p023 ozanimod demonstrates efficacy and safety in a phase...

P023

Ozanimod Demonstrates Efficacy and Safety in a Phase 3 Trial of Relapsing Multiple Sclerosis (SUNBEAM)Giancarlo Comi1, Douglas L. Arnold2, Bruce A. C. Cree3, Ludwig Kappos4, Krzysztof W. Selmaj5, Amit Bar-Or6, Lawrence Steinman7, Hans-Peter Hartung8, Xavier Montalbán9, Eva K. Havrdová10, James K. Sheffield11, Kartik Raghupathi11, Jeffrey A. Cohen12, on behalf of the SUNBEAM Investigators1Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; 2NeuroRx Research and Montréal Neurological Institute, McGill University, Montréal, Quebec, Canada; 3UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, United States; 4Department of Neurology, University Hospital and University of Basel, Basel, Switzerland; 5Department of Neurology, Medical University of Łódz, Łódz, Poland; 6Center for Neuroinflammation and Therapeutics, and Multiple Sclerosis Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 7Beckman Center for Molecular Medicine, Stanford University Medical Center, Stanford, California, United States; 8Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; 9University of Toronto, St Michael’s Hospital, Toronto, Canada and Multiple Sclerosis Center of Catalonia (Cemcat), Hospital Universitari Vall d’Hebron, Barcelona, Spain; 10Department of Neurology and Center for Clinical Neuroscience, First Medical Faculty, Charles University, Prague, Czech Republic, 11Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, California, United States; 12Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, Ohio, United States

Ozanimod Demonstrates Efficacy and Safety in a Phase 3 Trial of Relapsing Multiple Sclerosis (SUNBEAM)

BACKGROUND

• Ozanimodisanoral,once-dailyimmunomodulatorthatselectivelytargetssphingosine1-phosphatereceptor1(S1PR1)andS1PR5

• TheS1Preceptorspecificityandpharmaceuticalproperties(eg,lowmaximumplasmaconcentration)ofozanimod,combinedwithuseofaninitialdose-escalationregimen,areanticipatedtoresultinafavorablebenefit-riskprofile

OBJECTIVES

• ReportresultsfromSUNBEAM(NCT02294058),oneoftwophase3studiescomparingonce-dailyozanimodwithinterferon(IFN)β-1ainpatientswithrelapsingmultiplesclerosis(RMS)

METHODS

• SUNBEAMwasamulticenter,randomized,double-blind,double-dummy,parallel-group,active-controlledstudy(Figure1)

• Keyinclusioncriteria:

– Age18–55years

– Multiplesclerosisdiagnosisby2010McDonaldcriteria

– ≥1documentedrelapseinprioryearor≥1documentedrelapseinprior2yearsplus≥1gadolinium-enhancing(GdE)lesioninprioryear

– ExpandedDisabilityStatusScalescorebetween0–5.0

– Clinicallystable,withnorelapseorcorticosteroidtreatment1monthpriortoscreening

• Keyexclusioncriteria:

– Specificcardiacconditions,includingrecentmyocardialinfarction,stroke,orprolongedQTcFinterval

– Restingheartrate<55bpmatscreening

– Diabetesmellitustype1,uncontrolleddiabetesmellitustype2withhemoglobinA1c>9%,ordiabetespatientswithsignificantcomorbidities

• Patientswithcontrolleddiabetesmellitustype2ormacularedemawereeligible

• Patientswererandomized(1:1:1)toonce-dailyoralozanimodHCl1mgor0.5mgoronce-weeklyintramuscularIFNβ-1a30µgfor≥1year

• Aninitial7-daydose-escalationregimenwasemployedforallparticipants.Participantsrandomizedtoozanimodreceived0.25mgondays1–4,0.5mgondays5–7,andtheirassignedozanimoddosestartingonday8

Acknowledgments

Theauthorswouldliketothankalltheinvestigatorsandpatientswhoparticipatedinthetrial.TheSUNBEAMstudywassponsoredbyCelgeneCorporation.Supportforthird-partyeditorialassistanceforthisposterwasprovidedbyCodonMedical,anAshfieldCompany,partofUDGHealthcareplc,andwasfundedbyCelgeneCorporation.

DisclosuresGiancarloComireportscompensationforconsultingand/orspeakingactivitiesfromAlmirall,Biogen,CelgeneCorporation,EXCEMED,ForwardPharm,Genzyme,Merck,Novartis,Roche,Sanofi,andTeva.DouglasL.ArnoldreportspersonalfeesforconsultingfromAcorda,Biogen,CelgeneCorporation,MedImmune,MitsubishiPharma,Novartis,Roche,andSanofi;grantsupportfromBiogenandNovartis;andequityinterestinNeuroRxResearch.BruceA.C.CreereportspersonalcompensationforconsultingforAbbvie,Biogen,EMDSerono,Genzyme,Novartis,andShire.LudwigKappos’sinstitution(UniversityHospitalBasel)hasreceivedthefollowing,whichwasusedexclusivelyforresearchsupport:steeringcommittee,advisoryboard,andconsultancyfees(Actelion,Addex,Bayer,Biogen,Biotica,CelgeneCorporation,Genzyme,Lilly,Merck,Mitsubishi,Novartis,OnoPharma,Pfizer,Sanofi,Santhera,Siemens,Teva,UCB,andXenoport);speakerfees(Bayer,Biogen,Merck,Novartis,Sanofi,andTeva);supportofeducationalactivities(Bayer,Biogen,CSLBehring,Genzyme,Merck,Novartis,Sanofi,andTeva);licensefeesforNeurostatusproducts;andgrants(Bayer,Biogen,EuropeanUnion,Merck,Novartis,Roche,SwissMSSociety,andSwissNationalResearchFoundation).KrzysztofW.SelmajreportsconsultingforBiogen,CelgeneCorporation,Genzyme,Merck,Novartis,OnoPharma,Roche,Synthon,andTeva.AmitBar-Orreportspersonalcompensationforconsultingfor

Biogen,CelgeneCorporation,EMDSerono,Genzyme,Medimmune,Novartis,andRoche.LawrenceSteinmanreportsconsultingforAbbvie,Atreca,CelgeneCorporation,Novartis,Teva,Tolerion,andEMDSerono,andresearchsupportfromAtara,Biogen,andCelgeneCorporation.Hans-PeterHartungreportspersonalfeesforconsulting,servingonsteeringcommittees,andspeakingfromBayer,Biogen,Geneuro,Genzyme,Merck,MedImmune,Novartis,Octapharma,Opexa,Roche,Sanofi,andTeva.XavierMontalbánhasreceivedspeakinghonorariaandtravelexpensesforscientificmeetingsorhasparticipatedinsteeringcommitteesorinadvisoryboardsforclinicaltrialswithAlmirall,BayerScheringPharma,Biogen,Genentech,Genzyme,GSK,MerckSerono,MSInternationalFederation,NationalMultipleSclerosisSociety,Novartis,Roche,Sanofi-Aventis,andTeva;heisaneditorforClinicalCasesforMultiple Sclerosis Journal.EvaK.HavrdováreportspersonalcompensationforconsultingandspeakingforActelion,Biogen,CelgeneCorporation,Merck,Novartis,Roche,Sanofi,andTeva,andissupportedbyCzechMinistryofEducation,projectPROGRESQ27/LF1.JamesK.SheffieldandKartikRaghupathiareemployeesofReceptos,awhollyownedsubsidiaryofCelgeneCorporation.JeffreyA.CohenreportspersonalcompensationforconsultingforAdamasandCelgeneCorporation,andasaco-editorofMultiple Sclerosis Journal – Experimental, Translational and Clinical.

methods

• Patientsreceivedrandomized,blindedtreatmentuntilthelastactivepatientwastreatedfor≥12months

• Primaryendpoint: – Annualizedrelapserate(ARR)foreachozanimoddose

versusIFNβ-1aduringthetreatmentperiod• Secondaryendpoints: – NeworenlargingT2lesionsfrombaselineover1year – GdElesionsat1year – Timeto3-monthconfirmeddisabilityprogressionwas

evaluatedineachphase3study(seeResultssectionforSUNBEAMresults)andwasprespecifiedasapooledanalysisofSUNBEAMandRADIANCEPartB

– Wholebrainvolumelossat1year• Exploratoryendpoints: – Corticalgraymattervolumeandthalamicvolumelossat

1year• Theintent-to-treatpopulation,definedasallpatientswho

wererandomizedandreceived≥1doseofstudydrug,wasusedforallefficacyanalyses

• Thesafetypopulation,definedasallpatientswhoreceived≥1doseofstudydrug,wasusedforallsafetyanalyses,withpatientsgroupedaccordingtothehighestdoseofozanimodreceived

conclusions

• BothozanimoddosesdemonstratedsuperioritytoIFNβ-1aonARR

• Adjustedmeannumbersofnew/enlargingT2lesionsperscanandGdElesionsat1yearweresignificantlylowerforbothdosesofozanimodversusIFNβ-1a

• Wholebrainvolumeloss,corticalgraymattervolumeloss,andthalamicvolumelosswerereducedcomparedwithIFNβ-1a

• AdoseresponsewasconsistentlydemonstratedacrossARRandMRIefficacyendpoints

• Overall,ozanimodwaswelltoleratedwithanacceptablesafetyprofile

• Theseefficacyandsafetyresultsdemonstrateafavorablebenefit-riskprofileforozanimodinRMS

Figure 1. SUNBEAM Study Design

Figure 2. Patient Disposition

IFN β-1a, interferon β-1a.

RESULTS

Presentedatthe3rdAnnualAmericasCommitteeforTreatmentandResearchinMultipleSclerosis(ACTRIMS)Forum2018;February1–3,2018;SanDiego,California

Expanded Disability Status Scale: Every 3 months and at time of relapse. All magnetic resonance imaging (MRI) analyses performed by a blinded central imaging facility.


IFN β-1a

Ozanimod 1 mg

1-year active-controlledtreatment period

Randomization 1:1:1

–1 0 6 12

Baseline

Month

MRI:

Ozanimod 0.5 mg

Screening period

(30 days)

7-day dose- escalation

period

Efficacy• Ozanimod1mgand0.5mgreducedARRby48%(0.181,

P<0.0001)and31%(0.241,P=0.0013),respectively,versusIFNβ-1a(0.350)(Figure3A)

• Adjustedmeannumberofnew/enlargingT2lesionsperscanover12monthswasreducedby48%forozanimod1mg(1.465;P<0.0001)and25%forozanimod0.5mg(2.139;P=0.0032)versusIFNβ-1a(2.836)(Figure3B)

• AdjustedmeannumberofGdElesionsat1yearwasreducedby63%forozanimod1mg(0.160;P<0.0001)and34%forozanimod0.5mg(0.287;P=0.0182)versusIFNβ-1a(0.433)(Figure3C)

• Ozanimod1mgand0.5mgreducedtheriskof3-monthconfirmeddisabilityprogressionby31%and11%,respectively,versusIFNβ-1a,withalowrateofprogressionacrossallgroups(Figure4)

Total screenedN=1656

Total randomizedn=1346

Discontinuedtreatment

n=36 (8.0%)


n=26 (5.8%)


n=29 (6.5%)

Randomized andtreated

n=448 (100%)

Completedtreatment

n=412 (92.0%)


n=451 (100%)

Completedtreatment

n=425 (94.2%)


n=447 (100%)

Completedtreatment

n=418 (93.5%)

Ozanimod 0.5 mg Ozanimod 1 mgIFN β-1a

Table 1. Demographics and Baseline CharacteristicsIFN β-1a (n=448)

Ozanimod 0.5 mg(n=451)

Ozanimod 1 mg(n=447)

Age, mean years (SD) 35.9 (9.11) 36.0 (9.43) 34.8 (9.24)

Female, n (%) 300 (67.0) 311 (69.0) 283 (63.3)

Time since diagnosis, mean years (SD) 3.7 (4.36) 3.7 (4.52) 3.6 (4.19)

EDSS score, mean (SD) 2.6 (1.14) 2.7 (1.14) 2.6 (1.16)

Number of relapses in prior year, mean (SD) 1.3 (0.55) 1.3 (0.57) 1.3 (0.57)

Patients previously treated with a DMT, n (%) 151 (33.7) 132 (29.3) 128 (28.6)

Patients with GdE lesions, n (%) 216 (48.2) 202 (44.8) 214 (47.9)

Normalized whole brain volume, median cm3 1445.53 1453.03 1458.30

DMT, disease-modifying treatment; EDSS, Expanded Disability Status Scale; GdE, gadolinium-enhancing; IFN β-1a, interferon β-1a; SD, standard deviation.

Figure 3. (A) Primary Endpoint: ARR During Treatment Period (B) Secondary Endpoint: Number of New/Enlarging T2 Lesions Over 1 Year (C) Secondary Endpoint: Number of GdE Lesions at 1 Year

Annualized relapse rate (ARR) was analyzed using a Poisson regression model adjusted for region (Eastern Europe vs Rest of World), baseline age, and baseline number of gadolinium-enhancing (GdE) lesions, with the natural log transformation of time on study as an offset term. Analyses of T2 and GdE lesions were based on negative binominal regression models using observed data adjusted for region (Eastern Europe vs Rest of World), baseline age, and baseline number of GdE lesions, with the natural log transformation of number of available scans over 12 months as an offset term.

CI, confidence interval; IFN β-1a, interferon β-1a.

0.433

0.287

0.160

34% reductionP=0.0182

63% reductionP<0.0001

(n=382)Ozanimod 0.5 mgIFN β-1a

(n=397)Ozanimod 1 mg

(n=388)

Adju

sted

mea

n (±

95%

CI)

num

ber o

f GdE

lesi

ons

0.0

0.1

0.2

0.3

0.4

0.5

0.6

2.8362.139

1.465

25% reductionP=0.0032 48% reduction

P<0.0001

0

1

2

3

4

5

Adju

sted

mea

n (±

95%

CI)

num

ber o

f ne

w/e

nlar

ging

T2

lesi

ons

per s

can



(n=388)

0.350

0.2410.181

31% reductionP=0.0013 48% reduction

P<0.0001



(n=447)

Adju

sted

ARR

(± 9

5% C

I)

0.0

0.1

0.2

0.3

0.4

0.5(A)

(B)

(C)

Figure 5. (A) Whole Brain Volume Loss, (B) Cortical Gray Matter Volume Loss, and (C) Thalamic Volume Loss at Year 1 Relative to Baseline (Observed, ITT Population)

Brain volume loss was evaluated using the Jacobian integration method to assess changes in normalized whole brain, cortical gray matter, and thalamic volumes. P-values are based on rank analysis of covariance, adjusted for region (Eastern Europe vs Rest of World) and Expanded Disability Status Scale score randomization category (≤3.5 vs >3.5), with the residual of the rank of (A) whole brain volume, (B) cortical gray matter volume, and (C) thalamic volume at baseline as the dependent variable regressed on rank of percent change from baseline. Treatment effects are reported as percent reductions in median percent change from baseline in each ozanimod treatment group relative to interferon (IFN) β-1a.

ITT, intent-to-treat.

Med

ian

perc

ent c

hang

e fr

om b

asel

ine

(C)

Baseline to Month 12

Thalamic Volume Loss

P=0.000134.3% reduction

P<0.000138.5% reduction

-0.960%-1.025%

-1.560%

Med

ian

perc

ent c

hang

e fr

om b

asel

ine Baseline to Month 12

Cortical Gray Matter Volume Loss(B)



-0.160%-0.380%

-0.985%

Med

ian

perc

ent c

hang

e fr

om b

asel

ine Baseline to Month 12

Whole Brain Volume Loss(A)

IFN β-1a (n=334)Ozanimod 0.5 mg (n=347)Ozanimod 1 mg (n=338)



P=0.061512.3% reduction


-0.385%-0.500%-0.570%

0.00

-0.50

-1.00

-1.50

0.00

-0.50

-1.00

-1.50

0.00

-0.50

-1.00

-1.50

• Following1yearoftreatment,patientsintheozanimod1-mggrouphadslowingofwholebrainvolumelossversusIFNβ-1a(P<0.0001;32.5%reductioninmedianrelativetoIFNβ-1a;medianpercentchangefrombaseline:-0.385%[ozanimod1mg],-0.570%[IFNβ-1a]).Patientsintheozanimod0.5-mggroupdemonstratedatrendtowardslowingbrainvolumeloss(P=0.0615;12.3%reductioninmedianrelativetoIFNβ-1a;medianpercentchangefrombaseline:-0.500%)(Figure5A)

• Patientsinboththeozanimod1-mgand0.5-mggroupsdemonstratedslowingofcorticalgraymatterloss:P<0.0001;83.8%reductioninmedian;medianpercentchangefrombaseline:-0.160%andP<0.0001;61.4%reductioninmedian;medianpercentchangefrombaseline:-0.380%,respectively,relativetoIFNβ-1a(-0.985%)(Figure5B)

• Patientsinboththeozanimod1-mgand0.5-mggroupsdemonstratedslowingofthalamicvolumeloss:P<0.0001;38.5%reductioninmedian;medianpercentchangefrombaseline:-0.960%andP=0.0001;34.3%reductioninmedian;medianpercentchangefrombaseline:-1.025%,respectively,relativetoIFNβ-1a(-1.560%)(Figure5C)

Safety• Treatment-emergentadverseevents(AEs)andAEsleading

todiscontinuationweremorefrequentintheIFNβ-1agroup.SeriousAEsweresimilaracrosstreatmentgroups(Table2)

– Mosttreatment-emergentAEsweremild – IncidenceofseriousAEswaslow,withnodistinct

patternreported – AEsthatdifferedinincidencebetweenozanimod-and

IFNβ-1a–treatedpatientsareshowninTable3• Cardiacsafety: – Thelargestmeansupineheartratereductiononday1,

hours1–6,was-1.8bpmathour5.MinimumsupineheartratesareshowninTable4

– Noatrioventricularblockofseconddegreeorhigherwasreportedduringthestudy

– SeriouscardiacAEswereinfrequentandbalancedacrosstreatmentgroups

• Infections: – SeriousinfectionAEswereinfrequentandbalanced

acrosstreatmentgroups(Table5) – Noseriousopportunisticinfectionswerereportedin

ozanimod-treatedpatients• Alanineaminotransferase(ALT)elevations≥3timesthe

upperlevelofnormalwerereportedin4.3%(19/447)ofpatientstreatedwithozanimod1mg,1.8%(8/453)treatedwithozanimod0.5mg,and2.2%(10/445)treatedwithIFNβ-1a.AEsofelevatedALTweretransientandgenerallyresolvedwithoutstudydrugdiscontinuation

RESULTS

Baseline Demographics and Patient Disposition• Atotalof1346RMSpatientswererandomized(Figure2),

withsimilarbaselinecharacteristicsacrosstreatmentgroups(Table1)

• Meantreatmentdurationwas13.6months

Table 2. Summary of Adverse EventsIFN β-1a (n=445)



Any AE, n (%) 336 (75.5) 259 (57.2) 268 (59.8)

Any moderate or severe AEa, n (%) 182 (40.9) 113 (24.9) 138 (30.8)

Any severe AEa, n (%) 10 (2.2) 10 (2.2) 7 (1.6)

Serious AE, n (%) 11 (2.5) 16 (3.5) 13 (2.9)

AE leading to study drug discontinuation, n (%) 16 (3.6) 7 (1.5) 13 (2.9)

Death, n (%) 0 0 0aAs reported by the investigator.AE, adverse event; IFN β-1a, interferon β-1a.

Table 3. Adverse Events in ≥5% of Patients in Either Ozanimod Treatment Group With ≥1% Difference From IFN β-1a

IFN β-1a (n=445)



Nasopharyngitis, n (%) 36 (8.1) 44 (9.7) 30 (6.7)

Headache, n (%) 25 (5.6) 27 (6.0) 34 (7.6)

Upper respiratory tract infection, n (%) 24 (5.4) 31 (6.8) 18 (4.0)Highest incidences are denoted by red boxes. Adverse events are sorted by decreasing incidence in all ozanimod-treated patients (not shown).IFN β-1a, interferon β-1a.

Table 4. Minimum Supine Heart Rate on Day 1, Hours 1–6Minimum supine heart rate (day 1, hours 1–6), bpm

IFN β-1a (n=445)

Ozanimod 0.5 mga

(n=453)Ozanimod 1 mga

(n=448)

Patients with ≥1 assessment, n 442 443 441

≥65, n (%) 256 (57.5) 167 (36.9) 151 (33.7)

55–64, n (%) 167 (37.5) 242 (53.5) 246 (54.9)

45–54, n (%) 22 (4.9) 43 (9.5) 51 (11.4)

<45, n (%) 0 0 0aOn day 1, all patients in the ozanimod treatment groups received a dose of ozanimod 0.25 mg.bpm, beats per minute; IFN β-1a, interferon β-1a.

Table 5. Infections Adverse Events At any time during the study

IFN β-1a (n=445)



Infections: AEs, n (%) 119 (26.7) 131 (28.9) 128 (28.6)

Infections: serious AEs, n (%) 3 (0.7) 1 (0.2) 5 (1.1)

AEs: herpetic infectionsa, n (%) 5 (1.1) 3 (0.7) 4 (0.9)aPreferred terms include: oral herpes, herpes zoster, herpes simplex, herpes virus infection.AE, adverse event; IFN β-1a, interferon β-1a.

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Figure 4. Time to Onset of 3-Month Confirmed Disability Progression

Time to onset of 3-month confirmed disability progression analyzed using a Cox proportional hazards model adjusted for region (Eastern Europe vs Rest of World), baseline age, and baseline Expanded Disability Status Scale score. Estimated proportions based on Kaplan–Meier estimates. Results for SUNBEAM are shown above. Formal statistical testing of this endpoint was prospectively planned as a pooled analysis using data from both phase 3 studies (SUNBEAM and RADIANCE Part B).


0.0

0.00

0.01

0.02

0.03

0.04

0.05

Day 1 Month 3 Month 6 Month 9 Month 12 Month 15

Day 1 Month 3 Month 6 Month 9 Month 12 Month 15

448 (0) [0]451 (0) [0]447 (0) [0]

IFN β-1aOzanimod 0.5 mg

Ozanimod 1 mg

440 (5) [3]437 (5) [9]440 (4) [3]

427 (12) [9]430 (11) [10]427 (12) [8]

416 (21) [11]418 (19) [14]420 (17) [10]

377 (55) [16]381 (55) [15]390 (45) [12]

123 (306) [19]132 (302) [17]126 (308) [13]

0.2

0.4

0.8

0.6

1.0

Estim

ated

pro

babi

lity

of d

isab

ility

prog

ress

ion

(con

firm

ed a

t 3 m

onth

s)

IFN β-1a Ozanimod 0.5 mg

0.045

0.0300.039

11% Reduction

31% Reduction

Ozanimod 1 mg

Number at risk (censored) [events]

p023 ozanimod demonstrates efficacy and safety in a phase...

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