S1PR modulators target receptors on lymphocytes, leading to lymphocyte sequestration in lymph nodes. They can also cross the blood-brain barrier and directly impact the central nervous system by signaling to neurons, microglia, oligodendrocytes, and astrocytes. This results in effects such as reduced neuroinflammation and neuronal damage, enhanced remyelination, and inhibition of astrogliosis. Clinical trials demonstrate that S1PR modulators significantly reduce brain volume loss compared to placebo or other disease-modifying therapies, as well as improve measures of disability and cognitive function in people with multiple sclerosis.

1. S1PR modulators target
receptors on the surface of
naïve and central memory
lymphocytes, leading to
sequestration in the
lymph node
Neuron
Signaling
• S1PR1, S1PR2, S1PR3, S1PR5
• Neurogenesis, neural
progenitor migration, survival,
neurotransmission
Biological effects
• Reduced dendritic spine loss
• Restored neuronal function
• Protection from excitotoxic death
Peripheral and CNS Mechanisms of Action of S1PR Modulators
Microglia
Signaling
• S1PR1, S1PR2, S1PR3, S1PR5
• Proinflammatory cytokine production
Biological effects
• Reduced microglial activation
• Enhanced microgliosis
Oligodendrocyte and
precursor cells
Signaling
• S1PR1, S1PR3, S1PR5
• Survival, migration, differentiation,
process extension, retraction
Biological effects
• Promotion of OPC survival
• Effects on migration, differentiation,
process dynamics
• Enhanced remyelination
Synapse
• Prevention and reversal of
synaptic defects
Astrocyte
Signaling
• S1PR1, S1PR2, S1PR3, S1PR5
• Proliferation, migration,
gap junction, communication,
growth factor production
Biological effects
• Inhibition of proinflammatory
cytokine production
• Stimulation of cell migration
• Inhibition of astrogliosis
Effector memory
lymphocytes are free
to continue circulating
in the body
Entering circulation
S1PR modulators can cross
the blood–brain barrier and
potentially have direct
effects in the CNS
Blood–brain barrier
Lymph node
Drug
Drug
Drug
Drug
Drug
Drug
Drug
Drug
Drug
Blood–brain barrier
• Reduced leakiness
Distribution, Signaling, and Downstream Biological Effects of Targeting S1PR Subtypes in CNS Cells
Mechanisms of Action
for S1P Receptor Modulators1-8
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2. S1P Receptor Subtype
S1P1 S1P2 S1P3 S1P4 S1P5
Localization
and
Function
of
S1PRs
in
the
Context
of
MS
Care
CNS
Neurons (function,
migration),
astrocytes
(activation),
microglia,
oligodendrocytes
Neurons,
astrocytes,
microglia,
oligodendrocytes
Neurons (function,
migration),
astrocytes
(activation),
microglia,
oligodendrocytes
Oligodendrocytes
(function),
astrocytes,
microglia, neurons
Cardiovascular
Heart: HR slowing;
smooth muscle:
vascular tone
Smooth muscle:
vascular tone
Heart: slowed
conduction;
smooth muscle:
vascular tone
Endothelium Permeability Permeability Permeability
Immune system
Lymphocytes:
trafficking
Lymphoid tissues,
dendritic cells,
mast cells
NK cells
(S1PR5 > S1PR1
in blood NKs)
Potential
adverse
events
Activation may
contribute to HTN,
pathological retinal
angiogenesis
(rodents), profibrotic
responses (cultured
fibroblasts)
Activation may
contribute to
macular edema,
decreased retinal
cell death
Activation may
contribute to
secondary heart
block, profibrotic
response (cultured
fibroblasts)
S1P
receptor
modulator
specificity
Fingolimod
Siponimod
Ozanimod
Ponesimod
Fingolimod
Fingolimod
Siponimod
Ozanimod
Fingolimod
Mechanisms of Action
for S1P Receptor Modulators1-8
Full abbreviations, accreditation, and disclosure information available at
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1. Chun J et al. Drugs. 2021;81:207-231. 2. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. 3. Choi J, Chun J. Biochim Biophys Acta. 2013;1831:20-32. 4. Cohan S et al. Biomedicines. 2020;8:227.
5. Dillmann C et al. J Immunol. 2016;196:1579-1590. 6. Kulinski JM et al. Int J Mol Sci. 2018;19:1279. 7. Meissner A et al. Cardiovasc Res. 2017;113:123-133. 8. Obinata H, Hla T. Int Immunol. 2019;31:617-625.

3. Practical Clinical Considerations With the Use of
S1P Receptor Modulators in Patients With MS1-5
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Pharmacokinetics/Pharmacodynamics of S1P Receptor Modulators:
Implications for Clinical Care
Practical Aspects of Use: Monitoring and Titration
Assessments
• All approved S1P receptor modulators:
CBC, cardiac evaluation, liver function,
medications, vaccinations
• Siponimod, ozanimod, ponesimod:
ophthalmic assessment
• Siponimod: CYP92C9 genotype
Titrationc
Siponimod, ozanimod, ponesimod
(per prescribing information)
First-Dose Monitoringc
Siponimod and ponesimod
(patients with certain conditionsd
),
fingolimod
S1P Receptor Modulators T1/2
Elimination
Median Recovery Time
to Normal Lymphocyte Count
Fingolimod 6-9 da
1-2 months
Siponimod 30 h
10 days, but up to 3-4 weeks
for some patients
Ozanimod 21 h 30 daysb
Ponesimod 21-33 h 4 days
a
Increased by 50% in patients with moderate to severe heart disease. b
Ninety percent recovery to baseline lymphocyte count within 3 months. c
Also on reinitiation following treatment interruption.
d
Sinus bradycardia, Mobitz type I AV block, history of MI or HF.

4. Practical Clinical Considerations With the Use of
S1P Receptor Modulators in Patients With MS1-5
Full abbreviations, accreditation, and disclosure information available at
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1. Cohan S et al. Biomedicines. 2020;8:227. 2. Gilenya (fingolimod) Prescribing Information. https://www.novartis.us/sites/www.novartis.us/files/gilenya.pdf. 3. Mayzent (siponimod) Prescribing
Information. https://www.novartis.us/sites/www.novartis.us/files/mayzent.pdf. 4. Zeposia (ozanimod) Prescribing Information. https://packageinserts.bms.com/pi/pi_zeposia.pdf.
5. Ponvory (ponesimod) Prescribing Information. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/PONVORY-pi.pdf.
Contraindications Other Than Hypersensitivity
Common Adverse Reactions
Transaminase
increase
All
Headache, HTN
Siponimod
Headache, diarrhea,
cough, influenza,
sinusitis, pain
(back, abdominal,
extremity)
Fingolimod
Infection (upper
respiratory, urinary
tract), orthostatic
hypotension,
back pain, HTN
Ozanimod
Fingolimod, siponimod, ozanimod, ponesimod
• Recent (last 6 months): MI, unstable angina, TIA, decompensated HF with hospitalization, class III/IV HF
•
History (fingolimod) or presence (siponimod, ozanimod) of Mobitz type 2 second- or third-degree AV block or sick sinus
syndrome, unless patient has a pacemaker
Fingolimod
• BL QTc interval ≥500 ms
• Arrhythmias needing treatment with class Ia or class III antiarrhythmic agents
Ozanimod
• Severe untreated sleep apnea
• Concomitant MAOI use
Upper respiratory
tract infection,
HTN
Ponesimod

5. Imaging Outcomes of S1P Receptor
Modulators in Patients With MS1-13
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SUNBEAM RADIANCE Part B
Less Brain Volume Loss With Fingolimod: Pooled Data From Phase 3 Trials
Efficacy of Fingolimod, Siponimod, Ozanimod, and Ponesimod: Phase 3 Trials
ns
ns
ns
ns
Cortical Gray Matter
-1.77
-1.76
-1.55
-2.5
-2.0
-1.5
-1.0
-0.5
0
0.5
Baseline Month 12 Month 24
Change
in
Cortical
Gray
Matter,
%
b
c
c
ns
Thalamus
-1.53
-1.13
-0.77
-2.5
-2.0
-1.5
-1.0
-0.5
0
0.5
Baseline
a
P .001. b
P .05. c
P .01.
Month 12 Month 24
Change
in
Thalamus,
%
Fingolimod 0.5 mg
Fingolimod 1.25 mg
Placebo
a
b
b
ns
Deep Gray Matter
-2.14
-1.57
-1.83
-2.5
-2.0
-1.5
-1.0
-0.5
0
0.5
Baseline Month 12 Month 24
Change
in
Deep
Gray
Matter,
%
-2.5
-2.0
-1.5
-1.0
-0.5
0
0.5
Baseline Month 12 Month 24
Change
in
Brain
Volume
in
the
z
Block,
%
a
a a
a
Brain Volume
-1.01
-0.69
-0.61
FREEDOMS I
Fingolimod
0.5 mg/d
vs placebo
(24 mo)
↓ 74%
(P .001)
↓ 82%
(P .0001)
FREEDOMS II
Fingolimod
0.5 mg/d
vs placebo
(24 mo)
↓ 74%
(P .0001)
↓ 67%
(P .0001)
TRANSFORMS
Fingolimod
0.5 mg/d
vs IFN β-1a
30 mcg (12 mo)
↓ 35%
(P .001)
↓ 55%
(P .001)
EXPAND OPTIMUM
Siponimod
2 mg/d
vs placebo
↓ 81%
(P .0001)
↓ 86%
(P .0001)
Ozanimod
0.5 mg/d
vs IFN β-1a
(12 mo)
↓ 25%
(P = .0032)
↓ 34%
(P = .0182)
Ozanimod
1.0 mg/d
vs IFN β-1a
(12 mo)
↓ 48%
(P .0001)
↓ 63%
(P .0001)
Ozanimod
0.5 mg/d
vs IFN β-1a
(24 mo)
↓ 34%
(P = .0001)
↓ 47%
(P = .0030)
Ozanimod
1.0 mg/d
vs IFN β-1a
(24 mo)
↓ 42%
(P .0001)
↓ 53%
(P = .0006)
Ponesimod
20 mg/d vs
teriflunomide
↓ 56%
(P .0001)
↓ 59%
(P .0001)
Trial
NEL
GEL
Treatment
Groups

6. Imaging Outcomes of S1P Receptor
Modulators in Patients With MS1-13
Full abbreviations, accreditation, and disclosure information available at
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Less Brain Volume Loss With Ozanimod Versus IFN β-1a:
Phase 3 Clinical Trials
Less Brain Volume Loss With Ponesimod Versus Teriflunomide:
Phase 3 Clinical Trial
Similar changes have been reported for siponimod vs placebo in SPMS
(-0.71% vs -0.84% at 24 weeks; P .05)
Brain Volume Changes (12 Months)
-0.61
-0.49
-0.41
-1.00
-1.72
-1.12
-1.12
-0.94
-1.11
-0.50
-0.44
-1.85
-1.50
-1.40
-0.71
-0.71
-0.34
-0.16
Mean
Change,
%
Brain Volume Changes (24 Months)
-2.0
-1.5
-1.0
-0.5
0
-2.0
-1.5
-1.0
-0.5
0
Whole
brain
Cortical
gray matter
Thalamus
Whole
brain
Cortical
gray matter
Thalamus
Mean
Change,
%
IFN β-1a Ozanimod 0.5 mg Ozanimod 1.0 mg
IFN β-1a Ozanimod 0.5 mg Ozanimod 1.0 mg
No. of patients
Ponesimod 20 mg (N = 567) 403 376
Teriflunomide 14 mg (N = 566) 403 368
-0.91
-1.25
P .0001
-1.4
-1.3
-1.2
-1.1
-1.0
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
LS
Mean
Change
From
Baseline,
%
(95%
Cl)
Ponesimod 20 mg
Teriflunomide 14 mg
Visit, Week

7. Imaging Outcomes of S1P Receptor
Modulators in Patients With MS1-13
Full abbreviations, accreditation, and disclosure information available at
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1. Kappos L et al. N Engl J Med. 2010;362:387-401. 2. Calabresi PA et al. Lancet Neurol. 2014;13:545-556. 3. Cohen JA et al. N Engl J Med. 2010;362:402-415. 4. Kappos L et al. Lancet. 2018;391:1263-1273.
5. Comi G et al. Lancet Neurol. 2019;18:1009-1020. 6. Cohen JA et al. Lancet Neurol. 2019;18:1021-1033. 7. Kappos L et al. JAMA Neurol. 2021;78:558-567. 8. Gaetano L et al. Neurology. 2018;0:e1-e9.
9. Kappos et al. MSVirtual 2020, 8th Joint ACTRIMS-ECTRIMS Meeting (MSVirtual 2020). Poster P0071. 10. DeLuca J et al. ECTRIMS 2018. Abstract P556. 11. DeLuca J et al. Mult Scler Rel Dis. 2021;48:102673.
12. Langdon D et al. Eur J Neurol. 2021; doi:10.1111/ENE.15081. 13. Benedict R et al. Neurology. 2021;96:e376-e386.
a
b
Fingolimod Improved PASAT-3 Scores From Baseline Versus Placebo
More Clinically Meaningful Improvement in SDMT Scores With Ozanimod Versus IFN β-1a
Rate Ratios (Ozanimod vs IFN):
Proportion of Patients With
Clinically Meaningful Improvement
in Processing Speed
(Improvement in SDMT by ≥4 Points)
Proportion of Patients With
Clinically Meaningful Changes
in SDMT Score at Months 6 and 12 (N = 1,346)
More ozanimod-treated patients had improvements in SDMT score
(≥4 points) at months 6 and 12 vs those receiving IFN β-1a
34.9
27
Siponimod Improved SDMT Scores in Secondary Progress Multiple Sclerosis
0
5
45
40
35
30
25
20
15
10
50
Improved
(≥4 points)
40.6 41.9
No sustained
change
24.6
31.1
Worsened
(≥4 points)
Proportion
of
Patients,
%
Siponimod (n = 1,087)
Placebo (n = 540)
-2.0
-1.5
1.5
1.0
0.5
0
-0.5
-1.0
2.0
Month 6
P = .0510
Month 12 Month 18 Month 24
Change
From
Baseline
in
SDMT
Oral
Score
Siponimod
Placebo
IFN β-1a 30 mcg
Ozanimod 0.5 mg
Ozanimod 1.0 mg
-1.5 12 24 36 48 60 72 84 96 108 120
-1.0
-0.5
0
0.5
1.0
1.5
2.0
2.5
3.0
Mean
Change
From
Baseline
in
PASAT-3
Time, months
Fingolimod 0.5 mg
Placebo/fingolimod
Switch from
placebo
to fingolimod
Baseline PASAT-3 scores
Fingolimod 0.5 mg = 48.3
Placebo = 47.5
a
0 1 2
Favors
ozanimod
Favors
IFN
1.2 (1.00-1.56)
Ratio (95% CI) P
1.4 (1.10-1.71)
1.2 (0.94-1.40)
1.3 (1.05-1.55)
.0552
.0048
.1689
.0156
Ozanimod 0.5 mg
Ozanimod 1.0 mg
24
21 23
0
70
60
50
40
30
20
10
80
Worsened
(≥4 points)
53 51
48
Stable
(4-point
change)
22
28 30
Improved
(≥4 points)
28
24 22
Worsened
(≥4 points)
44 44 42
Stable
(4-point
change)
28
32
36
Improved
(≥4 points)
Patients,
%
Month 6 Month 12
Month 6
Month 12
a
P .05. b
P .01.

8. Screening and Monitoring for Cognitive
Impairment in MS1-3
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• Cognitive change because of MS occurs in 34% to 65% of adults and in 33% of patients
under 18 years of age
• Cognitive impairment can sometimes predate the appearance of structural abnormalities
on MRI and may serve as an early marker of disease activity in some individuals with MS
• Information processing and memory are the most commonly affected cognitive domains in MS
• Cognitive impairment predicts limitations in the workplace and in social settings independent
of level of physical disability in people with MS—for example
– Cognitive impairment at diagnosis predicts a change in vocational status 7 years later
– People who are cognitively impaired are more likely to be unemployed and to score lower
on measures of quality of life
– Cognitive impairment is related to work problems such as verbal reprimands and the need
for extra training in employed MS patients, representing an at-risk condition prior to job loss
– Slowed information processing is associated with lower income, independent of
physical dysfunction
– Cognitive impairment in children and teens is associated with lack of age-appropriate
cognitive development and academic difficulties, including grade retention, social
challenges, depression, and behavior problems
Prevalence and Impact of Cognitive Impairment in MS
The National MS Society, Consortium of MS Centers, and International MS Cognition Society
recommend the following cognitive screening guidelines
• For adults and children (8+ years of age) with MS, when stable
– At a minimum, early baseline screening with the SDMT or similarly validated test
– Annual reassessment with the same instrument, or more often as needed
• For adults (18+ years): more comprehensive neuropsychological assessment for anyone who
tests positive on initial cognitive screening or is experiencing consequences from significant
cognitive decline
• For children (18 years): more comprehensive neuropsychological assessment for
unexplained change in school functioning (academic or behavioral)
Expert Recommendations for Cognitive Screening and Monitoring in MS

9. Screening and Monitoring for Cognitive
Impairment in MS1-3
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BICAMS utilizes three tests to evaluate cognitive functioning domains most likely to be impaired in
patients with MS
• SDMT: information processing speed
• CVLT-II: verbal memory (immediate recall trials 1-5)
• BVMT-R: visual memory (immediate recall trials 1-3)
BICAMS:
A 15-Minute Tool to Implement in the Clinic
• Health professionals should practice administering the tests
• Testing should take place in a quiet room, with just the patient and assessor present
• Purpose of BICAMS should be explained to the patient
• BICAMS should not be used within 1 month of recovery from MS relapse or steroid therapy (or if
administered to the patient within that time frame, the data should not be interpreted as indicating
long-term decline), since they have a proven reversible detrimental effect on memory function
• Recommended order of administration: first SDMT, second CVLT-II, third BVMT-R
• In most clinical situations, yearly or biannual BICAMS evaluations will be appropriate
Test Implementation
• Consists of single digits paired with abstract symbols
• Rows of the nine symbols are arranged pseudorandomly
• The patient must say the number that corresponds with each symbol
• The SDMT can be completed within 5 minutes, including instructions,
practice, and testing
• Reported sensitivity of 82% and specificity of 60%
• Validated in several countries
• High sensitivity to cognitive impairment and cognitive change in MS
• Well validated against conventional brain MRI parameters
(including atrophy, brain parenchymal fraction and third ventricular
width, cortical lesion number, etc)
• Also shown to have external clinical validity (eg, significantly
linked to both current and future employment status)
SDMT, Oral Form

10. Screening and Monitoring for Cognitive
Impairment in MS1-3
Full abbreviations, accreditation, and disclosure information available at
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1. Benedict RHB et al. Lancet Neurol. 2020;19:860-871. 2. Kalb R et al. Mult Scler J. 2018;24:1665-1680. 3. Langdon DM et al. Mult Scler J. 2012;18:891-898.
• Test is comprised of a 16-item word list, with four items belonging to each of four
categories, arranged randomly
• List is read aloud five times in the same order to the patient, at a slightly slower rate than
one item per second
• Patients required to recall as many items as possible, in any order, after each reading
of the list
• The CVLT-II trials 1-5 can be completed in 5-10 minutes, including instructions, testing,
and responses
• Has been validated with brain MRI total lesion area and right superior frontal atrophy,
MR T1 and FLAIR lesion volume, BPF and third ventricular width, and
MR diffusion measures
• Full CVLT-II also has external clinical validity (eg, can differentiate employed MS
patients from patients not employed because of MS)
California Verbal Learning Test-II (CVLT-II)
• Test requires patient to inspect a 2 × 3 stimulus array of abstract
geometric figures
• There are three learning trials of 10 seconds
• Array is removed, and the patient is required to draw the array
from memory, with the correct shapes in the correct position
• Validity of BVMT-R trials 1-3 has been indicated by significant
association with brain MRI total lesion area, T1 lesion and
FLAIR lesion volume, BPF and third ventricular width, and right
superior frontal atrophy, and correlation with atrophy of DGM
nuclei, including thalamic atrophy
Brief Visuospatial Memory Test Revised (BVMT-R)

11. Shared Treatment Decision-Making
in Multiple Sclerosis1-6
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Yes
Consider
different
MOA and/or
route of
administration
Change therapy?
• Suboptimal response?
• Intolerable adverse events?
• Inadequate treatment
adherence?
• Disease-related factors
(phenotype, activity, severity)
• Patient-related factors
(preference, comorbidities)
• Drug-related factors (efficacy,
safety, route of administration)
• Relapsing or progressive
• Active or not active
• With or without progression
or worsening
Identify the multiple
sclerosis phenotype
• Clinical
• MRI
• Safety
• Biomarkers
Monitor
No
Oral
Self-
injection
Infusion
Choose therapy
in collaboration
with the patient

12. Shared Treatment Decision-Making
in Multiple Sclerosis1-6
Full abbreviations, accreditation, and disclosure information available at
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Please provide your answers to the following questions.
2. How do you prefer to take your medicine?
4. What are your thoughts about laboratory monitoring?
3. How much risk are you truly willing to accept?
I prefer to self-inject
I prefer to take a pill
I prefer to have an IV infusion
I have no preference of how I take my medication as long as it can be
taken as infrequently as possible
Risk averse: I am a safety first, benefits second type of person
Moderately risk averse: I am willing to accept a little bit of risk for some
extra benefit
Mildly risk averse: I can accept risks for more benefit, as long as they are
not serious
High risk, high reward: I can accept any potential risks if they are
outweighed by the potential benefits
No evidence of disease activity (no attacks, no new findings on my MRI,
no new disability)
Preserve or improve my current level of functioning
Sustain employment and normal daily activities
All of the above
I don’t want to be required to have any laboratory testing during treatment
I am okay with laboratory testing as long I don’t have to do it every month
or after I stop treatment
I have no issues with the frequency or duration of laboratory testing that
may be required during or after treatment
1. What are your goals for treatment?

13. Shared Treatment Decision-Making
in Multiple Sclerosis1-6
Full abbreviations, accreditation, and disclosure information available at
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1. Giovannoni G et al. Curr Opin Neurol. 2012;25(Suppl):S20-S27. 2. Rae-Grant A et al. Neurology. 2018;90:777-788. 3. Lublin FD et al. Neurology. 2014;83:278-286.
4. Gaetani L et al. J Neurol Neurosurg Psychiatry. 2019;90:870-881. 5. Hanson KA et al. Patient Prefer Adherence. 2014;8:415-422. 6. Wilson LS et al. Int J MS Care. 2015;17:74-82.
The Key Components of Engaging Patients
in the Decision-Making Process
2. Describe options
3. Help make decisions
Determine what patient already knows
List and describe options including risks and benefits
Provide decision support such as decision aids, which can help patients
understand their options
List options again and apply teach-back method by asking patient how
they would describe the options to a loved one
Focus on preferences
Check to see if patient is ready to make a decision or if they need more
time or have additional questions
Agree on treatment plan
Ensure patient understands plan can be modified and decisions can be
reviewed at any time
Identify/summarize problem
Offer choices
Emphasize importance of personal preferences
Discuss any uncertainties in treatment
Check reaction
Defer final decision until you are able to discuss options in more detail if
patient asks, “What would you do?”
1. Introduce choice