Mechanisms of Action for S1P Receptor Modulators1-7

Full abbreviations, accreditation, and disclosure information available at PeerView.com/VTT40

a Investigational agent.

S1P Receptor Specificity of Approved and Emerging S1P Receptor Modulators

Available/Investigational S1P

Receptor Modulators

Fingolimod

Siponimod

Ozanimod

Ponesimoda

App

rove

dEm

ergi

ng

S1P1 recycles and surface expression recovers in low S1P

Lymphocyte egress driven by

S1P gradientLymphocytes enter

lymphoid organ from blood

S1P receptor modulator binds S1P1 and induces sustained S1P1 internalization and degradation, preventing lymphocyte egress

S1P1 mostly internalized because

of high S1P

Blood

Lymphocyte

S1P1Egress

LymphSecondary lymphoid organs

S1P receptor modulator

Low S1P

High S1P

S1P1

P

P

P

P

S1P2

O

O

O

O

S1P3

P

O

O

O

S1P4

P

O

O

O

S1P5

P

P

P

O

S1P Receptor Modulators Improve MS by Isolating Lymphocytes

Mechanisms of Action for S1P Receptor Modulators1-7

Full abbreviations, accreditation, and disclosure information available at PeerView.com/VTT40

1. Cohan S et al. Biomedicines. 2020;8:227. 2. Obinata H, Hla T. Int Immunol. 2019;31:617-625. 3. Choi J, Chun J. Biochim Biophys Acta. 2013;1831:20-32. 4. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. 5. Meissner A et al. Cardiovasc Res. 2017;113:123-133. 6. Dillmann C et al. J Immunol. 2016;196:1579-1590. 7. Kulinski JM et al. Int J Mol Sci. 2018;19:1279.

S1P Receptor Subtype

Loca

lizat

ion

and

Func

tion

of S

1P R

ecep

tors

in

the

Cont

ext o

f MS

Care

S1P1 S1P2 S1P3 S1P4 S1P5

Neurons (function, migration), astrocytes

(activation), microglia,

oligodendrocytes

Activation may contribute to

macular edema, decreased retinal

cell death

Neurons, astrocytes, microglia,

oligodendrocytes

Activation may contribute to HTN, pathological retinal

angiogenesis (rodents),

profibrotic responses (cultured

fibroblasts)

Neurons (function, migration), astrocytes

(activation), microglia,

oligodendrocytes

Activation may contribute to

second-degree heart block, profibrotic

response (cultured fibroblasts)

Oligodendrocytes (function), astrocytes,

microglia, neurons

Heart: HR slowing

Smooth muscle: vascular tone

Permeability

Lymphocytes: trafficking

Smooth muscle: vascular tone

Permeability

Lymphoid tissues, dendritic cells,

mast cells

Heart: slowed conduction

Smooth muscle: vascular tone

Permeability

NK cells (S1P5 > S1P1

in blood NKs)

CNS

Potential adverse events

Cardiovascular

Endothelium

Immune system

Practical Clinical Considerations With the Use of S1P Receptor Modulators in Patients With MS1-4

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Pharmacokinetics/Pharmacodynamics of S1P Receptor Modulators: Implications for Clinical Care

Practical Aspects of Use: Monitoring and Titration

Assessments

• All agents: CBC, cardiac evaluation, liver function, medications, vaccinations

• Ophthalmic assessment: all agents (for ozanimod, only in patients with certain conditionse)

• CYP2C9 genotype: siponimod

Titrationd

Siponimod, ozanimod (per prescribing information)

First-Dose Monitoringd

Siponimod (patients with certain conditionsf),

fingolimod

S1P Receptor Modulators T1/2 Elimination Median Recovery Timeto 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 CC112273b

21 h11 d 30 daysc

Ponesimod (investigational) 21-33 h 4 days

a Increased by 50% in patients with moderate to severe heart disease. b Major ozanimod active metabolite. c Ninety percent recovery to baseline lymphocyte count within 3 months. d Also on reinitiation following treatment interruption. e For ozanimod, requirement for pre-initiation assessment is specific to patients with a history of uveitis or macular edema. f Sinus bradycardia, Mobitz type I AV block, history of MI or HF.

Practical Clinical Considerations With the Use of S1P Receptor Modulators in Patients With MS1-4

Full abbreviations, accreditation, and disclosure information available at PeerView.com/VTT40

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.

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

• 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 msec• Arrhythmias needing treatment with class Ia or class III antiarrhythmic agents

Ozanimod

• Severe untreated sleep apnea• Concomitant MAOI use

Imaging Outcomes of S1P Receptor Modulators in Patients With MS1-8

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SUNBEAM RADIANCE Part B

Less Brain Volume Loss With Fingolimod: Pooled Data From Phase 3 Trials

Efficacy of Fingolimod, Siponimod, and Ozanimod: Phase 3 Trials

nsns

nsns

Cortical Gray Matter

-1.77-1.76-1.55

-2.5

-2.0

-1.5

-1.0

-0.5

0

0.5Baseline Month 12 Month 24

Cha

nge

in

Cor

tical

Gra

y M

atte

r, %

b

c

c

ns

Thalamus

-1.53-1.13

-0.77

-2.5

-2.0

-1.5

-1.0

-0.5

0

0.5Baseline

a P < .001. b P < .05. c P < .01.

Month 12 Month 24

Cha

nge

in T

hala

mus

, %

Fingolimod 0.5 mgFingolimod 1.25 mgPlacebo

a

b

b

ns

Deep Gray Matter

-2.14

-1.57-1.83

-2.5

-2.0

-1.5

-1.0

-0.5

0

0.5Baseline Month 12 Month 24

Cha

nge

in

Dee

p G

ray

Mat

ter,

%

-2.5

-2.0

-1.5

-1.0

-0.5

0

0.5Baseline Month 12 Month 24

Cha

nge

in B

rain

Vol

ume

in th

e z

Blo

ck, %

a

a a

a

Brain Volume

-1.01

-0.69-0.61

FREEDOMS I

Fingolimod0.5 mg/d

vs placebo(24 mo)

↓ 74%(P < .001)

↓ 82%(P < .0001)

FREEDOMS II

Fingolimod0.5 mg/d

vs placebo(24 mo)

↓ 74%(P < .0001)

↓ 67%(P < .0001)

TRANSFORMS

Fingolimod0.5 mg/d

vs IFN β-1a30 mcg (12 mo)

↓ 35%(P < .001)

↓ 55%(P < .001)

EXPAND

Siponimod2 mg/d

vs placebo

↓ 81%(P < .0001)

↓ 86%(P < .0001)

Ozanimod0.5 mg/d

vs IFN β-1a

↓ 25%(P = .0032)

↓ 34%(P = .0182)

Ozanimod1.0 mg/d

vs IFN β-1a

↓ 48%(P < .0001)

↓ 63%(P < .0001)

Ozanimod0.5 mg/d

vs IFN β-1a

↓ 34%(P = .0001)

↓ 47%(P = .0030)

Ozanimod1.0 mg/d

vs IFN β-1a

↓ 42%(P < .0001)

↓ 53%(P = .0006)

Trial

NEL

GEL

TreatmentGroups

Imaging Outcomes of S1P Receptor Modulators in Patients With MS1-8

Full abbreviations, accreditation, and disclosure information available at PeerView.com/VTT40

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. Gaetan L et al. Neurology. 2018;0:e1-e9. 8. Kappos L et al. MSVirtual 2020. Poster P0071.

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

Mea

n C

hang

e, %

Brain Volume Changes (24 Months)

-2.0

-1.5

-1.0

-0.5

0

-2.0

-1.5

-1.0

-0.5

0

Wholebrain

Corticalgray matter

ThalamusWholebrain

Corticalgray matter

Thalamus

Mea

n C

hang

e, %

IFN β-1a Ozanimod 0.5 mg Ozanimod 1.0 mgIFN β-1a Ozanimod 0.5 mg Ozanimod 1.0 mg

No. of patientsPonesimod 20 mg (N = 567) 403 376

Teriflunomide 14 mg (N = 566) 403 368

-0.91

-1.25P < .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

00.1

LS M

ean

Cha

nge

From

Bas

elin

e (9

5% C

l)

Ponesimod 20 mgTeriflunomide 14 mg

Visit, Week