Transcript Document

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
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
►
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.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.
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
*>30 cases/100,000=high prevalence
1. Kurtzke JF. Neuroepidemiology. 1991;10:1-8.
2. Noseworthy JH et al. N Engl J Med. 2000;343:938-952.
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. 1998;338:278-285.
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
Common
Less Common
Vision problems
Headache
Fatigue
Hearing loss
Paresthesias
Bladder, bowel, sexual dysfunction
Gait problems, spasticity
Itching
Seizures
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.
What Causes Demyelination
and 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
10
5
Years
15
20
Types of Cortical Lesions
Type I
Type II
Type III
Lesion in white
matter and cortex
Intracortical lesions
Lesions extending into
the cortex from the
pial surface
Peterson JW, Kidd GJ, and Trapp BD. In: Waxman S, ed. Multiple Sclerosis as a Neurodegenerative Disease. 2005:165-184.
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
Unpublished data.
MS09
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
Measures of brain volume
Relapses and impairment
MRI burden of disease
MRI activity
Preclinical
SPMS
RRMS
Time
Adapted with permission from JS Wolinsky.
Progression of Disability*: EDSS Score
Death
Confined to
bed or
wheelchair
Walks with aid
(<5 yards)
Walks unaided
(≥330-550 yards)
Fully ambulatory
*Steps are variable.
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/SourcebookEarly.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-b: 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
0
1
2
3
4
5
6
7
8
Glatiramer acetate1
IM IFN b-1a2
10 11 12 13
47%*
12+ years
54%* 2 years
1.3%* 5 years
IFN b-1b3
SC IFN b
9
77%* 4 years
-1a4
91%* 2 years
Natalizumab5
*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
Natural history cohort
Glatiramer acetate
SC IFN b-1a
% Reached
EDSS Score of 6
Years
Studied
50%
15
8%
10-12
20%
7.4
45%
16
35%
8
1
2
3
4
IFN b-1b (>80)
IM IFN b-1a
5
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
Cumulative Probability of Patients
Experiencing a Relapse (%)
EVIDENCE Trial
50
IM IFN β-1a
IFN β-1b
40
30
20
10
0
0
4
8
12
16
20
24
28
Week
Adapted with permission from Panitch H et al. Neurology. 2002;59:1496-1506.
32
38
40
44
48
INCOMIN Study
IM IFN β-1a
Proportion of Patients
Relapse Free (%)
IFN β-1b
100
90
80
70
60
50
40
30
20
10
0
P=0.23
5%
P=0.02
19%
P=0.0013
47%
P=0.036
42%
0-6
7-12
Adapted with permission from Durelli L et al. Lancet. 2002;359:1453-1460.
13-24
0-24
Berlin, Germany
24-Month Open-Label Comparison
Glatiramer acetate
Mean Number of Relapses
IM IFN β-1a
1.4
SC IFN β-1a 22 μg
1.2
SC IFN β-1b
1.0
0.8
0.6
0.4
0.2
0.0
Before Study
6 Months
Adapted with permission from Haas J, Firzlaff M. Eur J Neurol.
12 Months
24 Months
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
Weeks 0-48
Weeks 48-96
Weeks 0-96
p = 0.018
Mikol D et al. Lancet Neurol 2008;7:903-914.
BEYOND: BEtaseron Yields
Outcomes with New Dose
BEYOND: Study Design
Randomized
N=2,244
IFN β-1b 500 µg
n = 899
premature EOS
19%
IFN β-1b 250 µg
n = 897
premature EOS
13%
EOS reached
81%
Glatiramer acetate
n = 448
premature EOS
17%
EOS reached
87%
EOS reached
83%
EOS = end of study
Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.
BEYOND: No Group Differences with Respect to
Demographics and Baseline Characteristics
n = 899
n = 897
Glatiramer
Acetate
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
IFN β-1b 500 µg IFN β-1b 250 µg
n = 448
Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.
BEYOND: Annualized Relapse Rate
One Year Before and During Treatment
IFN β-1b 500 µg
IFN β-1b 250 µg
Glatiramer Acetate
Annualized relapse rate
2
1.5
1
-79% -78% -79%
0.5
0
Before (retrospective)
During
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
Study Design
►
Data
●
●
●
►
Direct analysis of insurance claims for patients taking either interferonbeta 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
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
Diagnosis of MS in
the i3 LabRx Database
July 1, 2001 – June 30, 2006
(N = 51,162)
Users of
IFN-β-1b
(n = 1,550)
Users of
GA
(n = 3,057)
IFN-β-1b
Continuous Use of
IFN-β-1b or GA
for 24 months
(n = 418)
IFN-β-1b
(n = 110)
GA
(n = 308)
Users of
GA
(n = 3,057)
Users of
IFN-β-1a
IM
(n = 3,949)
IFN-β-1a IM
Continuous Use of
IFN-β-1a IM or GA
for 24 months
(n = 639)
GA
(n = 308)
IFN-β-1a IM
(n =331)
Users of
GA
(n =2667)
Users of
IFN-β-1a
SC
(n = 1,188)
IFN-β-1a SC
Continuous Use of
IFN-β-1a SC or GA
for 24 months
(n =410)
GA
(n = 267)
MET
INCLUSION
CRITERIA
IFN-β-1a SC
(n =143)
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
Impact of Medication on Probability of Relapse during
2 Years of Continuous Use of Single Drug
%
IFN-β-1b GA
P=0.0018
IFN-β-1a IM GA
P=0.0048
IFN-β-1a SC GA
P=0.0049
Continuous Use Cohorts
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
Impact of Medication on Probability of Relapse during
2 Years of Continuous Use of Single Drug
$
IFN-β-1b GA
P=0.0018
IFN-β-1a IM GA
P=0.0048
IFN-β-1a SC GA
P=0.0049
Continuous Use Cohorts
Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008
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 A
Ann Rheum Dis 1999, 58:182-185
Natalizumab: Humanized Monoclonal
Antibody Against 4 Integrins
Complementarity-Determining
Regions
(CDRs)
Human IgG4
Framework
Reprinted with permission from Dr. P Calabresi.
►
CDR grafted from murine
antibody
►
Human IgG4 framework
►
Retains full potency
Selective Adhesion Molecule Inhibition:
Implications for MS Therapy
Leukocyte
Chemoattractant signal
4β1 (VLA-4)
Blood vessel lumen
Leukocyte
infiltration
and brain
inflammation
Endothelial cells
Tissue
VCAM-1
Leukocyte
Chemoattractant signal
4β1 (VLA-4)
Blood vessel lumen
Endothelial cells
Tissue
VCAM-1
Reprinted with permission from Dr. P Calabresi.
Reduced
leukocyte
infiltration
and brain
inflammation
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
Number of Patients
Natalizumab Utilization and Safety in Patients with
Relapsing MS: Updated Results from TOUCH and TIGIRS
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.
b,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; 67:1242-1249
Jacobs L, et al NEJM 2000;343:989-904
Comi G, et al. Lancet 2001;357:1576-1582
Comi G, et al. AAN Annual Meeting 2008
Partial List of MS Drugs
Under Development
Drug
Monoclonal Antibody
Phase
MOA
1. Alemtuzumab
(Campath)
III
Anti CD 52
2. Rituximab
(Rituxan)
III
B cell inhibitor
Anti CD 20
3. Daclizumab
(Zenapax)
II
IL-2 receptor
Antagonist
4. Ustekinumab
CNTO 1275
II
Anti IL12/IL23
Partial List of MS Drugs
Under Development
Drug
Oral
Phase
MOA
Cladribine
III
Immunosuppressant
Laquinimod
III
Immunomodulator
FTY-720
(fingolimod)
III
Immunosuppressant
BG12
III
Immunomodulator
Estriol
III
Estrogen agonist
MBP 8298
III
Altered Peptide
Ligand
Teriflunomide
III
Immunosuppressant
Other
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