aan 2014: alemtuzumab sustainded improvement
TRANSCRIPT
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of Patients
EDSS
Sco
re
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of PatientsED
SS S
core
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of Patients
EDSS
Sco
re
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of Patients
EDSS
Sco
re
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of Patients
EDSS
Sco
re
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of Patients
EDSS
Sco
re
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of Patients
EDSS
Sco
re
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of Patients
EDSS
Sco
re
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
REFERENCES1. Hu Y, et al. Immunology 2009;128:260-70. 2. Weber MS, Hemmer B. Results Probl Cell Differ 2010;51:115-26. 3. Havari E, et al. Immunology 2014;141:123-31. 4. Cox AL, et al. Eur J Immunol 2005;35:3332-42. 5. Coles AJ, et al. N Engl J Med 2008;359:1786-801. 6. Cohen JA, et al. Lancet 2012;380:1819-28. 7. Coles AJ, et al. Lancet 2012;380:1829-39. 8. Graves J, et al. Neurology 2013;30 (abstract P3.158). 9. Fox EJ, et al. Neurology 2013;30 (abstract S41.001).
CONCLUSIONS• Interim data from the CARE-MS II extension study demonstrate that alemtuzumabhasdurableefficacyondisabilitythrough3yearsinpatientswhohadrelapsedonpriortherapy,despitethemajorityofpatientsreceivingnoadditionalalemtuzumabtreatmentcoursesorotherDMTs – AlmosthalfofalemtuzumabpatientsdemonstratedimproveddisabilityscoresatYear3comparedwiththatatstudybaseline
– Morethanonethirdofformeralemtuzumabpatientsattainedsustaineddisabilityimprovement(6-monthsustainedreductionindisability) by Year 3
– Similardisabilityoutcomeswereobservedinpatientswhoreceivedonly 2 treatment courses over 3 years
• Thesefindings,togetherwithpreviouslyreporteddata,supportthepositivebenefit-riskprofileforalemtuzumabasapotentialtreatmentforRRMSinpatientswhorelapsedonpriortherapy
INTRODUCTION• AlemtuzumabisahumanizedmonoclonalantibodyapprovedinAustralia,Brazil,Canada,theEuropeanUnion,andMexicoforthetreatmentofactiverelapsing-remittingmultiplesclerosis(RRMS)thatselectivelytargetsCD52,resultingindepletionandsubsequentrepopulationofcirculatingTandBlymphocytes1-4
• Alemtuzumab,administeredin2annualcourses,hasdemonstratedsuperiorefficacyvs.high-dosesubcutaneousinterferonbeta-1a(SCIFNB-1a)intreatment-naiveRRMSpatients(CAMMS223[NCT00050778];ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis[CARE-MS]I[NCT00530348])5,6;andinpatientswhorelapsedonapriortherapy(CARE-MSII[NCT00548405])7 – Intheseclinicaltrials,alemtuzumabhadaconsistentandmanageablesafetyprofile,withthemostcommonadverseevents(AEs)beinginfusion-associatedreactions,non-serious infections, and autoimmune AEs
• InCARE-MSII,alemtuzumabsignificantlyreduced6-monthsustainedaccumulationofdisabilityat2yearsby49%beyondthatwithSCIFNB-1a(p<0.0001),andalemtuzumabpatientsweremorethantwiceaslikelytodemonstrate6-monthsustainedimprovementinpreexistingdisability(hazardratio2.57;p=0.0002)7 – PatientstreatedwithalemtuzumabalsohadsignificantlyimprovedvisualoutcomesusingSloanlow-contrastacuitymetrics,andfunctionaloutcomesusingMultipleSclerosisFunctionalComposite,comparedwithSCIFNB-1aatYear2(p<0.05)7,8
OBJECTIVE• ThepresentstudyexaminedthedurabilityofdisabilityimprovementinYear3follow-upduringanongoingextensionstudy(NCT00930553)ofalemtuzumabpatientswhorelapsedonapriortherapy
METHODSStudy DesignCore Study7
• CARE-MSIIwasarandomized,rater-blinded,active-controlled,head-to-head,phase3trial of 24 months’ duration
• Entrycriteriaincludedage18–55years,baselineExpandedDisabilityStatusScale(EDSS)score ≤5,MSsymptomonsetwithin10years,activeRRMS(≥2relapsesinprior2yearsand ≥1intheprioryear),andrelapseonpriortherapy(≥1relapseduringtreatmentwithIFNBorglatirameracetate,afterreceivingthattherapyfor≥6months[priortreatmentwithothertherapieswasalsopermitted])
• Patientswererandomized2:1toreceivealemtuzumab12mg/dayviaintravenous(IV)infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SCIFNB-1a44µg3timesweekly
Extension Study9
• Patients who had received alemtuzumab in the core study received re-treatment as neededintheextension(12mg/dayIVon3consecutivedays) – Re-treatmentcriteriawereoneofthefollowing,basedontheinvestigator’sclinical
decision: ■ ≥1protocol-definedrelapse ■ ≥2neworenlargingT2and/orgadolinium-enhancingbrainorspinallesionsonmagneticresonanceimaging
– Useofotherdisease-modifyingtherapies(DMTs)wasallowedbasedoninvestigators’clinical decisions
– AlldatapresentedherearefrompatientswhoreceivedalemtuzumabinthecoreCARE-MS II study
Disability Assessment• EDSSwasassessedbyblindedratersatcorestudybaselineandevery3months• Disabilityoutcomes
– ChangefromcorestudybaselineonEDSS – Proportionofpatientsimproved,remainedstable,orworsenedonEDSS
■ Improvementandworseningweredefinedas≥0.5-pointdecreaseorincrease,respectively,fromcorestudybaselineEDSSscore
– Sustained reduction in disability: decrease from core study baseline by ≥1EDSSpointconfirmedover3,6,or12monthsforpatientswithbaselineEDSSscores≥2.0
Statistical Analysis• AnalyseswerebasedonYear3follow-updataonpatientswhohadreceivedalemtuzumab12mginthecoreCARE-MSIIstudy
• DatafromCARE-MSIIpatientswhotransitionedintotheextensionstudywereanalyzedfromthetimeoffirsttreatment
• Kaplan-Meieranalysisoftimeto3-,6-,and12-monthsustainedreductionindisability• Analyseswereundertakenforallpatientsintheextensionandforpatientswhoreceived
only 2 courses over 3 years
RESULTSPatients• Morethan90%(393of423)ofpatientswhohadreceivedalemtuzumab12mginCARE-MSIIandcompletedthecorestudyenteredtheextension
• Approximately80%didnotreceivere-treatmentduringYear3• Fewerthan3%offormeralemtuzumab-treatedpatientsreceivedanotherDMTinYear3Disability Improvement • MeanEDSSscoreswere2.7atcorestudybaseline,2.5atYear2,and2.6atYear3(Figure 1)
• MeanEDSSscoresremainedbelowpre-treatmentvaluesduringthethirdyear – Year2meanEDSSscorechangefromcorestudybaseline:−0.21 – Year3meanEDSSscorechangefromcorestudybaseline:−0.06
• AtYear3,70%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from core study baseline (Figure 2),similartotheresultsseenoverYears0–2
Acknowledgments and DisclosuresCARE-MSIIsteeringcommittee:DouglasLArnold,JeffreyACohen,AlasdairJColes,DAlastairSCompston,ChristianConfavreux*,EdwardFox,Hans-PeterHartung,EvaHavrdova,TamaraMiller,KrzysztofWSelmaj,CaryLTwyman,andHowardWeiner.Genzyme:AjiNair;LindaKasten.CARE-MSIIwassponsoredbyGenzyme,aSanoficompany,andBayerHealthcarePharmaceuticals.EditorialsupportforthisposterwasprovidedbyRichardHogan,EvidenceScientificSolutions,andwasfundedbyGenzyme.G.G.reportsreceivingcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogen-Idec,FivePrimeTherapeutics,Genzyme,GWPharma,Merck-Serono,Novartis,Roche,Synthon,Teva,andVertexPharmaceuticals.G.G.receivedcompensationforservingasajournaleditorforMultiple Sclerosis and Related DisordersandresearchsupportfromSerono.D.H.MandJ.P.reportreceivingpersonalcompensationasemployeesofGenzyme.J.H.reportsreceivingpersonalcompensationforconsulting,servingonascientificadvisoryboard,speaking,orotheractivitiesfromBiogenIdec.AlemtuzumabisapprovedinAustralia,theEuropeanUnion,andMexicofortreatmentofactiveRRMSdefinedbyclinicalorimagingfeatures,inBrazilfortreatmentofrelapsingformsofMS,andinCanadaforpatientswithinadequateresponsetointerferonbetaorotherDMTs.Rebif®isaregisteredtrademarkofEMDSerono,Inc.*Deceased.
Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-Year Follow-up
G Giovannoni,1DHMargolin,2 J Palmer,2 J Herbert3
1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicine,London,UK;2Genzyme,aSanoficompany,Cambridge,MA,USA;3NewYorkUniversityMedicalCenter,NewYork,NY,USA
Presented at the 66th Annual Meeting of the American Academy of Neurology (AAN), April 26–May 03, 2014, Philadelphia, PA
P3.165
Figure 2. Mean EDSS Change: Proportion Improved, Remained Stable, or Worsened in Patients Who Had Received Alemtuzumab 12 mg in the Core Study
• AtYear3,66%ofalemtuzumab-treatedpatientshadeitherstableorimprovedEDSSscores from extension study baseline (data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,75%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 3)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,58%remainedstableorimprovedfurtherfromYears2–3(Figure 3)
Sustained Reduction in Preexisting Disability• AtYear3,morethanonethirdofpatientswhohadreceivedalemtuzumab12mginthecorestudyattainedimprovementinpreexistingdisabilitysustainedfor6months,asmeasured by 6-month sustained reduction in disability (Figure 4) – Aboutonequarterofthepatientsachieved12-monthsustainedreductionindisability
at Year 3
Durability of Effect • MeanEDSSscoreatYear3was2.5forpatientswhoreceived2coursesofalemtuzumab
over 3 years – Year3meanEDSSscorechangefromcorestudybaselinewas−0.16inthispatientsubgroup
• AtYear3,EDSSscorewasimprovedfromcorestudybaselinein48%ofpatientswhoreceived2coursesofalemtuzumabover3yearsandstableinafurther28%ofpatients(data not shown)
• AmongpatientswhoseEDSSscoreremainedstablefrombaselinetoYear2,79%eithercontinuedtoremainstableorexperiencedimprovementfromYears2–3(Figure 5)
• AmongpatientswhoseEDSSscoreimprovedfrombaselinetoYear2,61%remainedstableorimprovedfurtherfromYears2–3(Figure 5)
Sustained Reduction in Preexisting Disability• Forpatientswhoreceivedonly2coursesofalemtuzumabover3years,theproportionsachieving3-,6-,and12-monthsustainedreductionindisabilitywere45%,37%,and28% at Year 3 (data not shown)
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale.
EDSS=ExpandedDisabilityStatusScale
Figure 1. EDSS Score over Time in the Core Study and Extension
0 6 12 18 24 30 363 9 15 21 27 33
426 419 422 410 416 373 370419 419 415 413 367 364
0
2.00
2.40
2.60
2.20
2.80Baseline EDSS
3.00
Follow-up MonthNo. of Patients
EDSS
Sco
re
Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
Prop
ortio
n of
Pat
ient
s (%
)
60 Improved
Remained stable
Worsened50
40
30
20
10
0
46
302524
30
45
(N=178)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
011.8
46.651.8
23.2
Figure 3. EDSS Improvement from Year 2 to Year 3 in Alemtuzumab-treated Patients Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
35%
43%
0 6 12 18 24 30 360
10
20
30
40
50
Follow-up Month
CARE-MS II Core Study Extension
321 280 241 222 200 172 1623-Month SRD
Prop
ortio
n of
Pat
ient
s w
ith S
usta
ined
R
educ
tion
in D
isab
ility
(%)
29%35%
321 290 262 245 221 190 1826-Month SRD
22%27%
321 294 275 263 245 215 20712-Month SRD
No. at Risk
Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;SRD=sustainedreductionindisability
Figure 5. EDSS Improvement from Year 2 to Year 3 in Patients Treated with 2 Courses of Alemtuzumab over 3 Years Who Improved or Remained Stable from Baseline to Year 2
EDSS=ExpandedDisabilityStatusScale
(N=148)
ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=96)
Remained stableYears 0–2
Prop
ortio
n of
Pat
ient
sat
Yea
r 3 (%
) 60
70
80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
50
40
30
20
10
012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale