Transcript Slides - Clinicians Channel

New Perspectives on the
Pathogenesis of MS
Douglas S. Goodin, MD
Professor of Neurology
Director, Multiple Sclerosis Center
University of California, San Francisco
Pathogenesis of Multiple Sclerosis
Clinical Course
PP MS
Disability
Disability
RR MS
Time
Time
RP MS
Disability
Disability
SP MS
Time
Time
Fauci AS. In: Harrison's Internal Medicine, 17th edition. McGraw Hill;2007, with permission from McGraw Hill.
Pathogenesis of Multiple Sclerosis
Epidemiology
Prevalence
5–200/100,000 population
Sex distribution
70%–75% female
Age at onset
20–40 years
Ethnic origin
Predominantly Caucasian
Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston, London. 2006.
Pathogenesis of Multiple Sclerosis
LFB Stain (Myelin Pathology)
LFB = Luxol fast blue.
Reprinted from Patrikios P, et al. Brain. 2006;129:3165-3172, with permission from Oxford Journals.
Pathogenesis of Multiple Sclerosis
In Vivo Pathology (MRI)
Courtesy of Douglas S. Goodin, MD.
Pathogenesis of Multiple Sclerosis
Evidence for Axonal Transection (Axon Bulbs)
Doinikow B. Z Gesamt Neurol Psych. 1915;27:151.
Reprinted from Trapp BD, et al. N Engl J Med.
1998:338:278. Copyright © 1998. Massachusetts
Medical Society. All rights reserved.
Pathogenesis of Multiple Sclerosis
Microscopic Pathology
Courtesy of D.P. Agamanolis, MD. http://neuropathology.neoucom.edu.
Pathogenesis of Multiple Sclerosis
Histopathology
Type I Lesions
Type II Lesions
I
I
Similar Except
Complement
MOG
Type III Lesions
MOG
MΦ
MΦ
Complement
MΦ
Type IV Lesions
LFB
MOG
MAG
Reprinted from Lucchinetti C, et al. Ann Neurol. 2000;47:707, with permission from John Wiley & Sons.
CNPase/
DNA frag
Pathogenesis of Multiple Sclerosis
Evidence for Genetic and Environmental Basis

An individual in the general population (from northern
Europe/northern North America) has a lifetime risk of MS
of approximately 0.1%–0.2%1

Risk in an individual with an affected family member is
increased, roughly in proportion to the degree of shared
genetic information1-5

In an identical twin, the relative risk approaches 200 times
that in the general population (~ 25%)1,2,4,5

Multiple genes must be involved in susceptibility

Environmental factors must also be involved in disease
pathogenesis
1. Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston, London. 2006. 2. Ebers GC, et al. Nature.
1995;377:150-151. 3. Sadovnick AD, et al. Lancet. 1996;347:1728-1730. 4. Nielsen NM, et al. Am J Epidemiol.
2005;162:873-874. 5. Compston A, Coles A. Lancet. 2002;359:1221-1231.
Timing of Environmental Events
New Perspectives
Pathogenesis of Multiple Sclerosis
Timing of Environmental Events


If several environmental events are necessary for MS
to develop in an individual, then it is only natural to
enquire as to :
–
how many such events are necessary and
–
whether it is important for these events to occur at any
particular time or in any particular order
3 pieces of MS epidemiologic evidence bear on these
issues
Courtesy of Douglas S. Goodin, MD.
Pathogenesis of Multiple Sclerosis
Timing of Environmental Events


First, there seems to be a maternal parent of origin effect in MS.
Evidence for this includes
–
When half-sibs are concordant for MS, the shared parent is almost
twice as likely to be the mother1,2
–
The concordance rate for MS in full sibs is less than the rate in
dizygotic twins3,4
–
Significantly more MS patients were born in May and fewer in
November5,6
–
Moreover, this may be flipped in the southern hemisphere5
These observations imply an early environmental event (timelocked to the solar cycle), which acts either in utero or in the
early postnatal period
1. Sadovnick AD, et al. Lancet.1996;347:1728-1730. 2. Ebers GC, et al. Lancet .2004;363:1773-1774. 3. Willer CJ, et al.
Proc Natl Acad Sci (U S A). 2003;100:12877-12882. 4. Compston A, Coles A. Lancet. 2002;359:1221-1231.
5. Willer CJ, et al. Br Med J. 2005;330:120. 6. Sadovnick AD, et al. Neurology.2007;69:60-62.
Pathogenesis of Multiple Sclerosis
Timing of Environmental Events

Second, when individuals migrate (prior to ~15 years) from a
region of high MS prevalence to one of low prevalence (or vice
versa), they seem to adopt a prevalence similar to that of the
region to which they moved.

By contrast, when they make the same move after the age 15,
they seem to retain the risk of the region from which they
moved

These observations point to an important environmental event
after birth but prior to young adulthood (~15 years)
1. Dean G, Kurtzke JF. BMJ. 1971;3:725-729. 2. Alter M, et al. Neurol. 1978;28:1089-1093. 3. Elian M, et al. J Neurol
Neurosurg Psychiatr. 1990;53:906-911. 4. Kahana E, et al. J Neurol.1994;241:341-346. 5. Cabre P, et al.
Brain.2005;128:2899-2910.
Pathogenesis of Multiple Sclerosis
Timing of Environmental Events

Third, the onset of clinical symptoms in MS is generally delayed
by many years (often decades) after these critical early events
(<15 years) have already taken place1-6

This delay implies that some subsequent environmental event
or events (i.e., after age 15) are also necessary for disease
pathogenesis or, at least, symptomatic onset
1. Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston, London: 2006. 2. Dean G, et al. BMJ.
1971;3:725-729. 3. Alter M, et al. Neurol. 1978;28:1089-1093. 4.Elian M, et al. J Neurol Neurosurg Psychiatr.
1990;53:906;-911. 5. Kahana E, et al. J Neurol. 1994;241:341-346. 6. Cabre P, et al. Brain. 2005;128:2899-2910.
Pathogenesis of Multiple Sclerosis
Timing of Environmental Events
In summary, there seems to be clear epidemiologic evidence for the
operation of at least 3 distinct environmental events in MS
Pathogenesis

The 1st operates in either in utero or in the early postnatal period

The 2nd operates beginning sometime after birth and continues
to operate until the age of ~15 years

The 3rd (which may be multiple) operates in adulthood, often
long after the 1st and 2nd event have already taken place
Pathogenesis of Multiple Sclerosis
Micro-Environmental Effects

Several studies of the micro-environment (ie, the environment in
which a person grows up and lives) have shown that:
–
MS risk is unchanged in adoptees, conjugal couples, individuals of
different birth order, and in siblings and half-siblings raised
together or apart

Thus, these studies suggest that micro-environmental influences
(either as an adult or as a child) do not contribute significantly to
MS risk

Consequently, it seems that, whatever the important
environmental factors are, they act at a population level
1. Sadovnick AD, et al. Lancet. 1996;347:1728-1730. 2. Ebers GC, et al. Lancet. 2004; 363:1773-1774. 3. Ebers GC, et al.
Ann Neurol. 2000;48:927-931. 4. Sadovnick AD, et al. Lancet Neurol. 2005;4:611-617. 5. Dyment DA, et al. J Neurol
Neurosurg Psychiatry. 2006;77:258-259.
Pathogenesis of Multiple Sclerosis
Environmental Factors

Many environmental factors have been proposed. Two currently
popular candidates for involvement in MS pathogenesis are:
–
EBV infection
–
Vitamin D deficiency
Pathogenesis of Multiple Sclerosis
Indirect Evidence for EBV

Late EBV infection is associated with MS

Symptomatic mononucleosis is associated with MS
Pathogenesis of Multiple Sclerosis
Evidence for EBV in Adult MS
Study
EBV+
MS Cases (%)
EBV+
Controls (%)
P Value
Sumaya, 1980
155/157 (98.7)
76/81 (93.8)
.05
Bray, 1983
309/313 (98.7)
363/406 (89.4)
.0001
93/93 (100)
78/93 (83.9)
.0001
104/104 (100)
23/26 (88.5)
.007
26/26 (100)
24/26 (92.3)
-
Munch, 1998
137/138 (99.3)
124/138 (89.9)
.0004
Myhr, 1998
144/144 (100)
162/170 (95.3)
.008
Wagner, 2000
107/107 (100)
153/163 (93.9)
.01
Ascherio, 2001
143/144 (99.3)
269/287 (93.7)
.008
Sundström, 2004
234/234 (100)
693/702 (98.7)
ns
Haahr, 2004
153/153 (100)
50/53 (94.3)
.05
Ponsonby, 2005
136/136 (100)
252/261 (96.6)
.05
1741/1749 (99.5)
2267/2406 (94.2)
p < 10-23
Larson, 1984
Sumaya, 1985
Shirodaria, 1987
Total
Courtesy of Douglas S. Goodin, MD.
Pathogenesis of Multiple Sclerosis
Worldwide Prevalence of MS
Reprinted from Kurtzke JF. Acta Neurol Scandinav. 1980;62:65-80, with permission from Blackwell Synergy.
Pathogenesis of Multiple Sclerosis
Indirect Evidence for Vitamin D







Latitude gradient for UVB is strikingly similar to MS prevalence1
Coastal regions of Norway had less MS than inland areas2
(? consumption of fish)
Inuit and Sami (very low MS) consume vitamin D in their diet2
No impact on MS from micro-environmental influences,
suggesting a population-wide exposure3-5
No convincing case of MS prior to 1822 (~onset of industrial
revolution in Europe) – indoor work, air pollution (↓ UVB)
The rate of skin cancer in MS patients is half that in controls;
whereas, rates for other cancers are similar6
There is an increasing use of sun-block and sun-avoidance
(↓ UVB by >94% at SPF = 15)7
1. Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston, London: 2006. 2. Gillie O. Br J Dermatol.
2006;154:1052-1061. 3. Ebers GC, et al. Ann Neurol. 2000;48:927-931. 4. Sadovnick. Lancet Neurol. 2005; 4:611-617.
5.Bager P, et al. Am J Epidemiol.2006;163:1112-1117. 6. Goldacre MJ, et al. J Epidemiol Community Health.2004;58:10321035. 7. Emmons KM, Colditz GA. J Natl Cancer Inst. 1999;91:1269-1270.
Pathogenesis of Multiple Sclerosis
Direct Evidence for Vitamin D

Munger et al. followed >185,000 women, interviewed about their
diet. The highest quintile for total vitamin D consumption had
significantly less new-onset MS compared with lowest quintile1

Van der Mei et al. studied past sun exposure in MS patients and
controls from Tasmania. There was a significant negative
association between total sun exposure during childhood
(especially in those 6–10 year old) and adolescence and the
subsequent development of MS2,3

Munger et al. utilized stored serum samples from 257 MS
patients (US Military). The risk of MS was significantly
decreased with increasing serum 25(OH) D3 levels prior to the
clinical onset of their illness4
1. Munger KL, et al. Neurology. 2004;62:60-65. 2. Van der Mei IA, et al. J Neurol. 2007;254:581-590. 3. Van der Mei IA, et al.
BJM. 2003;327:316. 4. Munger KL, et al. JAMA. 2006;296:2832-2838.
Pathogenesis of Multiple Sclerosis
EBV and Vitamin D

It is not necessary, however, to decide between the vitamin D
and EBV hypotheses. In fact, both factors represent populationwide exposures and both may be critical to MS pathogenesis
–
For example, we have already seen evidence that at least 3
environmental factors must be involved

Vitamin D and EBV may be 2 of them
Pathogenesis of Multiple Sclerosis
EBV and Vitamin D

Because EBV infection does not typically occur in utero or in
the early postpartum period, this agent unlikely to be the 1st
environmental factor

EBV would seem to be better suited as a candidate for the 2nd
factor, which must begin to act sometime after birth and must
continue to act until the age of ~15 years

By contrast, vitamin D is a much better candidate for the 1st
environmental factor
–
It is known to be involved in immune development and maturation
–
Vitamin D deficiency is associated with autoimmunity
–
Vitamin D production is coupled to the solar cycle
–
There are interactions between the physiologic effects of vitamin
D and gender in utero
Conclusions

Pathogenesis of MS involves complex interactions
between genetic and environmental factors

Multiple genes are involved

Timing of environmental factors is important
–
The 1st event: in utero or early postnatal period
–
The 2nd event: after birth to age 15
–
The 3rd event: in adulthood (may be several)

Vitamin D deficiency is a plausible candidate for the 1st factor;
EBV infection is a plausible candidate for the 2nd factor

MS incidence has increased over the past 30 years due to a
change in environmental exposure
Goals of Optimal Therapy
Bruce A. Cohen, MD
Professor
Davee Department of Neurology
Feinberg School of Medicine
Northwestern University
Chicago, Illinois
Therapeutic Goals in MS





Prevent disability
Prevent relapses
Relieve symptoms
Maintain well-being
Optimize quality of life
An effective therapy administered early in the
disease course can impact all of these goals
Relationship Between Relapses and
Disability





Key question in MS therapeutics
Relapses and enhancing MRI lesions are more
common early in the disease
Relapses decrease over time yet disability
worsens1
Current MS therapeutics suppress relapses and
enhancing lesions on MRI better than they prevent
progressive disability later in the disease course
Can optimal early therapy prevent later disability in
MS?
1. Patzold U, Pocklington PR. Acta Neurol Scand. 1982;65:248-266.
Natural History of MS
Clinical and MRI Measures
Relapses/Disability
MRI Activity
Disability
MRI T2 Burden of Disease
Axonal Loss
Preclinical
*
Secondary Progressive
MS
Relapsing-Remitting
MS
CIS
Time
Reprinted from Trapp BD, et al. Neuroscientist. 1999;5:48-57, with permission from Sage Publications.
Relationship Between Relapses and
Disability

Loss of axons and neurons considered the substrate
of disability in MS

Axonal damage has been shown to occur in acute
inflammatory plaques1

Axonal damage could be the result of

–
Cumulative inflammatory damage over time
–
A parallel degenerative process related to loss of trophic
support or an independent axonal degeneration2
Can effective immune therapy early in MS prevent
worsening disability?
1. Trapp BD, et al. N Engl J Med. 1998;338:278-285.
2. Trapp BD. Neuroscientist. 1999;5:48-57.
Persistent Disability After MS Relapses
Percentage of Patients
 1 pointa
50
45
40
35
30
25
20
15
N=62
N=85
42
27
44
29
N=77
41
30
10
5
0
30–59
aExtended
 .5 point
60–89
Days Since Exacerbation
90+
Disability Status Scale (EDSS)
Reprinted from Lublin FD, et al. Neurology. 2003;61:1528-1532, with permission from Lippincott, Williams & Wilkins.
Does Therapy that Reduces Relapses
Prevent Disability?





IFN β therapy in mild relapsing-remitting multiple sclerosis
(RRMS) reduced the risk of Extended Disability Status Scale
(EDSS) worsening compared with placebo1
IFN β therapy in RRMS associated with reduced relapses and
MRI activity2
IFN β given for 4 years reduced the risk of EDSS progression
compared with placebo for 2 years followed by IFN β for 2
years2
IFN β therapy at clinically isolated syndrome (CIS) reduced the
risk of subsequent EDSS worsening over 3 years3
However, relapses did not affect the rate of worsening from
EDSS scores of 4–6 in a French cohort4 and the authors
concluded that relapses do not significantly influence the
progression of irreversible disability
1. Jacobs LD, et al. Ann Neurol. 1996;39:285-294. 2. PRISMS Study Group. Neurology. 2001;56:1628-1636.
3. Kappos L, et al. Lancet. 2007;370:389-397. 4. Confavreux C, et al. N Engl J Med. 2000;343:1430-1438.
Median EDSS Score at Year 14
T2 Burden at CIS Presentation Predicts
Later Disability
7
6
5
4
3
2
1
0
0
0.6
0.9
5.6
0
1-3
4-10
>10
Median T2-Weighted MRI Lesion Volume (cm3)/number at CIS presentation
CIS = clinically isolated syndrome; EDSS = Extended Disability Status Scale; MRI = magnetic resonance imaging.
Brex PA, et al. N Engl J Med. 2002;346:158-164.
Dissociation Between Changes in T2
Lesion Burden and EDSS Over Time
2
Median Change
1.5
Median change in
EDSS score
Median change in
lesion volume (cm3)
r = correlation coefficient
r = 0.58
P <.001
1.5
1.1
r = 0.41
P = .002
1
r = 0.35
P = .02
0.85
0.83
0.5
0.5
n = 66 n = 66
n = 57
n = 57
0
0-5 Years
5-10 Years
0
n = 45
n = 45
10-14 Years
The mechanisms underlying the observed relation between clinical and MRI data are uncertain.
Brex PA, et al. N Engl J Med. 2002;346:158-164.
Measurement of Disability—EDSS

10-step scale of function

Steps 0–4 defined by number of neurologic
symptoms affected and estimated severity

Steps 4.5–8.0 defined by mobility and
distance walked

Step 10 (death) is rated most consistently
across examiners
Kurtzke JF. Neurology.1983;33:1444-1452.
Residual Impairment in MS
The Problem of Measurement






Current clinical measurement tools are
relatively crude
These tools emphasize motor changes
Limited assessment of cognitive functions
Do not discriminate among subtle influences
on endurance and fatigability
Conventional MRI tools are most useful for
prognosis in early stages
More-sensitive imaging tools detect change
in areas that appear normal on current MRI
Patterns of Cortical Activation
Functional MRI
Healthy Volunteers
MS Patients
Reprinted from Rocca MA, et al. Ann Neurol. 2002;51:330-339, with permission from John Wiley & Sons.
fMRI Measures of
Adaptation—Cerebral Reserve?


Patients with MS and no detectable disability
demonstrate increased cortical activation patterns in
maintaining simple task performance when
compared with normal subjects
–
MS patients within 3 years of diagnosis
–
Multiple Sclerosis Functional Composite (MSFC) scores
comparable in subjects and controls
Suggests that recruitment of additional neural
elements, ie, network expansion, allows the
maintenance of “normal” function
Staffen W, et al. Brain. 2002;125:1275-1282.
fMRI Measures of
Adaptation—Cerebral Reserve?

CIS patients tested within 3 months of presentation show
increased cortical activation on a simple repetitive finger
flexion-extension motor task (unaffected by their CIS)
compared with normal controls

Relative activation of the contralateral SMC correlates with
decreased WBNAA levels measured with HMRS1
(r = - 0.78, P <.001)

Demonstrates relationship between axonal pathology and
recruitment within a network, suggesting adaptations to limit
the functional impact from the axonal damage
CIS = clinically isolated syndrome; SMC = sensorimotor cortex; WBNAA = whole-brain N-acetylaspartate; HMRS = proton
magnetic resonance imaging.
1. Rocca MA, et al. Neuroimage. 2003;18:847-855.
Relationship between Relapses and
Disability—The Cerebral Reserve
Hypothesis



Early damage in MS is compensated for by
expansion of neural networks maintaining
performance by our measures for a time: reflecting
a cerebral reserve capacity
When a critical threshold is exceeded, persistent
deficits measurable by EDSS or other performance
measures occur
Further worsening may result from
–
–
–
Cumulative effects of temporally remote injuries
Metabolic stress on surviving neurons and axons due to
changes in trophic factors and increased performance
demands
Local pathologic processes within the CNS
microenvironment set in motion by earlier pathology
Courtesy of Bruce A. Cohen, MD.
Implications of the Hypothesis




Early onset of effective MS immune therapy can alter longterm natural history
Since individuals may differ in their response to a particular
agent, optimal therapy requires monitoring effectively for a
suboptimal response
Even with such a strategy, some individuals may do poorly
because of factors that favor a more severe disease course
and which are not amenable to current therapies
Expansion of the therapeutic armamentarium and
investigation of potential synergies based on mechanisms of
action may further optimize treatment results, particularly
when applied in early MS
Courtesy of Bruce A. Cohen, MD.
Suboptimal Response to MS Therapy
Potential Causes







Nonadherence
Pharmacogenomics: responsiveness to IFN β
related to single-nucleotide polymorphism
frequencies1
Variable pathologies with differing responses to
immune therapies
Dosage of an agent2
Need for more intense or broader spectrum of
immune therapies
NAbs
Too late in the course of disease
1. Byun E, et al. Arch Neurol. 2008;65:337-344. 2. Schwid SR, et al. Arch Neurol. 2005;62:785-792.
Conclusions

To date, treatment has been successful in
suppressing relapses and enhancing MRI lesions

Early damage in MS appears to be compensated for
by expansion of neural networks (“cerebral reserve”)

When this reserve is exceeded, persistent deficits
result

Early treatment with effective immune therapy may
alter the course of disease, preventing/ delaying later
disability
Current Therapies and Role of
Emerging Small-Molecule Therapies
in MS—Evolving Strategies
Bruce A.C. Cree, MD, PhD, MCR
Assistant Professor of Neurology
Multiple Sclerosis Center
University of California, San Francisco
San Francisco, California
Current First-Line MS Therapies

Interferon beta-1b

30 mcg Interferon beta-1a once weekly

Glatiramer acetate

40 mcg Interferon beta-1a thrice weekly

Similar efficacy for relapse rate reduction ~ 30%

Generally very safe and well tolerated

All require self-injection
Second Second-Line MS Therapies

Mitoxantrone

Natalizumab

Generally indicated for persons with
suboptimal response to first-line agents

Require intravenous infusion

Associated with life-threatening
adverse events
MS Disease Process

Believed to be heterogeneous

Multiple damage mechanisms
implicated

No therapy encompasses all these
mechanisms
MS Disease Pathology
Circulation
Rolling
Extravasation
Adhesion
B L O O D
F L O W
B cell
Activated T cell
a4 Integrin
VCAM
LUMEN OF
VENULE
B A S A L
Proteases
L A M I N A
BRAIN
TISSUE
astrocytes
Cytokines and
chemokines
IL-1, IL-12,
chemokines
Antigen presenting cell
(Astrocyte or Microglial cell)
Activated
microglia/macrophages
Activated
Macrophage
T CELL
REACTIVATION
Proteases
TNF-a
O2•NO•
Courtesy of Sergio Baranzini, PhD.
AXONAL
DAMAGE
Autoantibodies
Complement
MYELIN
oligodendrocyte
Oral MS Therapies in Phase III
Development

Fingolimod

Fumarate

Teriflunomide

Laquinimod

Cladribine
Proof of Concept Phase II
Study Design
Months
Gad +
MRI Scans
0
1
2
3
4
5
6
Placebo
Active Treatment Low Dose
Active Treatment High Dose
Primary outcome measure = cumulative number of
gadolinium-DPTA enhanced lesions over 6 months
Fingolimod
OH
NH2
HO
Fingolimod


Sphingosine-1-phosphate receptor modulator
Induces rapid and reversible sequestration of
lymphocytes in lymph nodes
– Prevents activated and autoreactive cells from
migrating to target organs


Lymphocytes remain functional and may still
be activated as part of an immune response
Crosses blood brain barrier and may have
neuroprotective properties
Brinkmann V, et al. J Biol Chem. 2002;277:21453-21457; Pinschewer DD, et al. J Immunol. 2000;164:5761-5770;
Chiba K, et al. J Immunol. 1998;160:5037-5044.
Fingolimod
Primary Endpoint
Cumulative Gad+ Lesion
(No. per patient)
16
43%
P <0.001
12
61%
P <0.006
8
4
14.8
8.4
Placebo
(n = 81)
Fingolimod 1.25 mg
(n = 83)
5.7
0
Fingolimod 5 mg
(n = 77)
Adapted from Kappos L, et al. N Engl J Med. 2006;355:1124-1140. Copyright ©2006. Massachusetts Medical Society.
All rights reserved.
Fingolimod—Long-Term Relapse Rate and
MRI Activity (N = 173)
Month 24
ARR
Relapse-free
Free of gad-enhanced MRI
lesions
No subjects retained (%)
No new/newly enlarging T2
lesions since month 24
Month 36
1.25 mga
5/1.25 mgb
1.25 mga
5/1.25 mgb
0.20
0.22
0.20
0.21
68%
73%
—
84%
89%
189/250 (76%)
173/250 (69%)
—
75%
aReceived
1.25 mg only.
bInitially treated with 5.0 mg; dose reduced to 1.25 mg between months 18 and 24.
ARR = annualized relapse rate.
Comi G, et al. 60th Annual Meeting AAN 2008; April 12-19, 2008. Abstract S12.005.
Fingolimod in MS
Conclusions

Treatment with fingolimod reduced disease activity
–
–
–
–

MRI activity reduced by up to 61%1
Relapses reduced by >55%1
Up to 73% relapse-free at 36 months2
89% free of GAD+ MRI lesions at 36 months2
Treatment generally well tolerated1,2
– Adverse events were dose dependent and reversible
– Seven skin cancers including 2 malignant melanomas2

Phase III trials are actively recruiting, expected to
conclude late 2010, launch in 2011
1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140.
2. Comi G, et al. 60th AAN Meeting 2008; April 12-19, 2008. Abstract S12.005.
Fumarate
O
O
O
O
O
O
O
O
Fumaric Acid Esters



Derived from common fumitory (Fumaria officinalis),
a plant rich in fumaric acid
Used to treat skin disorders since the 17th century
Fumaric acid esters used in severe psoriasis
– First reported by Schweckendiek in 1959

Inhibits T-cell activity
– Induction of activated lymphocyte apoptosis
– Shift in cytokine profile from Th1 to Th2


Effective in chronic experimental autoimmune
encephalomyelitis
May have neuroprotective properties by activating
antioxidant response genes
Schilling S, et al. Clin Exp Immunol. 2006;145:101-107.
Fumarate
Phase II Results



The 720-mg group had a 69% reduction
(P <0.001) in the mean number of new gadoliniumenhancing lesions vs placebo as measured monthly
from weeks 12–24 of the study
There was a non-statistically significant trend
favoring treatment for relapse reduction by 32%
(P =0.272)
The 120-mg and 360-mg treated groups were not
statistically significant vs placebo on any endpoints
Kappos L, et al. 22nd ECTRIMS 2006; September 27-30, 2006. Poster P325.
Kappos L et al. 59th AAN 2007. Boston, Mass. Abstract P06.086.
Fumarate
Conclusions



Fumarate reduced the cumulative number of
Gad+ lesions, with a trend toward reduced
relapses
Adverse effects profile favorable with
discontinuations due to nausea, flushing,
headache, nasopharingitis (known effects in
psoriasis)
Phase III trials are actively recruiting,
completion expected in 2011, launch in 2012
Teriflunomide
F
OH O
H3 C
N
H
N
F
F
Teriflunomide

Leflunomide parent compound used in
treatment of rheumatoid arthritis

Inhibits pyrimidine synthesis
– Binds dihydroorotate dehydrogenase, the fourth
enzyme in de novo pyrimidine synthesis

Inhibits T-cell division

Inhibits murine experimental autoimmune
encephalomyelitis
Zeyda M, et al. Arthritis Rheum. 2005;52:2730-2739.
Teriflunomide Phase II
Cumulative No. of Unique Active Lesions
Primary Outcome
16
14
13.4
61%, P <0.03
12
10
8
6
5.2
5.3
7 mg/day
14 mg/day
4
2
0
Placebo
O’Connor PW, et al. Neurology. 2006;66:894-900.
Teriflunomide Conclusions




Reduced cumulative number of Gad + lesions with favorable
trends for relapse rate reduction and disability
Overall well tolerated with acceptable adverse effect profile
Teriflunomide is teratogenic in animals
Reproductive toxicity in humans is not fully understood
–

Women who wish to become pregnant
–
–

Women are advised not to become pregnant and men cautioned not
to parent children while on therapy
Washout with cholestyramine or activated charcoal and confirmation
of acceptable plasma levels of teriflunomide
Without washout up to 2 years before plasma levels decrease
sufficiently
Phase III trials are actively recruiting, complete enrollment
uncertain
O’Connor PW, et al. Neurology. 2006;66:894-900.
Laquinimod
Cl
OH
O
N
N
CH3
O
CH3
Laquinimod

Parent compound: roquinimex
– Suppressed gadolinium-DPTA lesions in phase II/III
studies
– Study stopped due to serositis, myocardial infarction


Laquinimod developed to cause less
inflammation in dog model
In murine experimental autoimmune
encephalomyelitis (EAE), laquinimod
– Suppresses development of EAE; 20x more potent than
roquinimex
– Shifts cytokine balance from Th1 to Th2
Brunmark C, et al. J Neuroimmunol. 2002;130:163-172; Yang JS, et al. J Neuroimmunool. 2004;156:3-9.
Laquinimod
Phase IIb Results
Primary End Point: Weeks 24–36
24
Cumulative No. of
Gad-Enhancing T1 Lesions
P =0.005 vs placebo
19
14
38%
16.86
15.77
9
10.53
4
-1
Placebo
0.3 mg
0.6 mg
Laquinimod Laquinimod
Comi G, et al. 59th AAN Meeting; April 28-May 5, 2007. Abstract S02.002.
Courtesy of Bruce A.C. Cree, MD.
Placebo
0.3 mg
0.6 mg
Laquinimod
Conclusions

Reduced the cumulative number of
Gad+ lesions

No trend in favor of reductions in
relapse rate and disability

Overall well tolerated without indication
of systemic pro-inflammatory effects

Phase III trials are under way
Cladribine
NH2
N
N
HO
O
HO
N
N
Cl
Cladribine

Cladribine is a purine nucleoside analog
prodrug that is resistant to adenosine
deaminase degradation and is activated by
deoxycytidine kinase
–
–
–
–

Causes failure of DNA damage repair
Selective T lymphocyte depleting agent because of high
levels of deoxycytidine kinase in T-cells
FDA approved for treatment of hairy-cell leukemia
Oral cladribine formulation is fast-tracked by the FDA
Phase II single center 52 patient study in RRMS
Sipe JC. Expert Rev Neurother. 2005;5:721-727.
Cladribine—RRMS Phase II
Relapse Rate
Relapses
2
1.5
P =0.011
32%
1
Placebo
Cladribine
2.1 mg/kg
0.5
0
Baseline
Months
0–6
Months
7–18
RRMS = relapsing-remitting multiple sclerosis.
Adapted from Romine JS, et al. Proc Assoc Am Physicians. 1999;111:35-44, with permission from Blackwell Synergy.
Cladribine
Conclusions






Phase II study single-center, 52 patients1,2
Cladribine was administered subcutaneously1,2
94% suppression of new enhancing lesions in
cladribine group after month 6 (P <0.001)2
Well tolerated, can cause myelosuppression
that is usually reversible1,2
Phase III trial fully enrolled, completion in
12/2008; anticipate launch in 2009
Fast-tracked by FDA; expected to be 1st oral
treatment for MS
1. Romine JS, et al. Proc Assoc Am Physicians. 1999;111:35.
2. Sipe J, et al. 60th Annual Meeting AAN 2008; April 12-19, 2008. Abstract S02.004.
Summary
Cumulative Number of
Gad+ lesions
Annualized
Relapse Rate
Fingolimod (1.25 mg)
(3-arm study, N = 277)
-43%, P <0.001
-55%, P =0.009
Teriflunomide (7 mg)
(3-arm study, N = 178)
-61%, P <0.03
-32%, NS
Laquinimod (0.6 mg)
(3-arm study, N = 306)
-38%, P =0.005
-32%, NS
Fumarate (720 mg)
(4-arm study, N = 256)
-69%, P <0.001
-32%, NS
Cladribine (2.1 mg)
(2-arm study, N = 52)
-94%, P <0.001
-32%, P =0.01
1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 2. O’Connor PW, et al. Neurology. 2006;66:894-900. 3. Comi G, et
al. 59th AAN Meeting; April 28-May 5, 2007. Abstract S02.002. 4. Kappos L, et al. 22nd ECTRIMS 2006; September 27-30,
2006. Poster P325. 5. Romine JS, et al. Proc Assoc Am Physicians. 1999;111:35-44. 6. Sipe J, et al. 60th Annual Meeting
AAN 2008; April 12-19, 2008. Abstract S02.004.
Emerging Oral Therapies
Final Thoughts


Currently, most oral therapies not available outside of trials
Balance between efficacy and tolerability and safety will be
crucial
–
–
–

Less than equivalent efficacy likely to be acceptable
Likely to see switches as soon as an oral therapy becomes
available
Monotherapy, combination therapy, induction therapy?
All studies are very large and placebo controlled, will there be
enough subjects to fully enroll all trials?
–
Trials that recruit soonest will be successful, trials recruiting late
may not enroll a sufficient number of subjects
Controversies in MS
Mark S. Freedman, HBSc, MSc, MD
Professor of Neurology
Director, Multiple Sclerosis Research Clinic
University of Ottawa
Canada
Questions to Address

Clinically isolated syndrome
– To treat or not to treat?

Is there a way of choosing patient-specific
therapies?

How do you identify the suboptimal
responder?

How long do you treat?

Is there a role for combination therapy?
Timing of Therapy Key to Preventing
Disability
First
Pre- Demyelinating
Relapsing-Remitting
Event
clinical
Transitional
Secondary
Progressive
First Clinical Attack
Time
window for
early
treatment
Axonal loss
Clinical threshold
Demyelination
Inflammation
Time (years)
Courtesy of Mark S. Freedman, MD.
Rationale for Early Treatment

Time is ticking…

What is lost by delaying early therapy is
not regained by starting later
Studies of IFN Beta in CIS
IFN beta-1b EOD
Once-Weekly IFN beta-1a
BENEFIT3
% of patients
with CDMS at 2 years
ETOMS2
% of patients
with CDMS at 2 years
CHAMPS1
% of patients with CDMS
at 2 years
50
50
40
40
50
P = .047
40
30
30
20
20
20
10
10
10
30
0
P = .002
Placebo IFN beta-1a
0
Placebo IFN beta-1a
0
P < .0001
Placebo Betaseron
IFN = interferon; CIS = clinically isolated syndrome; EOD = every other day; CDMS = Clinically definite MS.
1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Comi G, et al. Lancet. 2001:357:1576-1582. 3. Kappos L, et al.
Neurology. 2006;67:1242-1249.
Courtesy of Mark S. Freedman, MD.
Results of CIS Treatment



Both CHAMPS and ETOMS showed that
treating CIS with IFN beta-1a once weekly
delays the time to a 2nd attack and reduces
MRI lesions
Preliminary data from PreCISe indicate that
treating CIS with GA also delays the time to
the 2nd attack and reduces MRI lesions
BENEFIT has shown that treating CIS with
high-dose, high-frequency IFN beta-1b has
the same effect on 2nd attack and MRI but
also delays disability
Choosing a Treatment?
Courtesy of Mark S. Freedman, MD.
How do any of the diseasemodifying agents compare with
one another in relapsing MS?
The concept of number needed to treat
or NNT helps
Comparing Efficacy


Direct “head-to-head” trials best
Cannot simply compare overall
results across trials
– Different populations
– Different study designs
– Different behaviour of placebo arms

Reduce outcomes to a common
independent variable, such as
number needed to treat (NNT)
Measuring Efficacy Across Trials—
Use of NNT

To compare results across studies
one needs to reduce individual study
results to a more common measure

The number needed to treat (NNT) is a
common measure of the effectiveness
of interventions

NNT = 1/absolute risk (rate) reduction
with intervention vs control
Number Needed to Treat




Number needed to treat (NNT) = the number
of patients needed to receive a treatment
over a set period (eg, 2 years) in order for 1
patient NOT to experience 1 negative event
(ie, relapse, progression, death, etc.)
Therapeutic gain = absolute difference
between treatment and placebo groups
Absolute risk reduction = therapeutic gain
NNT = 1/therapeutic gain or 1/absolute risk
reduction
Comparing Across Trials—Which to Use?
Absolute vs Relative Risk Reduction

Assuming all populations are at the same
“risk” of having a relapse, then RRR should
be constant

However, if patients are selected because
of their “high” risk but turn out to be at
lower risk then can you reliably use RRR?

In such cases, using the absolute risk
reduction and NNT may be a better
comparator
Absolute vs Relative Risk Reduction
What if all 3 had the same “baseline” RR?
Annualized Relapse Rate
2.0
1.6
D = .5 absolute
33% relative
1.4
1.2
Placebo
Treatment
D = .5 absolute
50% relative
1
0.8
D = .5 absolute
66% relative
0.6
0.4
Does
drug Z really demonstrate twice
0.2
the0 efficacy of drug X?
Drug X
Drug Y
Drug Z
Which drug is showing the greatest efficacy?
Reprinted from Freedman MS, et al. Euro Neurol. 2008;60:1-11, with permission from Karger.
Relationship Between Absolute vs
Relative Risk Reduction
Risk Reduction
(Depends on the number of events)
Relative Risk
Reduction (RRR)
Relapses in placebo = 10
Relapses in treatment = 5
Absolute difference = 5
RRR = 50%
When n is small, “relative”
changes are large
Courtesy of Mark S. Freedman, MD.
Absolute
Risk
Reduction
Relapses in placebo = 100
Relapses in treatment = 95
Absolute difference = 5
RRR
= 5%
# of
events
When n is large, “relative”
changes are small
Annualized Relapse Rate
Different Placebo Behavior
29%
2
1.8
17%
47%
1.6
32%
1.4
51%
Baseline
Placebo
Treatment
1.2
1
0.8
0.6
0.4
0.2
0
Glatiramer
Acetatea
IFN beta-1a
30 mcg IM qwb
IFN beta-1bc IFN beta-1a
Natalizumabe
44 mcg SC tiwd
aCopaxone; bAvonex; cBetaseron; dRebif; eTysabri.
Courtesy of Mark S. Freedman, MD.
Annualized Relapse Rate
Comparing Risk Outcomes
2
Baseline
Placebo
Treatment
1.8
1.6
34%
32%
~ same
baseline RR
1.4
1.2
1
28%
68%
18%
0.8
Can you really
therefore
compare these
differences?
0.6
0.4
0.2
0
Marked
difference in
“on study” RR
Glatiramer
Acetatea
IFN beta-1a IFN beta-1bc IFN beta-1a Natalizumabe
30 mcg IM qwb
44 mcg SC tiwd
aCopaxone; bAvonex; cBetaseron; dRebif; eTysabri.
Courtesy of Mark S. Freedman, MD.
Change in MS Study Populations in Trials
80
30th %tile time to first
relapse (months)
62
1
0.87
18
62
Annualized relapse rate
16.3
14.2
62
0.77
0.8
60
0.6
12
40
9.6*
8.0
34
32
0.59
0.54
0.4
0.34
0.3
0.29
6
3.0
Study
‘94
start
aMedian;
‘04
GA
‘91
IFN beta-1a
‘04
‘94
‘04
IFN beta-1a
GA
‘91
IFN beta-1a = 44 mcg TIW except for OWIMS (44 mcg QW).
OWIMS = Once Weekly Interferon for MS.
Courtesy of Mark S. Freedman, MD.
‘04
‘94
Johnson
REGARD
CAMPATH
REGARD
Johnson
REGARD
EVIDENCE
PRISMS
REGARD
Johnson
REGARD
EVIDENCE
PRISMS
IFN beta-1a
EVIDENCE
0
0
OWIMS
0
0.2
PRISMS
20
REGARD
Patients relapse-free
(%)
GA
‘04
‘91
‘04
Relapses NNT (2 years)
8
Number Needed to Treat
6.67
7
Lower NNT
denotes
greater efficacy
6
5
4.1
4
2.3
3
2.4
2.0
2
1
0
Glatiramer
Acetatea
IFN beta-1a
30 mcg IM qwb
aCopaxone; bAvonex; cBetaseron; dRebif; eTysabri.
NNT = number needed to treat.
Freedman MS, et al. Euro Neurol. 2008;60:1-11.
Courtesy of Mark S. Freedman, MD.
IFN beta-1bc
IFN beta-1a
44 mcg SC tiwd
Natalizumabe
% Relapse Free (95% CI) NNT
(2 years)
Number Needed to Treat
16
15a (6–∞)
14
12
9a (4–∞)
10
Lower NNT
denotes
greater efficacy
7 (4–23)
8
6 (4–11)
6
4 (3–5)
4
2
0
a ns
Glatiramer
Acetatea
IFN beta-1a
30 mcg IM qwb
IFN beta-1bd
= not significant; bCopaxone; cAvonex; dBetaseron; eRebif; fTysabri.
Freedman MS, et al. Euro Neurol. 2008;60:1-11.
Courtesy of Mark S. Freedman, MD.
IFN beta-1a
44 mcg SC tiwd
Natalizumabf
% Progression-Free (95% CI)
Over 2 Years
Number Needed to Treat
35
Lower NNT
denotes
greater efficacy
30
25
20
13a (6–∞)
15
9 (5–53)
8b (4–38)
10
8 (6–17)
5
0
a ns
33a(7–∞)
Glatiramer
Acetatea
IFN beta-1a
30 mcg IM qwb
IFN beta-1be
IFN beta-1a
44 mcg SC tiwf
Natalizumabg
= not significant; bBaseline expanded disability status score 1–3.5; cCopaxone; dAvonex; eBetaseron; fRebif; gTysabri.
Freedman MS, et al. Euro Neurol. 2008;60:1-11.
Courtesy of Mark S. Freedman, MD.
MRI Activity-Free
(No T2 Active Scans Over 2 Years)
Number Needed to Treat
6
5
Lower NNT
denotes
greater efficacy
5 (3–11)
4 (3–7)
4
3
2 (2–3)
2
1
NA
NA
0
Glatiramer
Acetatea
IFN beta-1a
30 mcg IM qwb
NA = not available.
cCopaxone; bAvonex; cBetaseron; dRebif; eTysabri.
Freedman MS, et al. Euro Neurol. 2008;60:1-11.
Courtesy of Mark S. Freedman, MD.
IFN beta-1bc
IFN beta-1a
44 mcg SC tiwd
Natalizumabe
Optimizing Therapy
How do you determine when there is
a suboptimal response?
Canadian Multiple Sclerosis Working
Group (CMSWG) Recommendations
on Optimizing Treatment with
Disease-Modifying Therapy
Optimizing Therapy
Important Relapse Features

Rate
– Probably the least sensitive index

Severity
–
–
–
–

Steroids required
Effects on activities of daily living
Mono/multiple systems involved
Motor (pyramidal/cerebellar)
Recovery
– Prompt vs delayed
– Complete vs residual deficit
Determining the Level of Concern to
Consider Treatment Modification Based
on Relapse Outcomes
Low
Medium
High
Ratea
Moderate reduction 75%–
100%
Modest reduction
35%–75%
Minimal reduction <35%
(= result of all clinical trials)
Severity
Mild
 No Steroids
 Minimal effect on ADL
 1 FS involved
 No motor/cerebellar
involvement
Moderate
 Steroids required
 Moderate effect on ADL
 >1 FS involved
 Moderate motor/cerebellar
involvement
Severe
 Steroids/hospital
 Severe effect on ADL
 >1 FS involved
 Severe motor/cerebellar
involvement
Recovery
Prompt
Incomplete at 3/12
Incomplete at 6/12
aRate
of change is relative to the baseline. Reference time frame for baseline ≥2 years prior to treatment
initiation.
Ideally, prospective and objective relapse data should be obtained during the reference period (minimum 6/12).
ADL = activities of daily living; FS = functional systems.
Adapted from Freedman MS, et al. Can J Neurol Sci. 2004:31:157-168, with permission from the Canadian Journal of
Neurological Sciences.
Determining the Level of Concern to
Consider Treatment Modification Based
on Progression Outcomes
Baseline EDSS
Low
Medium
High
≤3.5
• <2 points
• 2 points confirmed at
6/12
• >2 points confirmed at 6/12
• 2 points confirmed at 1 year
4–5
• <1 point
• 1 point confirmed at 6/12
• >1 point confirmed at 6/12
• 1 point confirmed at 1 year
• 0.5 point confirmed at
6/12
• >0.5 point confirmed at 6/12
• Some motor, cerebellar
or cognitive
• Multiple domains
affected
• Pronounced motor,
cerebellar, or cognitive
• Multiple domains affected
≥5.5
Clinically
documented
progression
• No motor
• Minor
sensory
EDSS = expanded disability status scale.
Adapted from Freedman MS, et al. Can J Neurol Sci. 2004:31:157-168, with permission from the Canadian Journal of
Neurological Sciences.
Determining the Level of Concern to
Consider Treatment Modification Based
on MRI Outcomes
Change in MRI Categories
Low
Medium
New Gd-enhancing lesions
New T2 lesions
Enlarging T2 (BOD)
Any new lesion
New T1 hypointense lesions
Increase in >2 MRI
categories
Enlarging T1 hypointense lesions
Atrophy
Adapted from Freedman MS, et al. Can J Neurol Sci. 2004:31:157-168, with permission from the Canadian Journal of
Neurological Sciences.
The Optimization Model
Assessing the Concern Whether to Modify
a Treatment Regimen
Each gauge represents
a continuum from no
concern (0 on the dial)
to a low, medium, or
high level of concern
Progression
Relapse
MRI
Consider 3 “low”, any
2 “medium”, or any 1
“high” as an indication
of suboptimal
treatment that might
warrant a change in
management
Adapted from Freedman MS, et al. Can J Neurol Sci. 2004:31:157-168, with permission from the Canadian Journal of
Neurological Sciences.
Applying TOR to Year 1 of PRISMS 4
IFN beta-1a SC
0.45
Level of Concern:
0.4
Patients (%)
0.35
0.3
None
Low
Medium
High
32%
29%
39%
29%
27%
0.25
22%
0.2
0.15
12%
10%
0.1
0.05
n = 58 n = 52 n = 49 n = 21
n = 70 n = 41 n = 52 n = 19
22 mcg sc tiw (n = 180)
44 mcg sc tiw (n = 182)
0
TOR = Treatment Optimization Recommendations.
Freedman MS, Forrestal. Multiple Sclerosis. 2008 (in press).
Courtesy of Mark S. Freedman, MD.
Relapses During Years 2–4 in “High” Concern
Year 1-Treated Patients
60
Relapses per Year:
48%
Patients (%)
50
40
53%
None
≤0.5
>0.5 and ≤1.0
>1.0
29%
30
21%
20
16%
14%
10
0
10%
11%
n = 3 n = 2 n = 6 n = 10
n = 3 n = 2 n = 4 n = 10
22 mcg sc tiw (n = 21)
44 mcg sc tiw (n = 19)
Freedman MS, Forrestal. Multiple Sclerosis. 2008 (in press).
Courtesy of Mark S. Freedman, MD.
Annualized Relapse Rates During
Years 2–4 vs Year 1 Level of Concern
1.4
Annualized Relapse Rate
1.26
1.2
1.08
Inactive
Low
Medium
High
1.18
1.08
1
0.8
0.68
0.6
0.6
0.45
0.4
0.29
0.2
n = 58 n = 52 n = 49 n = 21
n = 70 n = 41 n = 52 n = 19
22 mcg sc tiw
44 mcg sc tiw
0
Freedman MS, Forrestal. Multiple Sclerosis. 2008 (in press).
Courtesy of Mark S. Freedman, MD.
EDSS Progression During Years 2–4 in
Patients of “High” Concern in Year 1
Progressions per Year:
70
None
≤0.5
>0.5 and ≤1.0
>1.0
60
Patients (%)
50
43%
58%
40
32%
29%
30
19%
20
10%
10
0
n=9
n=6
n=2
n=4
22 mcg sc tiw
Freedman MS, Forrestal. Multiple Sclerosis. 2008 (in press).
Courtesy of Mark S. Freedman, MD.
n = 11
n=6
5%
5%
n=1
n=1
44 mcg sc tiw
Results of Using Canadian TOR to
Monitor Response to Therapy


89% (125/141) of medium/high concern
year 1 patients had ≥1
relapse/progression in years 2–4
11% (16/141) of this same group had no
clinical disease activity
– They may well have had MRI activity
– Further follow-up may well have
demonstrated continued activity
TOR = Treatment Optimization Recommendations.
Freedman MS, Forrestal. Multiple Sclerosis. 2008 (in press).
Length of Treatment
When do you consider
stopping treatment?
How Long is the Carry-Over Benefit
After Stopping IFN beta?
30
Patient 1
Total No. Contrast Enhancing
Lesions/T2-LL (cc)
25
IFN
20
15
10
5
0-30 -25 -20 -15 -10 -5
0
5
10 15 20 25 30 35 40
Patient 2
3
IFN
2
1
0
Courtesy of N. Richert, MD.
-15 -10 -5
0
5
10 15
Month
20
25
30
35
40
45
What is the Effect of First-Line Agents
in SPMS?
Proportion of Patients with Confirmed Progression
EUSPMS
(IFN beta-1b)
SPECTRIMS
(IFN beta-1a SC)
NA SPMS
(IFN beta-1b)
IMPACT
(IFN beta-1a IM)
N
718
618
939
436
Placebo
50%
65%
34%
34%
IFN beta
39%
59%
32%
29%
P >.05 in all studies (ie, insignificant).
SPMS = secondary progressive MS.
Courtesy of Mark S. Freedman, MD.
Combination Therapy

When?
– Early vs late

What?
– Whole array of agents tried, nothing
proven but mostly uncontrolled or
observational studies

Are they safe?
– Lessons from SENTINEL (IFN beta +
natalizumab)
Combination Therapy

How?
– Induction

Combine with first-line agent for a short
period, then stop & continue with firstline agent alone
– Pulse

Add agent to first-line agent for short
periods but at regular intervals
– Long-term combination

Maintain both agents
Panel Discussion
Question and Answer Session
Fingolimod and Fumarate Both
1.
May have neuroprotective effects
2.
Are immune suppressants
3.
Induce Th1 to Th2 cytokine shifts
4.
Are lymphocyte-sequestering agents
Which of the Following Statements
Best Characterizes Your Approach to
Clinically Isolated Syndrome (CIS)?
1.
CIS patients may not progress to MS; starting treatment
at this stage may commit them to long-term therapy they
do not need
2.
This is the earliest stage we can reasonably introduce
treatment
3.
Studies show that treatment leads to a short delay to next
relapse but doesn’t prevent MS, so what’s the point?
4.
It is better to wait until patients demonstrate disease
activity before starting an expensive treatment
The “Cerebral Reserve” Hypothesis
Suggests that
1.
Early damage of MS is compensated for by
an expansion of neural networks
2.
Treatment is largely ineffective in preventing
disability if given before the cerebral reserve
is exceeded
3.
Both 1 and 2
Evidence that the Timing of
Environmental Events is Important in
the Development of MS Includes
1.
2.
3.
4.
Studies in immigrants
The maternal parent-of-origin effect
The delay in clinical symptoms after 15
years
All of the above
Cladribine
1.
Is a prodrug metabolized by
deoxycytodine kinase
2.
Is a FDA-approved drug
3.
Can cause bone marrow suppression
4.
All of the above
Which of the Following Statements is
TRUE Regarding MS Treatment Trials?
1.
2.
3.
4.
Results from different studies cannot be directly
compared
Results of different studies can be directly compared
by using the NNT, which definitely identifies the
agent with the greatest efficacy
Therapeutic gain measured across studies is less
apt to be affected by a low event rate than is relative
reduction
Without direct comparative studies, there is no way
of knowing if one agent is more efficacious than
another
You have Started an RRMS Patient on a
DMT. Over the Next 1-2 Years Which of
the Following Would Prompt You to
Consider Changing Treatment?
1.
Recurrent relapses without worsening
residual impairment
2.
Recurrent relapses with cumulative residual
disability
3.
Slowing progressive worsening neurologic
disability
4.
1 or 2
5.
Any of the above
There is Some Evidence Suggesting
That the Increased Incidence of MS
Observed Over the Last 30 Years
Maybe Due to
1. A change in the genetic susceptibility to
MS
2. A change in the environmental exposure
3. Both