practical issues in multiple sclerosis practical issues in multiple sclerosis disease overview and...

Practical Issues in Multiple Sclerosis

Disease Overview and Current Perspectives on Patient Management

The Science and Medicine of Multiple Sclerosis

Kenneth P. Johnson, MDProfessor of Neurology

Director, Maryland Center for Multiple SclerosisUniversity of Maryland Medical Center

Baltimore, MD

Learning Objectives

► Differentiate MS from other similar diagnostic possibilities

► Identify existing disease-modifying therapies for relapsing-remitting MS (RRMS) and differentiate them in terms of activity, efficacy, safety, and side effect profiles

► Define patient and disease variables that may alter management approaches

Differential Diagnosis of MS

► Infection● Lyme disease● Neurosyphilis● PML, HIV, HTLV-1

► Inflammatory● SLE● Sjögren syndrome● Other CNS vasculitis ● Sarcoidosis● Behçet disease

· Metabolic– Vitamin B12 and E

deficiencies· CADASIL, other rare familial

diseases

· CNS lymphoma

· Cervical spondylosis

· Motor neuron disease

· Myasthenia gravis

Cohen J, Rensel M. In: Burks J, Johnson K, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos; 2000:127-138.

Epidemiology of MS

1. NMSS. National Multiple Sclerosis Society Information Sourcebook: Epidemiology. Available at: http://www.nationalmssociety.org/sourcebook.asp. Accessed March 31, 2006. 2. Anderson DW et al. Ann Neurol. 1992;31:333-336.3. Jacobsen DL et al. Clin Immunol Immunopathol. 1997;84:223-243.

► Patient characteristics ● 20 to 50 years of age1

● 70% are women2

► Incidence: 8,500 to 10,000 per year in US3

► Prevalence: 400,000 in US

Worldwide Prevalence of MS

► Varies geographically► High prevalence*1,2

● Northern US and Canada● Most of Europe● Southern Australia ● New Zealand● Northern Russia● Southern South America

1. Kurtzke JF. Neuroepidemiology. 1991;10:1-8. 2. Noseworthy JH et al. N Engl J Med. 2000;343:938-952.

*>30 cases/100,000=high prevalence

Trapp BD et al. N Engl J Med. 1998;338:278-285.

Pathology of MS

► An immune-mediated disease in genetically susceptible individuals

► Dual nature: inflammatory and neurodegenerative► Demyelination leads to slower nerve conduction► Axonal injury and destruction are associated with

permanent neurological dysfunction► Lesions occur in optic nerves, periventricular white

matter, cerebral cortex, brain stem, cerebellum, and spinal cord

Basic Principles of Diagnosing MS

► Clinical diagnosis; no definitive laboratory test

► Clinical profile

► Laboratory evaluation

► Evidence of dissemination of lesions in space and time

► Exclusion of other diagnoses

Coyle P. In: Burks J, Johnson K, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos; 2000:81-97.

Symptoms of MS

Vision problems

Paresthesias

Tremor, incoordination

Gait problems, spasticitySpeech, swallowing difficulties

Fatigue

Seizures

Dizziness, vertigo

Itching

Depression

Hearing loss

Cognitive dysfunction

Headache

Bladder, bowel, sexual dysfunction

Less CommonCommon

NMSS. About MS: Symptoms. Available at: http://www.nationalmssociety.org/Symptoms.asp. Accessed March 31, 2006.

What Causes Demyelinationand Axonal Loss in MS?

► Activation of autoreactive CD4+ T cells in peripheral immune system

► Migration of autoreactive lymphocytes across the BBB into CNS

► In situ reactivation by myelin autoantigens

► Activation of macrophages, B cells

► Secretion of proinflammatory cytokines, chemokines, and antibodies

► Focal inflammation, demyelination, axonal transection, degeneration

Use of MRI in Diagnosis

► MRI improves confidence in a clinical diagnosis of MS or makes a diagnosis of MS in CIS1

► May show dissemination in space and time(e.g., new lesions on follow-up MRI)1

► Total lesion load at diagnosis tends to be predictive of future disability2

1. Polman CH et al. Ann Neurol. 2005;58:840-846.2. Brex PA et al. N Engl J Med. 2002;346:158-164.

Inflammatory White Matter Lesions Cause Relapses

Types of Cortical Lesions

Peterson JW, Kidd GJ, and Trapp BD. In: Waxman S, ed. Multiple Sclerosis as a Neurodegenerative Disease. 2005:165-184.

Type ILesion in white matter and cortex

Type IIIntracortical lesions

Type IIILesions extending into the cortex from the pial surface

Cortical MS Lesions

► Significant in most MS brains

► Hypocellular compared with WM lesions

► May not be associated with BBB breakdown

► Cause neuritic transection and neuronal loss

► Contribute to neurological disability in MS patients

► Urgent need for noninvasive methods to detect cortical MS lesions

Brain Atrophy in MS

MS18 MS09

Unpublished data.

Brain Atrophy and Its Measures

► What is brain atrophy?● Brain parenchyma loss is a global process; occurs

in MS patients up to 0.5%/y-1.0%/y; pathological parenchyma loss exceeds this rate

● Size of lateral ventricles, CSF spaces● Anterior-posterior diameter of cervical spinal

cord, corpus callosum● Appears to correlate with disability

► Timing● Begins as early as disease manifestation; appears

essential to study effect of treatments in controlled clinical trials of long duration

Disease Type and Disability Progression

Adapted with permission from JS Wolinsky.

Measures of brain volumeRelapses and impairmentMRI burden of diseaseMRI activity

RRMSPreclinical

a bi l

Progression of Disability*: EDSS Score

*Steps are variable.

Confined to bed or wheelchair

Walks with aid(<5 yards)

Walks unaided (≥330-550 yards)

Fully ambulatory

Goals of MS Therapy

► Affect the neurodegenerative and inflammatory components

► Early intervention; initiate therapy as soon as possible for the best chance of controlling damage

► Reduction of disease activity measured by relapses, MRI findings, and disability

► Provision of therapy that is well tolerated and safe

National Multiple Sclerosis Society Disease Management Consensus Statement

“Initiation of therapy with an immunomodulator is advised as soon as possible following a definite diagnosis of MS with a relapsing course and may be

considered for selected patients with a first attack who are high risk for MS.”

NMSS. Disease Management Consensus Statement. Available at: http://www.nationalmssociety.org/Sourcebook-Early.asp. Accessed on November 29, 2006.

Immunotherapy of MS

► Selective immunomodulation● Glatiramer acetate (Copaxone)

► Nonspecific immunomodulation● IFN b-1a (Avonex, Rebif)● IFN b-1b (Betaseron)

► Selective adhesion molecule inhibitor● Natalizumab (Tysabri)

► Immunosuppression● Mitoxantrone (Novantrone) ● Corticosteroids

Glatiramer Acetate:Potential Mechanisms of Action

► Blocks autoimmune T cells

► Induces anergy

► Induces anti-inflammatory TH2 cells

► Induces bystander suppression

► Upregulates neuronal preservation

► Induction of regulatory TH2 and TH3 cells that penetrate CNS1

► Enhanced expression of BDNF, IL-10, TGF-β2

► Sustained augmentation of BDNF, NT-3, NT-4 in the brain3

► Augmentation of processes of neurogenesis: cell proliferation, migration, differentiation4

1. Aharoni R et al. Proc Natl Acad Sci U S A. 2003;100:14157-14162.2. Neuhaus O et al. Neurology. 2001;56:702-708. 3. Aharoni R et al. Proc Natl Acad Sci U S A. 2005;102:19045-19050.4. Aharoni R et al. J Neurosci. 2005;25:8217-8228.

IFN-: Potential Mechanisms of Action

► Induces an antiproliferative effect► Blocks T cell activation► Induces apoptosis of autoreactive T cells► IFN- antagonistic► Induces cytokine shifts► Has antiviral effect► Acts in periphery (ie, does not cross BBB)► Indirect effects on CNS

Noseworthy JH et al. N Engl J Med. 2000;343:938-952. Yong VW. Neurology. 2002;59:802-808.

Natalizumab:Potential Mechanisms of Action

► Primary mechanism related to blockade of interaction between the 4b1-integrin and brain receptors

● VCAM-1

► Alternative mechanisms● Block VLA-4–fibronectin CS-1 interaction● Block VLA-4 osteopontin interaction● Inhibit antigen presentation

MS Trials

► Short-term, class I placebo-controlled studies (±2 years) do not guarantee long-term effectiveness

► Neutralizing antibodies

► Intolerable side effects

► Change from RRMS to SPMS

► Safety issues

► Unknown factors

► Ethical considerations of placebo-controlled trials

Prospective RRMS Pivotal Trial Durations

Glatiramer acetate1

IM IFN -1a2

IFN -1b3

SC IFN -1a4

Natalizumab5

0 1 1312111098765432

12+ years

2 years

5 years

4 years

2 years

*Percent of patients completing the study.

1. Ford CC et al. Mult Scler. 2006;12:309-320.2. Jacobs LD et al. Ann Neurol. 1996;39:285-294.3. IFNB Multiple Sclerosis Study Group. Neurology. 1995;45:1277-1285.

4. PRISMS Study Group. Lancet. 1998;353:1498-1504.

5. Polman CH et al. N Engl J Med. 2006;354:899-910.

Data Summary: Long-Term Patients Reaching EDSS Score of 6

Study% Reached

EDSS Score of 6 Years

Studied

Natural history cohort1 50% 15

Glatiramer acetate2 8% 10-12

SC IFN b-1a3 20% 7.4

IFN b-1b4 (>80) 45% 16

IM IFN b-1a5 35% 8

1. Weinshenker BG, Ebers SC. Can J Neurol Sci. 1987;14:255-261.2. Ford CC et al. Mult Scler. 2006;12:309-320. 3. Kappos L et al. Neurology. 2006;67:944-953. 4. Ebers G et al. 57th AAN Meeting, 2005. 5. Fisher E et al. Neurology. 2002;59:1412-1420.

Direct-Comparison Trials

Adapted with permission from Panitch H et al. Neurology. 2002;59:1496-1506.

EVIDENCE Trial

IM IFN β-1aIFN β-1b

0 4 8 12 16 20 24 28 32 38 40 44 48

Adapted with permission from Durelli L et al. Lancet. 2002;359:1453-1460.

INCOMIN Study

0-6 7-12 13-24 0-24

P=0.23 P=0.02

P=0.00135% 19%

P=0.036

IM IFN β-1a

IFN β-1b

Berlin, Germany24-Month Open-Label Comparison

Adapted with permission from Haas J, Firzlaff M. Eur J Neurol. 2005;12:425-431.

IM IFN β-1a

SC IFN β-1b

Glatiramer acetate

SC IFN β-1a 22 μg1.4

0.0Before Study 6 Months 12 Months 24 Months

Mikol D et al. Lancet Neurol 2008;7:903-914.

REGARD: Clinical Outcomes

REGARD: MRI Outcomes

REGARD STUDY: MRI Endpoint Change in Brain Volume

p = 0.018

Weeks 0-48 Weeks 48-96 Weeks 0-96

BEYOND: BEtaseron Yields Outcomes with New Dose

RandomizedN=2,244

IFN β-1b 500 µgn = 899

IFN β-1b 250 µgn = 897

Glatiramer acetaten = 448

EOS reached81%

EOS reached87%

EOS reached 83%

premature EOS 19%

premature EOS 13%

premature EOS 17%

EOS = end of study

Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.

BEYOND: Study Design

BEYOND: No Group Differences with Respect toDemographics and Baseline Characteristics

IFN β-1b 500 µgn = 899

IFN β-1b 250 µg n = 897

Glatiramer Acetaten = 448

Female sex 70% 70% 68%

Age (years, mean) 35.9 35.8 35.2

Duration of disease (years, mean) 5.4 5.3 5.1

Number of relapses in previous year (mean) 1.6 1.6 1.6

EDSS at baseline(mean) 2.4 2.4 2.3

Volume of T2 lesions (cm3, median) 6.0 5.7 5. 9

Volume of T1 lesions (cm3, median) 0.5 0.6 0.6

BEYOND: Annualized Relapse Rate One Year Before and During Treatment

-79%-78%-79%

IFN β-1b 500 µg

Before (retrospective) During

Glatiramer Acetate IFN β-1b 250 µg

BEYOND: Adherence and Tolerability

► No unexpected safety issues

► Discontinuation rate by study arm:● IFN β-1b 250 mcg: 13%● Glatiramer acetate: 17%● IFN β-1b 500 mcg: 19%

MedScape Web site. http://www.medscape.com/viewarticle/573185Accessed March 3, 2009.

Direct Comparison of Multiple Sclerosis Relapses and Total Medical Costs Over 2

Years: Glatiramer Acetate compared to IFN-β-1b, IFN-β-1a IM, and IFN-β-1a SC

► Data● Direct analysis of insurance claims for patients taking either interferon-

beta or glatiramer acetate. ● Outcomes data from a health-claims database, i3 LabRx, which

contains laboratory test results, hospitalization and pharmacy data, and demographic information for more than 20 million de-identified individuals from a major US managed care organization.

● Data for multiple sclerosis spanned the period from July 1, 2001 through June 30, 2006.

► Continuous Use (CU) Cohorts of patients on individual DMT for at least 24 months

● IFN-β-1b (n = 110)● IFN-β-1a IM (n = 331)● IFN-β-1a SC (n = 143)● GA:

• (n = 308) - IFN-β-1b comparison• (n = 308) - IFN-β-1a IM comparison• (n = 267) - IFN-β-1a SC comparison

Study Design

Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008

Study Design

► Outcomes● Costs

• Direct medical costs, including inpatient, outpatient, and prescription drug services.

• Based upon paid amounts, including insurer and health plan payments, co-payments, and deductibles.

• All costs converted to 2006 values (medical component of the Consumer Price Index).

● Relapse• Defined as either a hospitalization with a primary diagnosis of

MS or an outpatient visit with a diagnosis of MS accompanied by a prescription for steroids within 7 days after the outpatient visit.14

Patient Disposition

MET INCLUSIONCRITERIA

Diagnosis of MS inthe i3 LabRx Database

July 1, 2001 – June 30, 2006 (N = 51,162)

Continuous Use of IFN-β-1b or GA for 24 months

(n = 418)

Users of IFN-β-1b

(n = 1,550)

IFN-β-1b (n = 110)

GA (n = 308)

Users of IFN-β-1a

IM(n = 3,949)

Continuous Use ofIFN-β-1a IM or GA

for 24 months (n = 639)

Continuous Use ofIFN-β-1a SC or GA

for 24 months (n =410)

Users of GA

(n = 3,057)

Users of IFN-β-1a

SC(n = 1,188)

Users of GA

(n =2667)

IFN-β-1a IM (n =331)

IFN-β-1a SC (n =143)

GA (n = 267)

Users of GA

(n = 3,057)

GA (n = 308)

IFN-β-1b IFN-β-1a IM IFN-β-1a SC

US Managed Care Database Analysis

Percent of Patients per Drug per Region

Northeast Midwest South West

IFNβ-1b 8% 38% 44% 10%

IFNβ-1a IM 10% 35% 42% 12%

IFNβ-1a SC 13% 48% 28% 11%

GA 12% 39% 34% 15%

All US regions were included in the database There were no significant differences among immunomodulators in

their regional distribution

Impact of Medication on Probability of Relapse during 2 Years of Continuous Use of Single Drug

Continuous Use Cohorts

IFN-β-1b GA IFN-β-1a IM GA GAIFN-β-1a SC

P=0.0018 P=0.0048 P=0.0049

Impact of Medication on Probability of Relapse during 2 Years of Continuous Use of Single Drug

Continuous Use Cohorts

IFN-β-1b GA IFN-β-1a IM GA GAIFN-β-1a SC

P=0.0018 P=0.0048 P=0.0049

P < 0.05

Results

► For the Continuous Use cohorts, the risk of relapse in the 2 years after medication initiation is significantly lower for patients on GA vs. on an interferon.

► In the Continuous Use cohorts, the 2-year total direct medical costs with GA use are significantly lower than those using an interferon.

● Prior research found lower annual costs associated with GA than with IFN-β-1b.

► This study relied on data collected throughout the United States.► Practicing physicians made all treatment decisions free of

influence by drug company sponsored studies or known bias.

Limitations

► Analysis was done on an administrative claims database and included only patients with medical and prescription benefit coverage.

► Studies used different method of defining relapses than traditional clinical studies; however the algorithm used to define relapses was applied equally to all treatment groups.

► The use of medical claims data precludes the use of physician or patient-reported functioning.

► The studies focused only on direct medical costs. Other research has indicated that indirect costs (worker productivity, lost work days) from MS are also large.

Conclusion

► This outcomes multivariate analysis indicates that patients with MS who use glatiramer acetate have significantly lower chances of relapse and significantly lower two-year direct medical costs than patients who use beta interferon.

► These data represent practicing physicians’ treatment decisions nationwide and do not rely on drug company sponsored clinical studies.

► Analysis includes the broad range of treated MS patients in the U.S. rather than narrowly defined cohorts from clinical trials.

► These studies probably best mirror unbiased clinical and cost related outcomes of MS treatment in the U.S.

Pharmacoeconomic Evaluation of New Treatments: Efficacy versus Effectiveness

Current pivotal phase III trials …….. are designed to test safety and efficacy (does the drug work under optimal circumstances?) and not to answer questions about the effectiveness of a drug ……..(does the drug work in usual care?)

Bombardier C, Maetzel AAnn Rheum Dis 1999, 58:182-185

Human IgG4Framework

Complementarity-Determining Regions (CDRs)

Natalizumab: Humanized Monoclonal Antibody Against 4 Integrins

► CDR grafted from murine antibody

► Human IgG4 framework

► Retains full potency

Reprinted with permission from Dr. P Calabresi.

Reduced leukocyte infiltration and brain inflammation

Leukocyte infiltration and brain inflammation

Leukocyte

Chemoattractant signal

4β1 (VLA-4)

Blood vessel lumen

Endothelial cells

Tissue VCAM-1

LeukocyteChemoattractant signal

4β1 (VLA-4)

Blood vessel lumen

Endothelial cells

Tissue VCAM-1

Selective Adhesion Molecule Inhibition: Implications for MS Therapy

Reprinted with permission from Dr. P Calabresi.

Potential Mechanisms of Action of Natalizumab

► Primary mechanism related to blockade of interaction between the 4b1 integrin and brain receptors● VCAM-1

► Alternative mechanisms● Block VLA-4–fibronectin CS-1 interaction● Block VLA-4–osteopontin interaction● Inhibit antigen presentation

Rice GP, Hartung HP, Calabresi PA. Neurology. 2005;64(8):1336-42.12

Panzara M, et al. P488 Presented at WCTRIMS September 2008.

Natalizumab Utilization and Safety in Patients with Relapsing MS: Updated Results from TOUCH and TIGIRS

a) 13,900 treated for ≥ 1 yearb) 6,600 treated for ≥ 18 monthsc) 31,800 patients receiving natalizumab worldwided) 21,099 in TOUCH (median # of doses = 8)

ab,c d

The Interferons and Glatiramer Acetate Delay the Risk of CDMS

Study Conversion to CDMS in the Placebo Group

CHAMPS 50%

ETOMS 45%

BENEFIT 45%

PreCISe 41%

Kappos L, et al. Neurology 2006; 67:1242-1249Jacobs L, et al NEJM 2000;343:989-904Comi G, et al. Lancet 2001;357:1576-1582 Comi G, et al. AAN Annual Meeting 2008

Partial List of MS Drugs Under Development

DrugMonoclonal Antibody

Phase MOA

1. Alemtuzumab (Campath) III Anti CD 52

2. Rituximab (Rituxan) III

B cell inhibitorAnti CD 20

3. Daclizumab (Zenapax) II

IL-2 receptorAntagonist

4. Ustekinumab CNTO 1275 II Anti IL12/IL23

Partial List of MS DrugsUnder Development

DrugOral

Phase MOA

Cladribine III Immunosuppressant

Laquinimod III Immunomodulator

FTY-720 (fingolimod) III Immunosuppressant

BG12 III Immunomodulator

Estriol III Estrogen agonist

MBP 8298 IIIAltered Peptide Ligand

Teriflunomide III Immunosuppressant

Summary

► Understanding of multiple sclerosis is expanding rapidly yet remains incomplete

► Current therapies provide clinically equivalent benefit but glatiramer acetate is best tolerated

► New era emerged with natalizumab when risk vs. benefit ratio required consideration

► Numerous new therapies in Phase III trials. Practice decisions may become more complicated

practical issues in multiple sclerosis practical issues in multiple sclerosis disease overview and...

epidemiology of ms

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ms rrms

pathology of ms

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worldwide prevalence

high prevalence slide

existing disease

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