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Home , Ozanimod, Ponesimod, Siponimod

Navigating the Expanding -1-Phosphate Armamentarium for Management Greater Opportunities for Patients With MS

This symposium is neither sponsored nor endorsed by the Consortium of Multiple Sclerosis Centers. Disclosures

Bruce Cree, MD, PhD, MAS, has a financial Anne Haney Cross, MD, has a financial interest/ interest/relationship or affiliation in the form of: relationship or affiliation in the form of: Consultant for AbbVie Inc.; Biogen; EMD Serono, Consultant for Biogen; EMD Serono, Inc.; Inc.; GeNeuro SA; Pharmaceuticals Genentech, Inc.; Novartis Pharmaceuticals Corporation; and sanofi-aventis U.S. LLC/Genzyme Corporation; and sanofi-aventis U.S. LLC/Genzyme Corporation. Corporation. Advisory Board for Akili. Grant/Research Support from Genentech, Inc. (as part of multicenter trial). Bruce Cree, MD, PhD, MAS, does intend to discuss either non-FDA-approved or investigational use for Anne Haney Cross, MD, does intend to discuss the following products/devices: sphingosine-1- either non-FDA-approved or investigational use for phosphate receptor modulators that are currently the following products/devices: sphingosine-1- under investigation for the treatment of MS. phosphate receptor modulators that are currently under investigation for the treatment of MS.

This CME/CE/CPE activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. This activity is supported by an educational grant from Corporation. Disclosures

CME Reviewer CPE Reviewer Randy Rosenberg, MD, FAAN, FACP Shelley Chun, PharmD Lewis Katz School of Medicine at Temple University MedImpact Healthcare Systems, Inc. Fort Washington, Pennsylvania San Diego, California Randy Rosenberg, MD, FAAN, FACP, has no Shelley Chun, PharmD, has no financial interests/ financial interests/relationships or affiliations in relationships or affiliations in relation to this activity. relation to this activity. Medical Director CE Reviewer Kirk A. Tacka, PhD Bobbie Perrin, RN, OCN PVI, PeerView Institute for Medical Education Harrington Cancer Center Kirk A. Tacka, PhD, has no financial interests/ Amarillo, Texas relationships or affiliations in relation to this activity. Bobbie Perrin, RN, OCN, has no financial interests/ relationships or affiliations in relation to this activity.

The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and PVI, PeerView Institute for Medical Education do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME activity during the past 12 months.

Visit us at www.peerview.com/MSS1PR

• Watch for the onDemand version in the coming weeks • Download the slides and Practice Aids • Apply for CME/CE/CPE credit • Join the conversation on Twitter @PeerView • Need more information? Send an email to [email protected] Download Infographic Practice Aids Introduction

Bruce Cree, MD, PhD, MAS Associate Professor of Neurology Director, Clinical Research UCSF Multiple Sclerosis Center San Francisco, California Evolution of the MS Treatment Landscape

Mitoxantrone, IV IFN β-1a, SubQ , IV

1990s 2000s 2010s

IFN β-1b, SubQ , Oral IFN β-1a, IM , Oral GA, SubQ , Oral PEG IFN β-1a , IV , SubQa , IV a Withdrawn from the market in early 2018. GA: ; IFN: ; PEG: pegylated. Fingolimod: The First Oral Disease-Modifying Therapy1

• Approved in 2010 – Mechanism of action: Nonselective sphingosine-1-phosphate receptor (S1PR) modulator – Clinical efficacy results from modulation of S1PR subtype 1 (S1PR1), leading to sequestration in lymph nodes and presumably reduced migration to the CNS • However, interactions with other S1PR subtypes in other tissues and off-target pharmacologic effects (ie, bradycardia, macular edema) have limited its use in certain populations • Thus, there has been interest in more selective S1PR modulators

1. Subei AM, Cohen JA. CNS Drugs. 2015;29:565-575. The Current S1PR Modulator Landscape1

Approved In Clinical Development Clinical Development Discontinued

Fingolimod Ceralifimod

Siponimod Amiselimod

1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. Moving on to This Afternoon’s Agenda

First, we’ll review some of the underlying biology related to S1P and S1PR in the context of the treatment of MS

Then, we’ll discuss available data on approved and emerging S1PR modulators for the treatment of MS

Be prepared for polling questions both before and during this afternoon’s scientific sessions

S1P: sphingosine-1-phosphate. Sphingosine-1-Phosphate Receptor Modulation: A Unique Mechanism of Action for Treating MS

Anne Haney Cross, MD Professor of Neurology and Head of the Neuroimmunology Section Washington University School of Medicine St. Louis, Missouri Sphingosine-1-Phosphate (S1P)1,2

Bioactive second messenger

Also is a first messenger acting extracellularly via cell-surface S1P receptors 1, 2, 3, 4, and 5, found on many different cell types

Regulates diverse biological processes in health and disease

1. Spiegel S, Milstien S. Nat Rev Immunol. 2011;11:403-415. 2. Prager B et al. Trends Mol Med. 2015;21:354-363. S1P Synthesis1

1. Hla T, Brinkmann V. Neurology. 2011;76(suppl 3):S3-S8. S1P Receptor1

• S1PRs have seven transmembrane segments

• Coupled to G-proteins, which transduce their actions

• Regulates diverse cellular responses involved in immunity, heart rate, smooth muscle tone, and endothelial barrier function

• Five subtypes (S1PR1-S1PR5) expressed by differing cell types

1. Tsai H-C, Han MH. Drugs. 2016;1067-1079. S1PR1 Mechanism of Action in Lymph Nodes

Blood Efferent lymph T and B cells expressing S1PR1 migrate out of lymphoid tissues along an T and B cells enter S1P gradient between secondary lymphoid S1P lymphoid tissue and efferent tissues from blood gradient lymphatic vessels1-4 via high endothelial venules

S1P concentration is high in efferent lymphatics

B cells and naïve and central memory T cells express S1PR1 on surface

1. Brinkmann V et al. Am J Transplant. 2004;4:1019-1025. 2. Mandala S et al. Science. 2002;296:346-349. 3. Matloubian M et al. Nature. 2004;427:355-360. 4. Pinschewer DD et al. J Immunol. 2000;164:5761-5770. S1PR1: Interference by S1PR1 Modulators in Lymph Nodes1

S1P receptor eventually recycles back to cell surface, allows Blood Efferent lymph egress of cells

T and B cells enter secondary lymphoid Lymph node This leads to temporary retention of tissues from blood S1P these cells in secondary lymphoid via high endothelial gradient tissues venules

Without surface S1PR1, B cells and naïve and memory T cells cannot respond to the S1P gradient in efferent lymphatics

When S1P-like agonists interact with S1P receptors on naïve and central memory T cells and B cells, the receptor is internalized

1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. Other Common Cell Types Expressing S1PR11

AV node and Neurons conduction system

Function Function Neuron migration and function Heart rate slowing

Endothelial Smooth cells muscle Function Function Vascular tone relaxation via Permeability barrier eNOS; permeability barrier

AV: atrioventricular; eNOS: endothelial nitric oxide synthase. 1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. S1PR2a: Common Tissue Expression and Function1

Other CNS cells, including Neurons microglia and astrocytes

Function Function Still being elucidated Still being elucidated

Endothelial cells, Smooth including in CNS muscle Function Function Permeability/BBB; Increased vascular tone3 pro-inflammatory on HUVECs2 a S1PR2 not targeted by any approved or experimental S1PR modulators. BBB: blood-brain barrier; HUVECs: human umbilical vein endothelial cells. 1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. 2. Ren K et al. J Physiol Biochem. 2017;73:287-296. 3. Meissner A et al. Cardiovasc Res. 2017;113:123-133. S1PR3: Common Tissue Expression and Function1

AV node and Neurons conduction system

Function Function Neuron migration and function Slowed heart conduction

Endothelial Smooth cells muscle

Function Function Permeability barrier Increased vascular tone2

1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. 2. Meissner A et al. Cardiovasc Res. 2017;113:123-133. S1PR4a: Common Tissue Expression and Function1

Lymphoid tissues

Function Still being elucidated

Plasmacytoid Mast cells3 dendritic cells2 Function Function Chemotaxis/migration Modulates function (human) (mouse data) a S1PR4 not found in CNS or heart. 1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. 2. Dillmann C et al. J Immunol. 2016;196:1579-1590. 3. Kulinski JM et al. Int J Mol Sci. 2018;19:1279. S1PR5a: Common Tissue Expression and Function1

Associated cell types

CNSb Function NK cells2

NK cell migration out of lymph Oligodendrocyte nodes and bone marrow; function S1PR5 > S1PR1 in blood NKs a S1PR5 not found in heart. b Preferentially on mature oligodendrocytes, but also on neural progenitors. NK: natural killer. 1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. 2. Jenne CN et al. J Exp Med. 2009;206:2469-2481. Fingolimod: The First Approved Oral DMT for MS Management

Upon Phosphorylation, Fingolimod Is a Structural Analog of S1P1

Sphingosine Fingolimod

S1P Fingolimod phosphate

1. Brunkhorst R et al. Front Cell Neurosci. 2014;8:283. However… Fingolimod Is a Nonselective S1PR Modulator for Receptors 1, 3, 4, and 51

S1PR Subtype

S1PR1

S1PR2

S1PR3

S1PR4 2 Fingolimod, t1/2 = 6-9 days S1PR5

t1/2: half-life. 1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. 2. David OJ et al. Clin Pharmacokin. 2012;51:15-28. Many Adverse Effects Associated With Fingolimod Are Related to Off-Target Modulation of S1PRs1

EC: endothelial cell 1. Camm J et al. Am Heart J. 2014;168:632-644. Adverse Effects Associated With Fingolimod Related to Off-Target Modulation of S1PRs1

Cardiac1,2 • Contraindicated for recent myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure, or class III/IV heart failure; Mobitz type II 2nd- or 3rd-degree AV block; sick sinus syndrome without pacemaker • primarily via S1PR2 and S1PR3; S1PR3 may be responsible for 2nd-degree heart block Eye3-5 • Macular edema: unclear which receptors, probably S1PR1 and others via effects on endothelial cells; S1PR1—decreases RGC death in experimental glaucoma (rat); S1PR2—pathologic retinal angiogenesis (rodents)

Pulmonary6 • ↓ FEV1, ↓ DLCO can occur, due in part to S1PR signaling profibrotic responses; in cultured human lung fibroblasts, occurs via S1PR2 and S1PR3

DLCO: diffusing capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 1 second; RGC: retinal ganglion cell. 1. Chaudhry BZ et al. Neurotherapeutics. 2017; 2. Camm J et al. Am Heart J. 2014;168:632-644. 3. Sabbadini RA. Brit J Pharmacol. 2011;. 4. Blanco R et al. Exp Eye Res. 2017;164:37-45. 5. Skoura A. J Clin Invest. 2007;117:2506-2516. 6. Sobel K et al. J Biol Chem. 2013;288:14839-14851. Ozanimod: Emerging Selective S1PR1 S1PR5 Modulator1

S1PR Subtype Does not require phosphorylation for activation S1PR1

S1PR2 Dose-dependent ↓ in circulating lymphocyte counts S1PR3

S1PR4 Low Cmax due to high distribution a S1PR5 volume and delayed absorption Ozanimod: t½ = 19 hours a CC112273 is active metabolite accounting for 90% of activity: t½ = 10-13 d2 1. Chaudhry BZ et al. Neurotherapeutics. 2017;14:859-873. 2. Cree BA et al. 70th Annual Meeting of the American Academy of Neurology (AAN 2018). Abstract S36.006. : Emerging Selective S1PR1 and S1PR5 Modulator1

S1PR Subtype Does not require phosphorylation for activation S1PR1

S1PR2 Much shorter t½ than fingolimod

S1PR3 Lymphocyte counts recover to S1PR4 baseline levels within a week of treatment discontinuation Siponimod, t1/2 = 30 hours S1PR5

1. Selmaj K et al. Lancet Neurol. 2013;12:756-767. Ponesimod: Emerging Therapy with S1PR1 Selectivity1

S1PR Subtype Does not require phosphorylation for activation S1PR1 Causes a dose-dependent ↓ in S1PR2 circulating lymphocyte counts Ponesimod, S1PR3 t1/2 = 21.7 to 33.4 hours Eliminated within 1 week of S1PR4 discontinuation; pharmacologic S1PR5 effects rapidly reversible

1. Brossard P et al. Br J Clin Pharmacol. 2013;76:888-896. Summary

• S1PR modulators possess a unique mechanism of action in the treatment of MS • Fingolimod was the first S1PR modulator to be approved for the treatment of RRMS – However, fingolimod, upon phosphorylation, interacts with all known S1PR subtypes except S1PR2; the different subtypes are differentially expressed in diverse tissues, including cardiac myocytes, and these “off-target” effects can be undesirable • Agents that specifically are more selective for subtype 1 of the S1PR are under investigation – Some selective S1PR modulators have an advantage of a shorter half-life and more rapid lymphocyte recovery post discontinuation relative to fingolimod – Despite the selectivity of the new S1PR modulators, some side effects such as 1st-dose bradycardia and conduction block have been observed in early studies of some of these agents – Gradual up-titration of the dose may abrogate 1st-dose cardiac effects for some S1PR modulators An Examination of the Efficacy, Safety, and Tolerability of Approved and Emerging Sphingosine-1-Phosphate Receptor Modulators in the Treatment of MS

Bruce Cree, MD, PhD, MAS Associate Professor of Neurology Director, Clinical Research UCSF Multiple Sclerosis Center San Francisco, California Efficacy of Fingolimod in RRMS

Trial FREEDOMS I1 FREEDOMS II2 TRANSFORMS3 Fingolimod 0.5 mg/d Fingolimod 0.5 mg/d Fingolimod 0.5 mg/d Outcome vs vs vs placebo placebo IFN β-1a 30 mcg ARR ↓ 55% ↓ 48% ↓ 52% NEL ↓ 74% ↓ 74% ↓ 35% FREEDOMS I: GEL Effects of Fingolimod↓ 82% vs PBO ↓ 67% ↓ 55% 3-mo CDP ↓ 30% NS NS

ARR: annualized relapse rate; CDP: confirmed disability progression; GEL: gadolinium-enhancing lesion; NEL: new/enlarging T2 lesions 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. INFORMS: Randomized, Double-Blind, Placebo-Controlled Trial of Fingolimod in PPMS1

Placebo Fingolimoda • N = 970 3-Month P • Randomized to: CDP KM KM n (%) n (%) − Placebo Estimate Estimate − Fingolimod • Composite 3-mo Composite 338 (69) 80.3% 232 (69) 77.2% .54 CDP based on ∆ from baseline in: EDSS 240 (49) 58.7% 154 (46) 54.3% .22 − EDSS − 9HPT 9HPT 133 (27) 41.3% 84 (25) 33.6% .61 − T25FW T25FW 276 (57) 70.0% 184 (55) 62.9% .55

a 0.5 mg/d. 9HPT: 9-Hole Peg Test; EDSS: Expanded Disability Status Scale; KM: Kaplan-Meier; T25FW: Timed 25-Foot Walk. 1. Lublin F et al. Lancet. 2016;387:1075-1084. Fingolimod: Safety Profile and Monitoring Requirements1

b Most Common AEsa Monitoring (≥10% and >PBO)

• Prior to Tx Initiation During Tx Course • LFT elevation • Diarrhea • LFT • VZV titer • Cough • BP • LFT • Influenza • Follow-up • CBC ophthalmalogic exam • Sinusitis • Ophthalmologic exam • Evaluate suspicious • Back • 1st-dose monitoring skin lesions • Abdominal pain • Spirometric evaluationc • Pain in extremity

a As per prescribing information. b Consult prescribing information regarding risk of progressive multifocal leukoencephalopathy. c When indicated. 1. Gilenya (fingolimod) Prescribing Information. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/ gilenya.pdf. Accessed April 20, 2018. Fingolimod: Contraindications1

• Recent (previous 6 months) MI, unstable angina, stroke, TIA, decompensated heart failure with hospitalization, or Class III/IV heart failure

• History of Mobitz type II 2nd-degree or 3rd-degree AV block or sick sinus syndrome, unless patient has a pacemaker

• Baseline QTc interval ≥500 ms • Treatment with Class Ia or Class III anti-arrhythmic drugs

1. Gilenya (fingolimod) Prescribing Information. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/ gilenya.pdf. Accessed April 20, 2018. RADIANCE Part B: Phase 3 Trial Comparing Ozanimod vs IFN β-1a in Relapsing MS1

30-Day 7-Day 2-Year Screening Dose Active-Controlled Period Escalation Treatment Period Period

Ozanimod 0.5 mg/d (n = 439) Primary Endpoint: R Ozanimod 1 mg/d (n = 433) ARR

IFN β-1a 30 mcg/wk IM (n = 441)

1. Cohen JA et al. AAN 2018. Poster P3.410. RADIANCE Part B: Efficacy1

% Reduction vs IFN β-1a 0.50 Endpoint (over 2 years) Ozanimod Ozanimod 0.5 mg/d 1.0 mg/d 0.40 34% 42% NEL, 2 year 0.30 ↓ 21% P = .0001 P < .0001 (P = .0167) ↓ 38% 47% 53% GEL, 2 year 0.20 (P < .0001) P =.0030 P = .0006 24% 27% WBV loss Adjusted ARR Adjusted 0.10 P < .0001 P < .0001 57% 58% 0.28 0.22 0.17 CGV loss 0.00 P < .0001 P < .0001 IFN β-1a Ozanimod Ozanimod 30% 32% TV loss 0.5 mg/d 1.0 mg/d P = .0012 P < .0001 CGV: cortical gray-matter volume; TV: thalamic volume; WBV: whole brain volume 1. Cohen JA et al. AAN 2018. Poster P3.410. RADIANCE Part B: Safety and Tolerability1

Overall, ozanimod generally safe and well tolerated

IFN β-1a Ozanimod Ozanimod Adverse Event, n (%) 30 mcg 0.5 mg/d 1.0 mg/d (n = 440) (n = 439) (n = 434) Any 365 (83.0) 326 (74.3) 324 (74.7) Hypertension 14 (3.2) 26 (4.6) 24 (5.5) ↑ ALTa 20 (4.5) 29 (6.6) 26 (6.0) ↑ γ-Glutamyltransferase 9 (2.0) 16 (3.6) 25 (5.8) Supine heart rate <40 bpm on day 1, h 1-6 0 0 0 ≥2nd-degree AV block 0 0 0 186 (42.3) 171 (39.0) 182 (41.9) Herpetic 11 (2.5) 10 (2.3) 9 (2.1) a ↑ ALT transient and generally resolved without study drug discontinuation. 1. Cohen JA et al. AAN 2018. Poster P3.410 SUNBEAM: Phase 3 Trial Comparing Ozanimod vs IFN β-1a in Relapsing MS1

30-Day 7-Day Dose 1-yr Screening Treatment Period Escalation Period Period

Ozanimod 0.5 mg/d (n = 451) Primary Endpoint: R Ozanimod 1 mg/d (n = 448) ARR IFN β-1a 30 mcg/wk IM (n = 447)

Treatment continued until last active patient treated for 12 mo

1. Comi G et al. AAN 2018. Poster P3.396. SUNBEAM: Efficacy

% Reduction vs IFN β-1a 0.50 Endpoint (1 year) Ozanimod Ozanimod 0.40 0.5 mg/d 1.0 mg/d 25% 48% ↓ 31% NEL 0.30 P = .0032 P < .0001 (P = .0013) ↓ 48% 34% 63% (P < .0001) GEL 0.20 P = .0182 P < .0001 12% 32% Adjusted ARR Adjusted WBV loss 0.10 NS P < .0001 0.35 0.24 0.18 61% 84% CGV loss 0.00 P < .0001 P < .0001 IFN β-1a Ozanimod Ozanimod 34% 38% 0.5 mg/d 1.0 mg/d TV loss P = .0001 P < .0001

1. Comi G et al. AAN 2018. Poster P3.396 Pooled Data From RADIANCE Part B and SUNBEAM: Time to 3-Month Confirmed Disability Progression1

1. Cohen JA et al. AAN 2018. Poster P3.410 SUNBEAM: Safety and Tolerability1

Safety and tolerability profile of ozanimod similar to that observed in RADIANCE Part B

No patients had a 2nd-degree AV block or higher

Infection risk comparable to treatment with IFN β-1a

ALT increases transient and generally resolved without study drug discontinuation

1. Comi G et al. AAN 2018. Poster P3.396 EXPAND: Randomized, Double-Blind, Placebo-Controlled Trial of Siponimod in SPMS1

• N = 1,651 • Randomized − Diagnosis of SPMS − Placebo − EDSS 3.0-6.5 − Siponimod 2 mg/da

a Siponimod titrated from 0.25 mg/d to the 2 mg/d maintenance dose from days 1 to 6. RRR: relative risk reduction. 1. Kappos L et al. Lancet. 2018;391:1263-1273. EXPAND: Additional Efficacy Endpoints1

0.20 Endpoint Placebo Siponimod P 0.16 Adjusted Mean ∆ From Baseline in T2LV, mm3 0.16 12 month 818.0 204.9 < .0001 24 month 940.4 162.9 < .0001 0.12 P < .0001 Adjusted Mean ∆ From Baseline in BV, %

ARR 0.08 0.07 12 month -0.46 -0.28 < .0001 24 month -0.84 -0.71 .020

0.04 • No significant difference observed in time to 3-month confirmed worsening ≥20% in T25FW for the overall 0.00 population Placebo Siponimod • No significant difference in adjusted mean ↑ in MSWS-12 across all visits observed with siponimod vs placebo BV: brain volume; MSWS-12: 12-Item MS Walking Scale; T2LV: T2 lesion volume. 1. Kappos L et al. Lancet. 2018;391:1263-1273. EXPAND: Safety1

Adverse Event, n (%) Placebo (n = 546) Siponimod (n = 1,099) Any 445 (82) 975 (89) Hypertension 41 (8) 115 (10) Herpes zoster 25 (2) 4 (1) Lymphopenia 0 9 (1) Macular edema 1 (<1) 18 (2) Bradycardia during tx initiation 14 (3) 48 (4) Bradyarrhythmia 2 (0.4) 29 (3) ALT ↑ 2 (<1) 10 (1) AST ↑ 1 (<1) 5 (<1)

Initial dose titration mitigated 1st-dose cardiac effects

1. Kappos L et al. Lancet. 2018;391:1263-1273. Randomized Phase 2 Trial of Ponesimod in RRMS1

10.0 8.0 • N = 464 6.0 • Randomly assigned: ↓ 43% 4.0 – Placebo (P < .05) ↓ 77% – Ponesimod 10 mg/d (12-24 wk ) 2.0 ↓ 83% 6.2 3.5 (P < 1.1.0001) (P < 1.4.0001) – Ponesimod 20 mg/d 0.0

– Ponesimod 40 mg/d Cumulative # New GEL Placebo Ponesimod Ponesimod Ponesimod 10 mg/d 20 mg/d 40 mg/d

Ponesimod also showed a beneficial effect on clinical endpoints and was generally well tolerated

1. Olsson T et al. J Neurol Neurosurg Psychiatry. 2014;85:1198-1208. Ongoing Phase 3 Studies of Ponesimod in MS

POINT Trial1 • N = 600 Placebo • Relapsing MS 1x/d • Ongoing tx with DMF ≥6 months R • Active disease in 12 months prior to Ponesimod screening and ≥3 months DMF tx 20 mg/da

OPTIMUM Trial2 Teriflunomide • N = 1,100 14 mg/d • Relapsing forms of MS R • Active disease Ponesimod 20 mg/d a Up-titration will be implemented from day 1 to day 14 with dose strength increasing from 2 mg to 20 mg. DMF: dimethyl fumarate. 1. https://clinicaltrials.gov/ct2/show/NCT02907177. Accessed May 14, 2018. 2. https://clinicaltrials.gov/ct2/show/NCT02425644. Accessed May 14, 2018. Summary

• Phase 3 data have shown fingolimod is superior to both placebo and IFN β-1a IM in patients with RRMS with a good safety and tolerability profile • More selective S1PR modulators—ozanimod and siponimod —have been shown to be effective in the treatment of RRMS and SPMS, respectively, with good safety and tolerability reported for these agents • A third selective S1PR modulator, ponesimod, continues to undergo clinical evaluation Conclusions

• The approval of fingolimod for the treatment of relapsing MS validated S1PR as a treatment target for this disease • The newer selective agents also show promise in maintaining that efficacy, while adding the potential advantages of improved pharmacodynamics and tolerability • Thus far, phase 3 data appear to support these assertions in patients with relapsing MS; data also support the use of at least one of these agents in patients with SPMS Please remember to complete and submit the Post-Test and Evaluation for CME/CE/CPE credit at www.peerview.com/MSS1PR You can also … • Download slides and Practice Aids • Watch for the onDemand version of this symposium • Join the conversation on Twitter @PeerView

Thank you and good evening.