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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

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• 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.

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• 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


17

MRI of Cortical Onset MS


MRI, magnetic resonance imaging.

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• 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.


Diagnosis of MS

22

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


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


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


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


*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


35

MS Lesions on MRI (cont’d)


CSF Findings

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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


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

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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

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Relapse Response Rate to Interferons


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


Johnson REGARD BEYOND CONFIRM0.0

0.2

0.4

0.6

0.8

0.59

0.290.34

0.29

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• 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

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ing

Ye

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• 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.

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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.

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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

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Med

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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


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.

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• 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


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.

64

• 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.

66

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


Ocrelizumab Recombinant human anti-CD20 monoclonal antibody

Intravenous infusion

Phase 2 trial—reduction in annual relapse rate


BAF312 Selective modulator of sphingosine 1-phosphate receptor types 1 and type 5

Oral BOLD trial—reduction in active lesions


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


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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


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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


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


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


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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


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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


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Clinical Attacks


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)


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Clinical Attacks


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



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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



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