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
Pain
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
5 10
Years
15 20
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
SPMS
Disease Type and Disability Progression
Time
Adapted with permission from JS Wolinsky.
Measures of brain volumeRelapses and impairmentMRI burden of diseaseMRI activity
RRMSPreclinical
Dis
a bi l
i ty
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
Death
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
54%*
47%*
1.3%*
77%*
91%*
*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
10
20
30
40
50
0 4 8 12 16 20 24 28 32 38 40 44 48
Week
Cum
ulat
ive
Pro
babi
lity
of P
atie
nts
Exp
erie
ncin
g a
Rel
apse
(%
)
Adapted with permission from Durelli L et al. Lancet. 2002;359:1453-1460.
INCOMIN Study
0
10
20
30
40
50
60
70
80
90
100
0-6 7-12 13-24 0-24
Pro
port
ion
of P
atie
nts
Rel
apse
Fre
e (%
)
P=0.23 P=0.02
P=0.00135% 19%
47%
P=0.036
42%
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
1.2
1.0
0.8
0.4
0.6
0.2
0.0Before Study 6 Months 12 Months 24 Months
Mea
n N
umbe
r of
Rel
apse
s
Mikol D et al. Lancet Neurol 2008;7:903-914.
REGARD: Clinical Outcomes
Mikol D et al. Lancet Neurol 2008;7:903-914.
REGARD: MRI Outcomes
Mikol D et al. Lancet Neurol 2008;7:903-914.
REGARD STUDY: MRI Endpoint Change in Brain Volume
p = 0.018
Weeks 0-48 Weeks 48-96 Weeks 0-96
Mikol D et al. Lancet Neurol 2008;7:903-914.
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
Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.
BEYOND: Annualized Relapse Rate One Year Before and During Treatment
-79%-78%-79%
IFN β-1b 500 µg
0
0.5
1
1.5
2
Before (retrospective) During
Ann
ualiz
ed r
elap
se r
ate
Glatiramer Acetate IFN β-1b 250 µg
Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.
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
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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)
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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%
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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.
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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.
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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.
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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
Nu
mb
er
of P
atie
nts
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
Other
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
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