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, interferon β-1a.
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%)
Discontinuedtreatment
n=26 (5.8%)
Discontinuedtreatment
n=29 (6.5%)
Randomized andtreated
n=448 (100%)
Completedtreatment
n=412 (92.0%)
Randomized andtreated
n=451 (100%)
Completedtreatment
n=425 (94.2%)
Randomized andtreated
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=382)Ozanimod 0.5 mgIFN β-1a
(n=397)Ozanimod 1 mg
(n=388)
0.350
0.2410.181
31% reductionP=0.0013 48% reduction
P<0.0001
(n=448)Ozanimod 0.5 mgIFN β-1a
(n=451)Ozanimod 1 mg
(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)
P<0.000161.4% reduction
P<0.000183.8% reduction
-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)
IFN β-1a (n=336)Ozanimod 0.5 mg (n=343)Ozanimod 1 mg (n=339)
IFN β-1a (n=329)Ozanimod 0.5 mg (n=338)Ozanimod 1 mg (n=331)
P=0.061512.3% reduction
P<0.000132.5% 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)
Ozanimod 0.5 mg(n=453)
Ozanimod 1 mg(n=448)
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)
Ozanimod 0.5 mg(n=453)
Ozanimod 1 mg(n=448)
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)
Ozanimod 0.5 mg(n=453)
Ozanimod 1 mg(n=448)
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).
IFN β-1a, interferon β-1a.
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]
