Practical Issues in Multiple Sclerosis

1
The Science and Medicine of Multiple Sclerosis

• Practical Issues in Multiple Sclerosis
• Disease Overview and Current Perspectives on
  Patient Management

Kenneth P. Johnson, MD Professor of Neurology
Director, Maryland Center for Multiple
Sclerosis University of Maryland Medical
Center Baltimore, MD
2
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

3
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 2000127-138.
4
Epidemiology of MS

• 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

1. NMSS. National Multiple Sclerosis Society
Information Sourcebook Epidemiology. Available
at http//www.nationalmssociety.org/sourcebook.as
p. Accessed March 31, 2006. 2. Anderson DW et
al. Ann Neurol. 199231333-336. 3. Jacobsen DL
et al. Clin Immunol Immunopathol. 199784223-243.
5
Worldwide Prevalence of MS

• Varies geographically
• High prevalence1,2
• Northern US and Canada
• Most of Europe
• Southern Australia
• New Zealand
• Northern Russia
• Southern South America

gt30 cases/100,000high prevalence

• Kurtzke JF. Neuroepidemiology. 1991101-8.
• 2. Noseworthy JH et al. N Engl J Med.
  2000343938-952.

6
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

Trapp BD et al. N Engl J Med. 1998338278-285.
7
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 200081-97.
8
Symptoms of MS
Less Common
Common
Vision problems
Headache
Fatigue
Hearing loss
Paresthesias
Itching
Bladder, bowel, sexual dysfunction
Seizures
Gait problems, spasticity
Speech, swallowing difficulties
Tremor, incoordination
Dizziness, vertigo
Pain
Depression
Cognitive dysfunction
NMSS. About MS Symptoms. Available at
http//www.nationalmssociety.org/Symptoms.asp.
Accessed March 31, 2006.
9
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

10
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.
200558840-846. 2. Brex PA et al. N Engl J Med.
2002346158-164.
11
Inflammatory White Matter Lesions Cause Relapses
12
Types of Cortical Lesions
Type III Lesions extending into the cortex from
the pial surface
Type I Lesion in white matter and cortex
Type II Intracortical lesions
Peterson JW, Kidd GJ, and Trapp BD. In Waxman S,
ed. Multiple Sclerosis as a Neurodegenerative
Disease. 2005165-184.
13
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

14
Brain Atrophy in MS
MS09
MS18
Unpublished data.
15
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

16
Disease Type and Disability Progression
Time
Adapted with permission from JS Wolinsky.
17
Progression of Disability EDSS Score
Steps are variable.
18
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

19
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/Sou
rcebook-Early.asp. Accessed on November 29, 2006.
20
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

21
Glatiramer AcetatePotential 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-ß2
• 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.
200310014157-14162. 2. Neuhaus O et al.
Neurology. 200156702-708. 3. Aharoni R et al.
Proc Natl Acad Sci U S A. 200510219045-19050. 4.
Aharoni R et al. J Neurosci. 2005258217-8228.
22
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.
2000343938-952. Yong VW. Neurology.
200259802-808.
23
NatalizumabPotential Mechanisms of Action

• Primary mechanism related to blockade of
  interaction between the ?4b1-integrin and brain
  receptors
• VCAM-1
• Alternative mechanisms
• Block VLA-4fibronectin CS-1 interaction
• Block VLA-4 osteopontin interaction
• Inhibit antigen presentation

24
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

25
Prospective RRMS Pivotal Trial Durations
Glatiramer acetate1





12 years
47
IM IFN ?-1a2
2 years
54
IFN ?-1b3
1.3
5 years
SC IFN ?-1a4
4 years
77
Natalizumab5
2 years
91
Percent of patients completing the study.
1. Ford CC et al. Mult Scler. 200612309-320.2.
Jacobs LD et al. Ann Neurol. 199639285-294.3.
IFNB Multiple Sclerosis Study Group. Neurology.
1995451277-1285.
4. PRISMS Study Group. Lancet. 19983531498-1504.
5. Polman CH et al. N Engl J Med.
2006354899-910.
26
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 (gt80) 45 16
IM IFN b-1a5 35 8
1. Weinshenker BG, Ebers SC. Can J Neurol Sci.
198714255-261. 2. Ford CC et al. Mult Scler.
200612309-320. 3. Kappos L et al. Neurology.
200667944-953. 4. Ebers G et al. 57th AAN
Meeting, 2005. 5. Fisher E et al. Neurology.
2002591412-1420.
27
Direct-Comparison Trials
28
EVIDENCE Trial
Adapted with permission from Panitch H et al.
Neurology. 2002591496-1506.
29
INCOMIN Study
IM IFN ß-1a
IFN ß-1b
100
P0.23
P0.02
90
19
5
P0.0013
80
47
70
P0.036
60
Proportion of Patients Relapse Free ()
42
50
40
30
20
10
0
0-6
7-12
13-24
0-24
Adapted with permission from Durelli L et al.
Lancet. 20023591453-1460.
30
Berlin, Germany24-Month Open-Label Comparison
Adapted with permission from Haas J, Firzlaff M.
Eur J Neurol. 200512425-431.
31
Mikol D et al. Lancet Neurol 20087903-914.
32
REGARD Clinical Outcomes
Mikol D et al. Lancet Neurol 20087903-914.
33
REGARD MRI Outcomes
Mikol D et al. Lancet Neurol 20087903-914.
34
REGARD STUDY MRI Endpoint Change in Brain Volume
Weeks 0-48 Weeks 48-96
Weeks 0-96
p 0.018
Mikol D et al. Lancet Neurol 20087903-914.
35
BEYOND BEtaseron Yields Outcomes with New Dose
36
BEYOND Study Design
Randomized N2,244
IFN ß-1b 500 µg n 899
IFN ß-1b 250 µg n 897
Glatiramer acetate n 448
premature EOS 19
premature EOS 13
premature EOS 17
EOS reached 81
EOS reached 87
EOS reached 83
EOS end of study
Information presented during a European Charcot
Foundation satellite symposium. November 29,
2007. Fiuggi, Italy.
37
BEYOND No Group Differences with Respect
toDemographics and Baseline Characteristics
IFN ß-1b 500 µgn 899 IFN ß-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.
38
BEYOND Annualized Relapse Rate One Year Before
and During Treatment
IFN ß-1b 500 µg
IFN ß-1b 250 µg
Glatiramer Acetate
2
1.5
Annualized relapse rate
1
-79
-78
-79
0.5
0
Before (retrospective)
During
Information presented during a European Charcot
Foundation satellite symposium. November 29,
2007. Fiuggi, Italy.
39
BEYOND Adherence and Tolerability

• No unexpected safety issues
• Discontinuation rate by study arm
• IFN ß-1b 250 mcg 13
• Glatiramer acetate 17
• IFN ß-1b 500 mcg 19

MedScape Web site. http//www.medscape.com/viewart
icle/573185Accessed March 3, 2009.
40
Direct Comparison of Multiple Sclerosis Relapses
and Total Medical Costs Over 2 Years Glatiramer
Acetate compared to IFN-ß-1b, IFN-ß-1a IM, and
IFN-ß-1a SC
41

Study Design

• 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-ß-1b (n 110)
• IFN-ß-1a IM (n 331)
• IFN-ß-1a SC (n 143)
• GA
• (n 308) - IFN-ß-1b comparison
• (n 308) - IFN-ß-1a IM comparison
• (n 267) - IFN-ß-1a SC comparison

Adapted from Johnson and Lage, ANA 2008
Castelli-Haley, CMSC 2008 and Castelli-Haley,
E-ISPOR, 2008
42
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
43
Patient Disposition
IFN-ß-1b
IFN-ß-1a IM
IFN-ß-1a SC
MET INCLUSION CRITERIA
44
US Managed Care Database Analysis
Percent of Patients per Drug per Region Percent of Patients per Drug per Region Percent of Patients per Drug per Region Percent of Patients per Drug per Region Percent of Patients per Drug per Region
Northeast Midwest South West
IFNß-1b 8 38 44 10
IFNß-1a IM 10 35 42 12
IFNß-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

Adapted from Johnson and Lage, ANA 2008
Castelli-Haley, CMSC 2008 and Castelli-Haley,
E-ISPOR, 2008
45
Impact of Medication on Probability of Relapse
during 2 Years of Continuous Use of Single Drug

IFN-ß-1b
GA
IFN-ß-1a IM
GA
GA
IFN-ß-1a SC
P0.0018
P0.0048
P0.0049
Continuous Use Cohorts
Adapted from Johnson and Lage, ANA 2008
Castelli-Haley, CMSC 2008 and Castelli-Haley,
E-ISPOR, 2008
46
Impact of Medication on Probability of Relapse
during 2 Years of Continuous Use of Single Drug

IFN-ß-1b
GA
IFN-ß-1a IM
GA
GA
IFN-ß-1a SC
P0.0018
P0.0048
P0.0049
P lt 0.05
Continuous Use Cohorts
Adapted from Johnson and Lage, ANA 2008
Castelli-Haley, CMSC 2008 and Castelli-Haley,
E-ISPOR, 2008
47
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-ß-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
48
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
49
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
50
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 A Ann Rheum Dis 1999,
58182-185
51
Natalizumab Humanized Monoclonal Antibody
Against ?4 Integrins
Complementarity-Determining Regions (CDRs)

• CDR grafted from murine antibody
• Human IgG4 framework
• Retains full potency

Human IgG4 Framework
Reprinted with permission from Dr. P Calabresi.
52
Selective Adhesion Molecule Inhibition
Implications for MS Therapy
Reprinted with permission from Dr. P Calabresi.
53
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-4fibronectin CS-1 interaction
• Block VLA-4osteopontin interaction
• Inhibit antigen presentation

Rice GP, Hartung HP, Calabresi PA. Neurology.
200564(8)1336-42.12
54
Natalizumab Utilization and Safety in Patients
with Relapsing MS Updated Results from TOUCH and
TIGIRS
Number of Patients
b,c
d
a
a) 13,900 treated for 1 year b) 6,600 treated
for 18 months c) 31,800 patients receiving
natalizumab worldwide d) 21,099 in TOUCH (median
of doses 8)
Panzara M, et al. P488 Presented at WCTRIMS
September 2008.
55
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
671242-1249 Jacobs L, et al NEJM
2000343989-904 Comi G, et al. Lancet
20013571576-1582 Comi G, et al. AAN Annual
Meeting 2008
56
Partial List of MS Drugs Under Development
Drug Monoclonal Antibody Phase MOA
Alemtuzumab (Campath) III Anti CD 52
Rituximab (Rituxan) III B cell inhibitor Anti CD 20
Daclizumab (Zenapax) II IL-2 receptor Antagonist
Ustekinumab CNTO 1275 II Anti IL12/IL23
57
Partial List of MS DrugsUnder Development
Drug Oral Phase MOA
Cladribine III Immunosuppressant
Laquinimod III Immunomodulator
FTY-720 (fingolimod) III Immunosuppressant
BG12 III Immunomodulator
Estriol III Estrogen agonist
Other
MBP 8298 III Altered Peptide Ligand
Teriflunomide III Immunosuppressant
58
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