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Oral Therapies in MS Management:Where We Are and What Is on the Horizon

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Oral Therapy for MS Management:State of the Union

Bruce Cree, MD, PhD, MAS

Associate Professor of Clinical Neurology

Clinical Research Director

University of California San Francisco

San Francisco, CA



Existing and Emerging MS Therapies

Phase III completed In Phase IIIApproved therapies

2009 2010 201120051995 2000

Gilenya (Fingolimod)

Aubagio(Teriflunomide)

Extavia(IFNβ-1b)

Tysabri (natalizumab)

Betaseron(IFNβ-1b)

Copaxone(glatiramer acetate)

Avonex (IFNβ-1a)

Rebif(IFNβ-1a)

Novantrone (mitoxantrone)

Laquinimod

Approval date Estimated launch date

Cladribine

2012

*In March 2011, the FDA did not approve cladribine and requested Merck KGaA provide an improved understanding of its safety risks and overall benefit-risk profile.

Daclizumab

Ocrelizumab

Ofatumumab

Siponimod

Ampyra(4-amino pyradine)

Nuedexta (Dextromehtorphan

Quinidine)

2013

Lemtrada(alemtuzumab)

Tecfidera(Dimethyl Fumarate)

(BG-12)

Ozanimod

Oral Therapies Overview

• In theory, orally bioavailable therapies will be better tolerated than parenterally administered medications.

• In practice, adherence to treatment is dependent on more than route of administration. Frequency of treatment, common adverse events, as well as, more rare but serious adverse events influence adherence.

• A recent non-industry sponsored, single-center study using a patient reported outcome found that adherence for never missing a dose was highest for an infusible medication, followed by injectables, and then by oral therapies.

– 93.3% vs 70.8% vs 55%, P<.005, N=209

Dione C, CMSC 2015, Abstract DX19.

Fingolimod: Efficacy

• Indicated for relapsing MS, single once-daily capsule

• Proven efficacy1

– 54% relative reduction in relapses

– 30% reduction in hazard ratio for disability (3 month sustained change)

– Superior to interferon β-1a IM (TRANSFORMS Study)2

– Robust effects on lesion evolution and brain volume loss

1. Kappos K, et al. N Engl J Med. 2010;362:387-401. Reprinted with permission. 2. Cohen J, et al. N Engl J Med. 2010;362:402-415.

Fingolimod 0.5 mg vs placebo HR=0.70P=.02 in time to disability progression

Fingolimod 1.25 mg vs placebo HR=0.68P=.02 in time to disability progression

Fingolimod 1.25 mg (17%)†

90 180 270 360 450 540 630 720

5

10

15

20

25

30

Placebo (24%)

Fingolimod 0.5 mg (18%)*

Days on Study

% W

ith

3-M

on

th C

on

firm

ed

E

DS

S P

rog

ress

ion

*P=.03 vs placebo†P=.01 vs placebo

0.4

0.16 0.18

00.050.1

0.150.2

0.250.3

0.350.4

0.45

AnnualizedRelapse

Rate



Therapeutic Satisfaction: EPOC Study Primary Results

Change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction Scores in Subjects Switching to Fingolimod Versus

Staying on Injectables

• LSM changes (± standard error) in TSQM Global Satisfaction scores from baseline to 6 months were significantly superior following a switch to fingolimod compared with remaining on GA (17.08 ± 1.56 vs 0.81 ± 2.89, respectively), IM IFN beta-1a (17.57 ± 1.51 vs 2.10 ± 3.22, respectively), SC IFN beta-1a (24.70 ± 1.62 vs 2.29 ± 2.96, respectively) or IFN beta-1b (22.34 ± 1.85 vs 4.45 ± 3.29, respectively); all P<.001.

Calkwood J, et al. BMC Neurology. 2014;14:220.

IFN, interferon; GA, glatiramer acetate

S1P=sphingosine-1 phosphate.

Activation Proliferation anddifferentiation

Afferent lymphatic vessel

S1PLymphatic sinus

Sinus-lining endothelium

Efferent lymphatic vesselNaïve T cell

Lymph node

S1P1 receptor

Activated T cells

Fingolimod

S1P1

downregulationSinus-lining endothelial cell

barrier enhancement

Reduced T cell egress

Fingolimod: Mechanism of Action

Horga A, et al. Expert Rev Neurother. 2008;8:699-714.

Fingolimod Suppression of Peripheral Lymphocytes

• Fingolimod diminishes peripheral lymphocyte counts by ~75%1,2

1. Mehling M, et al. Neurology. 2008;71:1261-1267.2. Kappos K, et al. N Engl J Med. 2010;362:387-401.



Airways hyperactivity

(S1P1–3)

Vasoconstriction, blood pressure

increase (S1P1–3)

Heart-rate reduction and regulation (S1P1, 3)

Angiogenesis (S1P1)Vasodilation (S1P1, 3)

Barrier decrease (S1P2–3)Barrier enhancement (S1P1)

S1PS1P

Bronchial smooth muscle

Bronchial smooth muscle

Vascular endothelium

Vascular endothelium

Atrial myocytes

Atrial myocytes

Vascular smooth muscle

Vascular smooth muscle

RetinaRetina

Swelling(S1P2)

Vascular formation

during embryogenesis

Vascular formation

during embryogenesis

S1P Receptor Is Located in Multiple Organ Systems

Brinkmann V. Pharmacol Ther. 2007;115:84-105.

Potential AE or Risk Mitigation Strategy

Bradycardia/AV block

• Observe all patients for 6 h after initial dose for signs and symptoms of bradycardia, ECG pre- and post- first dose

• If patients go off medication for prolonged time period, they must be observed when restarting therapy

Macular edema• Ophthalmologic exam at baseline and 3 to 4 months after

treatment initiation

Infection

• Patients should be vaccinated for varicella zoster virus (VZV)

• Risk of VZV reactivation, especially with corticosteroids

• PML and crypotoccal infection risks

• Avoid live attenuated vaccines for at least 2 months after stopping therapy

↓FEV1 and ↓DLCO • Spirometric evaluation when indicated

LFT elevations • Monitor regularly, as needed

Pregnancy risk category C• Counsel patients about fetal risks

• Use effective contraception on treatment and for at least 2 months after stopping therapy

Current Strategies for Mitigating the Potential Risks Associated With Fingolimod

AV: atrioventricular; DLCO: diffusion capacity of the lung for carbon monoxide; FEV1: forced expiratory volume over 1 second.

Gilenya (fingolimod) 0.5 mg capsules. http://www.fda.gov/downloads/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/UCM227965.pdf. Accessed September 30, 2015.

Fingolimod as an Immune Suppressant

• Opportunistic infection risk1

• Three reported PML cases with >100,000 MS patients treated1

– Also 1 neuromyelitis optica spectrum disorder patient with prior immune suppressant exposure

• Several cases of cryptococcal infections including disseminated cryptococcus and cryptococcal meningitis2

• One case of Kaposi sarcoma3

• One case of primary CNS lymphoma1

• Risk of primary herpes virus infections and reactivation1

• How risk of all these potential complications should be communicated to patients remains to be determined

– Overall risk of serious IS complications might be ~1:10,000, not accounting for duration of exposure

1. http://www.fda.gov/Drugs/DrugSafety/ucm366529.htm. 2. Huang D. Neurology. 2015;85:1001.3. Tully T, et al. Neurology. 2015;84:1999-2001.



Teriflunomide

• Indicated for relapsing MS1

• Antimetabolite, inhibits dihydro-orotate dehydrogenase thereby inhibiting de novo DNA synthesis in proliferating lymphocytes


– 32% relative reduction in relapses (14 mg)

– 30% reduction in hazard ratio for disability

• Single once-daily pill

• Generally, well-tolerated, but with boxed warnings

• No known PML risk

1. http://products.sanofi.us/aubagio/aubagio.pdf 2. O’Connor P, et al. N Engl J Med. 2011;365:1293-1303.

Evaluating Treatment Satisfaction:TSQM in the TENERE Phase 3 trial of Teriflunomide vs IFNβ-1a

Vermersch P, et al. Mult Scler. 2014;20:705-716.

0

20

40

60

80

100

120

Effectiveness Side effects Convenience Global satisfaction

Teri 7 mg Teri 14 mg IFN-b

P=.02

NS

P<.0001P<.0001

P=.02

N=324

Teriflunomide: Targeting Activated Lymphocyte Proliferation

• Teriflunomide selectively and reversibly inhibits mitochondrial dihydro-orotate dehydrogenase (DHODH), impairing the proliferation of activated lymphocytes while sparing resting and slowly dividing cells*1,2

• Pyrimidine salvage pathway is not affected by teriflunomide1

1. Gold R, et al. Acta Neurol Scand. 2011;124:75-84. 2. Warnke C, et al. Neuropsychiatr Dis Treat. 2009;5:333-340.

Stimulated lymphocyte

PYRIMIDINE DEMAND

Resting and slowly dividing lymphocytes

De novo pyrimidine synthesis pathway: DHODH

SALVAGE PATHWAY

* The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood

Homeostaticproliferationpreserved

Inhibition of activelyproliferating lymphocytes

X



Mean Lymphocyte and Neutrophil Counts in the Pivotal Clinical Trials

Comi G, et al. ACTRIMS-ECTRIMS 2014. P060.

Mean Lymphocyte Counts*† Mean Neutrophil Counts*‡

• Decreases observed with teriflunomide occurred during the first 6 weeks (neutrophils) or 12 weeks (lymphocytes) of treatment; mean counts remained within normal range and stable thereafter

*For weeks 26 and 28, only data from the Phase 2 study were available.†Normal range for general population: 1.0–4.0 × 109/L. ‡Normal range for general population: 2.5–7.5 × 109/L.

No. of patients

14 mg7 mg

Placebo

10011044992

826861845

818873848

774833799

688744700

No. of patients

14 mg7 mg

Placebo

10011044992

826861845

818872847

774833799

687744699

Ly

mp

ho

cyte

s, m

ean

S

E (

gig

a/L

)

0 12 24 36 48

Week

0.5

1.0

1.5

2.0

2.5 Teriflunomide 14 mgTeriflunomide7 mgPlacebo

Neu

tro

ph

ils,

mea

n

SE

(g

iga/

L)

0 12 24 36 48

Week

2.0

2.5

3.5

4.0

5.0

3.0

4.5

Teriflunomide 14 mgTeriflunomide 7 mgPlacebo

LLN†

LLN‡

Teriflunomide Risk Stratification

• Parent compound leflunomide is associated with severe and fatal liver injury in rheumatoid arthritis patients

– Similar risk to MS patients is assumed

• Based on animal studies, teriflunomide could cause fetal death and malformations

• Additional risks include tuberculosis reactivation, nephropathy, peripheral neuropathy, alopecia, hypertension

• Pretreatment: screen for tuberculosis, infection, pregnancy, renal failure, peripheral neuropathy, interstitial pulmonary disease, hypertension; assess WBC, renal function, and LFTs

• During treatment: Blood pressure monitoring; serum transaminase determinations; renal function

• Women of childbearing age should not be started on therapy until pregnancy is excluded and confirmation of reliable contraception (Category X)

http://products.sanofi.us/aubagio/aubagio.pdf

http://products.sanofi.us/aubagio/aubagio.pdf

Pregnancies Reported in Teriflunomide Clinical Trial Database

• Pregnancies in patients exposed to teriflunomide, in unblinded data:– 83 pregnancies in women

– 22 pregnancies in partners of men

• Pregnancy outcomes– No structural defects in newborns

– No functional deficits in newborns

– Median birth weight: 3300 grams (7.2 pounds)

– Rate of miscarriage: 17%

Similar to previous reports for GA and IFN

Elimination procedure – Discontinue treatment

– Undergo elimination procedure

Cholestyramine or activated charcoal until plasma drug levels <0.02 mcg/mL

– Male patients are advised the same

Kieseier B, et al. Neurol Ther. 2014;3:133-138.



Dimethyl Fumarate

• Indicated for relapsing MS1

• Mechanism unclear, may induce anti-oxidative genes through Keap1 inhibition that allows Nrf2 to translocate to nucleus and induce antioxidative response


– 53% relative reduction in relapses

– 38% reduction in hazard ratio for disability (3 month sustained change in EDSS)

• Twice daily capsule

• Generally well tolerated

• Risk of PML in setting of chronic lymphopenia and hypothetical risk of RCC based on dimethyl fumarate used for psoriasis3

1. http://www.tecfidera.com/pdfs/full-prescribing-information.pdf

2. Gold R, et al. N Engl J Med. 2012;367:1098-1107.

3. Sheremata W, et al. Expert Opin Drug Saf. 2015;14(1):161-170.

DMF and its Metabolite, MMF, “Inhibit the Inhibitor”

Adapted from Brück W, et al. JAMA Neurol. 2013;70:1315-1324.

Keap1

Gene Transcription

GSTA2NQO1HO-1

MMF

MMF Keap1CYTOPLASM

NUCLEUS

Dimethyl Fumarate

• Nrf2 is reported to have antiproliferative and immunomodulatory activity.1-3

• DMF 56% and multiple ethyl fumarates promotes development of anti-inflammatory type II DC.4

• DMF may also exert effects through other pathways.

– For example, flushing induced by DMF has been attributed to activation of the nicotinic acid receptor, HCA2.5

The protective effect of DMF is mediated, in part, by HCA2.6

1. Williams MA, et al. J Immunol. 2008;181(7):4545-4559. 2. Rockwell CE, et al. J Immunol. 2012;188(4):1630-1637.3. Lehmann JC, et al. J Invest Dermatol. 2007;127(4):835-845.4. Ghoreschi K, et al. J Exp Med. 2011;208(11):2291-2303.5. Tang H, et al. Biochem Biophys Res Commun. 2009;378(3):662-667. 6. Chen H, et al. J Clin Invest. 2014;124(5):2188-2192.



PML in a Patient Without Severe Lymphocytopenia Receiving Dimethyl Fumarate

Nieuwkamp DJ, et al. N Engl J Med. 2015;372(15):1474-1476. Reprinted with permission.

CD8 Lymphocytes Are Disproportionately Suppressed With DMF Treatment

• Lymphocyte counts go down over time with each of the subsets, whether you look at CD3, CD19, CD56 NK cells, or CD4 or CD8 cells

• The level of CD8 lymphopenia is relatively low

• The CD4/CD8 ratio is reversed over time

Spencer CM, et al. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e76.

Risk Mitigation With DMF

• GI symptoms and flushing are common• May cause lymphopenia: recent complete blood cell count (<6 months)

before starting treatment and every 6 months thereafter or as clinically indicated

• Liver function tests at baseline• Administration with food may decrease flushing

– Co-treatment with aspirin can reduce flushing• Withholding treatment should be considered in patients with severe

infections• Check JCV serology?

– 1 case of PML reported in MS patients treated with DMF, several other cases associated with DMF in psoriasis patients

• Will checking lymphocyte subsets help mitigate risk of potential opportunistic infections?



Is Tiered Treatment Still Applicable?

• Oral therapies have changed the way relapsing MS is managed

• Oral treatment options are likely to be better tolerated compared to auto-injectable medications

• Some oral DMTs may be more effective than injectable therapies inreducing relapses

– Fingolimod was compared to interferon β-1a IM and showed superior efficacy1

– Dimethyl fumarate was compared to glatiramer acetate and showed apparent superior efficacy (post-hoc analysis)2

• Oral therapies may be associated with greater therapeutic satisfaction

• Whether adherence is improved remains to be established

• Each oral therapy has a unique risk/benefit ratio

• Is therapeutic satisfaction (and potentially greater efficacy) worth theadded risk?

1. Cohen JA, et al. N Engl J Med. 2010;362:402-415.

2. Fox RJ, et al. N Engl J Med. 2012;367:1087-1097.

Emerging Oral Agents for MS Management

Amit Bar-Or, MD, FRCPC

Professor, Neuroimmunology

Montreal Neurological Institute McGill University

Montreal, Quebec, Canada



Objectives

• Clinical review of oral agents in late-stage development for MS therapy:– Ponesimod – Phase 2; OPTIMUM

– Ozanimod (RPC1063) – RADIANCE/SUNBEAM

– Siponimod/BAF312 – BOLD; EXPAND

– (MT-1303 – MOMENTUM)

– Laquinimod – CONCERTO, ARPEGGIO

Objectives






Ponesimod

• Profile suitable for once-daily oral dosing

• Selective S1P1 receptor modulator

• Lymphocyte reduction is rapid, dose-dependent, reversible

• Penetrates into brain and spinal cord

Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85(11):1198-1208.



Randomization

40 mg o.d. ponesimod (N=119)

Placebo (N=121)



Follow-upTreatment 24 weeks

Baseline

Follow-upScreening

ExtensionCore

Phase 2 Dose-finding Study in MS

Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85(11):1198-1208.

6.2 3.5 1.1 1.40

1

2

3

4

5

6

7

8

Placebo(N=110)

Ponesimod 10 mg(N=88)



Cu

mu

lati

ve n

ew T

1G

d+

lesi

on

sfr

om

wee

k 12

to

wee

k 24

(M

ean

±S

E)

*P<.05, ***P<.0001 vs placebo

******

Per-protocol population

*43% reduction

83% reduction77% reduction

Primary Endpoint: Cumulative Number of New T1 Gd+ Lesions (Week 12 to Week 24)

Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85(11):1198-1208. Reprinted with permission.

Mea

n ch

ange

from

bas

elin

e in

lym

phoc

yte

coun

t (%

)

-80

-70

-60

-50

-40

-30

-20

-10

0

10

Ponesimod 40 mg

Ponesimod 20 mg

Ponesimod 10 mg

Placebo

All-treated set

Day

8

Day

13

We

ek 4

We

ek 8

We

ek 1

2

Wee

k 16

Wee

k 20

Wee

k 24

Maximum Effect on Lymphocytes With 20 mg

Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85(11):1198-1208. Reprinted with permission.



40 mg ponesimod

20 mg ponesimod

10 mg ponesimod

Treatment 24 weeks

Randomization

Treatment Period 1 Up to 96 weeks

40 mg ponesimod

20 mg ponesimod

10 mg ponesimod

ExtensionCore

Placebo

Randomization

End of Treatment

Follow-up

Treatment Period 2 Up to 432 weeks

10 mg ponesimod

20 mg ponesimod

10 mg ponesimod

20 mg ponesimod

Ongoing Phase 2 Extension Study in MS1,2

1. Freedman M, et al. AAN 2013 (P01.156). 2. Pozzilli C, et al. ECTRIMS 2013 (P995).

Ponesimod Phase 3 Study Ongoing

OPTIMUM: Oral Ponesimod versus Teriflunomide in RMS

• A multicenter, randomized, double-blind, parallel-group, active-controlled, superiority study

• 200 centers in North America, Latin America, Eastern and Western Europe, Pacific

• 1100 patients randomized 1:1 ratio to either ponesimod 20 mg or teriflunomide 14 mg

• New dose up-titration scheme implemented

• Enrollment ongoing

ClinicalTrials.gov Identifier: NCT02425644

Objectives








Phase 2

1 mg RPC1063

1 mg RPC1063

0.5 mg RPC1063

0.5 mg RPC1063

Blinded Safety-Extension

Phase 3

IFN -1a 30 g IM (N=400)

Interim analysis of Phase 2 (Nov 2013) gated initiation of

Phase 3 (Dec 2013)

RADIANCE Phase 2/3 Trial Overview

Cohen J, et al. Program and abstracts of the 2014 Joint ACTRIMS/ECTRIMS Meeting; September 10-13, 2014; Boston, Massachusetts. Abstract LB1.1. Used with permission.

Patient Disposition

Randomized (N=258)

Placebo (N=88)RPC1063 0.5 mg

(N=87) RPC1063 1 mg (N=83)

Discontinued 3 (3.4%)

Adverse event 0

Lost to follow-up 1 (1.1%)

Protocol violation 0

Consent withdrawn 2 (2.3%)


Adverse event 0

Lost to follow-up 0

Protocol violation 1 (1.1%)



Adverse event 0

Lost to follow-up 0

Protocol violation 0


Completed 85 (96.6%) Completed 85 (97.7%) Completed 82 (98.8%)

• Very high rate of study compliance and completion (252 of 258)

• Favorable tolerability with 249 of 252 completers entering the extension


Effects of Ozanimod on GdE Lesions

Primary Endpoint: Total Cumulative Number of GdE Lesions (Weeks 12 to 24)

Secondary Endpoint: Number of GdE Lesions at Week 24


GdE: Gadolinium-enhancing



SafetySafety: Ozanimod Adverse

Events (AEs) of Special Interest

• Likely due to S1P pharmacology (eg, fingolimod)

• No notable cardiac, pulmonary, ophthalmologic, infectious, or malignancy TEAEs

• 3 TEAEs of elevated liver enzymes ( ≥3x ULN) without clinical signs issues

– All were isolated ALT elevations, without AST or Bilirubin elevations

– None ≥5x ULN

– Transient elevations despite continued treatment

• Thorough QT Study: Therapeutic dose-titration and supra-therapeutic dosing (N=62); Placebo (N=62)

– No effect on QTc or other CV parameters

Cohen J, et al. Program and abstracts of the 2014 Joint ACTRIMS/ECTRIMS Meeting; September 10-13, 2014; Boston, Massachusetts. Abstract LB1.1.

Adverse Events of Special Interest (AESI)

AEs reported in fingolimod’s label, most related to S1P pharmacology

• S1P1R: Bradycardia (symptomatic or HR<35 bpm), first dose AV block

• S1P3R: Hypertension, cardiac conduction abnormalities (QT prolongation, long-term AV conduction delays)

• S1P1R: Hepatic: confirmed ALT or AST ≥3x ULN

• S1P3R: Pulmonary function: decline in FEV1 or FVC <50% predicted

• S1P1R: Ophthalmologic: new onset or significantly worse macular edema (not explained by an alternative cause)

• Immunomodulation: Malignancy and infection: serious & opportunistic infections

Fingolimod prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022527s019lbl.pdf

Objectives








• Selective S1P receptor modulator

Novel chemotype, highly lipophilic

Peripheral and potentially CNS effects

• Safety and efficacy of Siponimod in RRMS patients was investigated in BOLD* study

• BOLD primary endpoint Met; Siponimod reduced CUAL at 3 months compared to placebo

Siponimod (BAF312): S1P1 and S1P5 Selective Modulator1-4

BBB, blood-brain barrier; CNS, central nervous system; EC50, half maximal effective concentration; Emax, maximum effect; MS, multiple sclerosis; S1P, sphingosine 1-phosphate; SD, standard deviation

1. Jackson SJ, et al. J Neuroinflammation. 2011;8:76. 2. Gergely P, et al. Br J Pharmacol. 2012;167:1035-1047. 3. Seabrook TJ, et al. Mult Scler. 2010;16:S301. Abstract P858. 4. Brinkmann V. Br J Pharmacol. 2009;158:1173.

0.58 0.550.61

0.23 0.2*

0.3

0.0

0.2

0.4

0.6

0.8

Placebo(n=45)

Siponimod0.25 mg(n=51)



Siponimod2 mg

(n=49)

Siponimod10 mg(n=50)

AR

R**

(95

% C

I)

(0.34-1.00) (0.32-0.93) (0.34-1.07) (0.08-0.61) (0.08-0.48) (0.15-0.61)

61% 66% 48%

BOLD: ARR Over 6 Months(Cohorts 1 and 2)a

aMain secondary outcome; Interim extension analyses of all doses. 0.25 mg and 1.25 mg are post-hoc analysis.1,2

*P<.05. **0.25 mg and 1.25 mg are post-hoc analysis.ARR, annualized relapse rate; CI, confidence interval.

1. Selmaj K, et al. Mult Scler J. 2011;17:S510. Abstract P1107. 2. Stuve O, et al. Neurology. 2012;78:S30.001.

Randomized, double-blind, placebo-controlled, multicentre, event-driven Phase 3 study

Event-driven study design: Study will be stopped when the required number of patients with 3-month confirmed disability progression is observed (374 events are required)

Studyend

Double-blind treatment phase (with a variable duration)

Planned extension

phase

Screening and baseline phase

Matching placebo (N ~510)

2 mg/day (N ~1020)

6-day dose titrationa,b

Siponimod

362412

MRI EDSS/T25W

15 18 21 279630 30 33 39

Randomization (2:1)

Month

aRegimen: 0.25 mg on day 1, 0.25 mg on day 2, 0.5 mg on day 3, 0.75 mg on day 4, 1.25 mg on day 5, and 2 mg on day 6

EXPAND: Ongoing Event-driven Phase 3 Trial Investigating Safety and Efficacy of Siponimod in SPMS1-3

1. Clinical Trials.gov. Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND). Available at www.clinicaltrials.gov/ct2/show/NCT01665144.2. Novartis Pharma AG, data on file. Use with permission. 3. Kappos L, et al. P07.126 presented at AAN 2013.



Total patient populationN=1649

Disease Duration (1st Sx)

N

Mean ± SD

1623

16.8 ± 8.4

Disease Duration (Dx)

N

Mean ± SD

1632

12.5 ± 7.9

Time since SPMS Dx (yrs)

N

Mean ± SD

1637

3.8 ± 3.5

EXPAND MS History and Baseline Disease Characteristics

Kappos L, et al. P07.126 presented at AAN 2013.

EXPAND MS History and Baseline Disease Characteristics

Kappos L, et al. P07.126 presented at AAN 2013.

2.9

6.69.5 9.2

6.89.0

30.3

24.9

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

≤3 3.5 4 4.5 5 5.5 6 ≥6.5

Baseline EDSS score (N=1649)

Distribution of baseline EDSS scores

Objectives








Results of MOMENTUM, a randomized, double-blind, placebo-controlled, Phase 2 trial with

MT-1303, a novel selective sphingosine 1-phosphate receptor 1 (S1P1) modulator, in

relapsing-remitting MS

Ludwig Kappos, Douglas Arnold, Amit Bar-Or, John Camm, Tobias Derfuss, Bernd Kieseier, Till Sprenger, Kristin Greenough, Pingping Ni, Tomohiko Harada and the

MOMENTUM [email protected]

Late Breaking News Presentation, Saturday,October 10, 2015

Objectives






Laquinimod: Results From RRMS That Provide a Rationale for PPMS Study1,2

0

5%

10%

15%

25%

27%

4.8%

7.6%

Placebo

Laquinimod 0.6 mg

20%

18.9%

22.1%

39%

Relapse-free (n=1220) Relapsing (n=770)

prop

ortio

n of

pat

ient

s ex

peri

enci

ng 3

-mon

th C

DP

1. Comi G, et al. AAN 2014: P3.195. 2. Sorman MP, et al. Neurology. 2010 27;75(4):302-309.Reprinted with permission.

CDP: confirmed disability progression



A multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study followed by an active treatment period, to evaluate the efficacy, safety, and tolerability of 2 doses of oral administration of laquinimod (0.6 or 1.2 mg/day) in subjects with relapsing remitting multiple sclerosis (RRMS).

CONCERTO Design

Primary endpoint: 3 months confirmed disability progression

Secondary endpoints: BA and time to first relapse

Exploratory endpoints: Include cognitive (Symbol Digital Modalities Test), MRI, and quality of life measures

Vollmer T, et al. ECTRIMS 2013:P1054. Used with permission.

= EDSS, T25FW, 9HPT, SDMT, MSWS

= MRI Brain and C-spine

4Week 80 12 24 36 48 Every 12 weeks

Completion visit

Screening

LAQ 1.5 mg/dayLAQ 1.5 mg/day

Placebo dailyPlacebo daily

LAQ 0.6 mg/dayLAQ 0.6 mg/day

Part A(Core)

Part B(Data Analysis)

= OCT, BICAMS= LCVA

1:1:1 Randomization1:1:1 Randomization

ARPEGGIO Design

Giovannoni G, et al. AAN 2015:P7.210. Used with permission.

Objectives








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