2009;5(10):553-560.
42
Choosing a Disease-modifying Therapy
(DMT)
• 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
Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.
43
Important Considerations Before Making
Therapeutic Decisions
 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
Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10.
44
Recommendations for Treatment of
Acute MS Exacerbations
• 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
IV, intravenous; IVIG, intravenous immunoglobulin.
Goodin DS, et al. Neurology. 2002;58:169-178.
45
DMTs Approved for RRMS
First-line Agents
Second-line Agents
Interferon beta-1a
Interferon beta-1b
Glatiramer acetate
Mitoxantrone
Natalizumab
Oral therapies:
Fingolimod
Teriflunomide
Dimethyl fumarate
Oral therapies:
Fingolimod
Río J, et al. Curr Opin Neurol. 2011;24(3):230-237; Coyle PK. CNS Drugs. 2013;27(4):239-247.
46
Current Trials in SPMS
 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 LowInflammatory 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
ClinicalTrials website. www.clinicaltrials.gov. Accessed December 2, 2013.
47
Overview of Available
Agents for MS
48
Relapse Response Rate to Interferons
INTERFERONS
0.87
0.84
0.77
0.8
0.67
0.6
0.64
0.54
0.4
0.34
0.36
0.33
0.30
0.27
INF β-1a subcutaneous
‘94
INF β-1a intramuscular
‘07
Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.
‘93
BEYOND
INFβ-b
BRAVO
TRANSFORMS
EVIDENCE
MSCRG
REGARD
CAMMS223
EVIDENCE
0.0
OWIMS
0.2
PRISMS
Annualized Relapse Rate
1.0
INF β-1b
‘11
‘88
‘07
49
Clinical Evidence for Glatiramer Acetate
Study 1 (N=50)
Study 2 (N=251)
Study 3 (N=239)
(RRMS)
•
•
•
•
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
REGARD trial
(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
BEYOND trial
(RRMS)
• Results similar to IFNβ-1b for relapse risk,
disease progression, or MRI measures of
lesion burden
IFN, interferon.
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.
50
Relapse Response Rate to Therapies
GLATIRAMER ACETATE
Annualized Relapse Rate
0.8
0.6
0.59
0.4
0.34
0.29
0.29
0.2
0.0
Johnson
REGARD
1991
Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.
BEYOND
CONFIRM
2011
51
Clinical Evidence for Natalizumab
(mAb against leukocyte integrin α4)
Study 1
(RRMS or
relapsing
SPMS)
Study 2
(RRMS)
• 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
• 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
mAb, monoclonal antibody.
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.
52
Newer Oral Therapies
53
Survey of Patients Taking Self-injected
DMT: Route of Administration
Would you switch to a new therapy that was oral or injectable and was
associated with mild or severe risk and vigilance?
% Patients Responding Yes
100
97
92
84
78
80
63
59
60
40
31
28
20
0
New Oral Therapy
Mild Risk/Vigilance
New Oral Therapy
Severe Risk/Vigilance
Disease and DMT <5 years (n=100)
Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.
New Therapy
Mild Risk/Vigilance
New Therapy
Severe Risk/Vigilance
Disease and DMT ≥5 years (n=100)
54
Clinical Evidence for Dimethyl Fumarate
CONFIRM trial
(RRMS)
• 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
DEFINE 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%)
Long term
• Results similar to glatiramer acetate in CONFIRM trial
• Long-term benefits unclear
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.
55
Practice Recommendations for Dimethyl
Fumarate
Indicated for relapsing forms of MS
Dosing: 240 mg twice-a-day, oral
Warnings and Precautions
• 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
infections
National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/corecurriculum/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/managingms/comprehensive-care/disease-modification/warnings-safety-management/index.aspx.
56
Clinical Evidence for Fingolimod
FREEDOMS
trial
(RRMS)
TRANSFORM
MS trial
(RRMS)
Long term
• 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)
• 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
• 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
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.
57
Adherence with Fingolimod Therapy
Probability of Staying on Index Medication
Naïve disease-modifying therapy users
1.0
0.9
0.8
0.7
0.6
0.5
0.4
5
25
45
65
85
105 125 145 165 185 205 225 245 265 285 305 325 345 365
Days
Fingolimod
Subcutaneous interferon beta-1a
Interferon beta-1b
Glatiramer acetate
Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print]
Intramuscular interferon beta-1a
58
Adherence with Fingolimod Therapy (cont’d)
Probability of Staying on Index Medication
Experienced disease-modifying therapy users
1.0
0.9
0.8
0.7
0.6
0.5
0.4
1
31
61
91
121
151
181
211
241
271
301
331
361
Days
Fingolimod
Subcutaneous interferon beta-1a
Interferon beta-1b
Glatiramer acetate
Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print]
Intramuscular interferon beta-1a
59
Practice Recommendations for
Fingolimod
Indicated for relapsing forms of MS
Dosing: 0.5 mg once daily (qd), oral
Warnings and Precautions
• 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
Singer BA. Ther Adv Neurol Disord. 2013;6(4):269-275; National MS Society. http://www.nationalmssociety.org/msclinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/diseasemodification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinicalresources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/warnings-safetymanagement/index.aspx.
60
Clinical Evidence for Teriflunomide
TEMSO trial
(RRMS)
• 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
TOWER trial
(RRMS)
• Teriflunomide (7/14 mg po qd) vs placebo
over 48 weeks
• 36% reduction in annual relapse rates
• 32% reduction in disability progression
Long term
• History not well established to date
• However, have long history of leflunomide
use in rheumatoid arthritis (black boxed
warnings for leflunomide)
po, by mouth.
O’Connor, et al. N Engl J Med. 2011;365(14):1293-303; Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205.
61
Comparison of Teriflunomide with IFNβ-1a
TENERE trial
(RRMS)
• 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)
Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205; Vermersch et al. Mult Scler. 2013 Oct 14. [Epub
ahead of print].
62
Practice Recommendations for
Teriflunomide
Indicated for relapsing forms of MS
Dosing: 7 mg or 14 mg; qd oral
Warnings and Precautions
• 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)
National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/corecurriculum/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/managingms/comprehensive-care/disease-modification/warnings-safety-management/index.aspx.
63
Ideal Therapy
• 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)
Fox EJ, et al. Curr Opin Neurol. 2012;25(suppl):S11-S19.
64
Investigational Agents
Agent
Mode of Action
Route 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
FDA, US Food and Drug Administration.
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.
65
Investigational Agents (cont’d)
Agent
Mode of Action
Daclizumab
Route of
Administration
Promising
Outcomes
Current
Status
Humanized
Subcutaneous
monoclonal
antibody against IL2R
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 1phosphate receptor
types 1 and type 5
Oral
BOLD trial—reduction Ongoing
in active lesions
phase 3
trials
Masitinib
Tyrosine kinase
inhibitor
Oral
Promising in PPMS
and SPMS
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.
Ongoing
phase 2b/3
trials
66
Case Study #2:
Carl, 40-year-old Male
67
New Imaging Results—New Strategy for
Treatment?
• T2-weighted image
• Recent scans show
multiple new lesions
• What are the next steps
for this patient?
68
Case Discussion
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
69
Considerations for Switching Medications
70
Proposed Algorithm
Treatment with disease-modifying
agents commences
MRI and clinical assessments
at 6 to 12 months
Relapse and/or
observed progression
Negative MRI result
Consider change
in therapy
Periodic clinical and
MRI assessment
Active MRI result
Relapses and/or
disease progression
No relapses and
no disease progression
Consider change
of therapy
Close clinical and
MRI monitoring
Modified from original in Río J, et al. Curr Opin Neurol. 2011;24(3):230-237.
71
Indications for Switching Therapies
Indication
Intolerable side
effects
Detection of
antibodies
Category
Example
Adverse reactions
Injection site reaction, infusion
reaction, infections
Persistent symptoms
Flu-like symptoms, headache,
nausea
Significant and persistent
laboratory abnormality
Increased liver enzymes, low WBC
JC (John Cunningham) virus
antibody positivity
Pertinent for natalizumab use
Persistent neutralizing
antibodies
Pertinent for natalizumab and IFNβ
(high-titer antibodies)
Clinical activity
Relapses, disability, cognitive
status, transition to progressive
disease
Neuroimaging activity
Brain MRI, spinal cord MRI
abnormalities
Unacceptable
breakthrough activity
Coyle PK. CNS Drugs. 2013;27(4):239-247.
72
Considerations for Switching Therapies
Baseline
prognostic
factors
• African American, Hispanic, older age (≥35 years),
male gender
• Clinical and MRI features
Tolerability
history
Careful analysis
of breakthrough
disease activity
Coyle PK. CNS Drugs. 2013;27(4):239-247.
• Clinical parameters (relapse, disability, cognitive
deterioration, conversion to progressive disease)
• MRI parameters (contrast-positive lesions, T2 lesions,
T1 lesions, atrophy)
73
Switching Recommendations
Side effects or poor
adherence
• Switch between approved
first-line agents
Poor prognosis or
significant
breakthrough
activity
• Switch from first- to secondline agent (natalizumab)
Failed therapy with
approved DMTs or
restricted
• Switch to off-label use,
investigational gents
Coyle PK. CNS Drugs. 2013;27(4):239-247.
74
Washout Considerations
• 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
Coyle PK. CNS Drugs. 2013;27(4):239-247.
75
Individualized Treatment and Patient
Education Are Necessary
76
Roadmap for Individualized Treatment
Increasingly
complex
environment
Treatment
strategy
Patient’s
treatment
goals
Economic
factors
Individualized
treatment
Patient’s
risk/benefit
tolerance
Patient’s adherence
to monitoring or
drug regimen
Other
Patient’s
disease profile
and characteristics
Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.
77
Supportive Treatments
• 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
National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-andtools/core-curriculum/managing-ms/comprehensive-care/symptom-management/index.aspx.
78
Patient Education
• 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
Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.
79
Treatment Goals
• 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
Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.
80
Summary
• 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 progress
and switch therapies
• Individualizing treatment goals and interventions for
patients with MS
81
Questions & Answers
82
Thank You!
83
Revised 2010 McDonald Criteria
to Confirm Diagnosis of MS—
Reference Slides
84
Revised 2010 McDonald Criteria
to Confirm Diagnosis of MS
Clinical
Attacks
Lesions
Additional Criteria for Diagnosis
1
Objective
clinical
evidence
of 1 lesion
DIS, demonstrated by:
• 1 T2 lesion in at least 2 MS-typical CNS regions
OR
• 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
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
85
Revised 2010 McDonald Criteria
to Confirm Diagnosis of MS (cont’d)
Clinical
Attacks
Lesions
Additional Criteria for Diagnosis
1
Objective clinical evidence
of 2 or more lesions
DIT, demonstrated by:
• Simultaneous asymptomatic
contrast-enhancing and nonenhancing 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
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
86
Revised 2010 McDonald Criteria
to Confirm Diagnosis of MS (cont’d)
Clinical
Attacks
Lesions
Additional Criteria for Diagnosis
2 or more
Objective clinical evidence
of 2 or more lesions or
objective clinical evidence
of 1 lesion with reasonable
historical 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 evidence
of 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
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
87
Revised 2010 McDonald Criteria
to Confirm Diagnosis of MS (cont’d)
Clinical Attacks
Lesions
0 (progression
from onset)
Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.
Additional Criteria for Diagnosis
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
88
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