AAN 2014: Alemtuzumab Sustainded Improvement
9
REFERENCES 1. 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 alemtuzumab has durable efficacy on disability through 3 years in patients who had relapsed on prior therapy, despite the majority of patients receiving no additional alemtuzumab treatment courses or other DMTs – Almost half of alemtuzumab patients demonstrated improved disability scores at Year 3 compared with that at study baseline – More than one third of former alemtuzumab patients attained sustained disability improvement (6-month sustained reduction in disability) by Year 3 – Similar disability outcomes were observed in patients who received only 2 treatment courses over 3 years • These findings, together with previously reported data, support the positive benefit-risk profile for alemtuzumab as a potential treatment for RRMS in patients who relapsed on prior therapy INTRODUCTION • Alemtuzumab is a humanized monoclonal antibody approved in Australia, Brazil, Canada, the European Union, and Mexico for the treatment of active relapsing-remitting multiple sclerosis (RRMS) that selectively targets CD52, resulting in depletion and subsequent repopulation of circulating T and B lymphocytes 1-4 • Alemtuzumab, administered in 2 annual courses, has demonstrated superior efficacy vs. high-dose subcutaneous interferon beta-1a (SC IFNB-1a) in treatment-naive RRMS patients (CAMMS223 [NCT00050778]; Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis [CARE-MS] I [NCT00530348]) 5,6 ; and in patients who relapsed on a prior therapy (CARE-MS II [NCT00548405]) 7 – In these clinical trials, alemtuzumab had a consistent and manageable safety profile, with the most common adverse events (AEs) being infusion-associated reactions, non- serious infections, and autoimmune AEs • In CARE-MS II, alemtuzumab significantly reduced 6-month sustained accumulation of disability at 2 years by 49% beyond that with SC IFNB-1a (p<0.0001), and alemtuzumab patients were more than twice as likely to demonstrate 6-month sustained improvement in preexisting disability (hazard ratio 2.57; p=0.0002) 7 – Patients treated with alemtuzumab also had significantly improved visual outcomes using Sloan low-contrast acuity metrics, and functional outcomes using Multiple Sclerosis Functional Composite, compared with SC IFNB-1a at Year 2 (p<0.05) 7,8 OBJECTIVE • The present study examined the durability of disability improvement in Year 3 follow- up during an ongoing extension study (NCT00930553) of alemtuzumab patients who relapsed on a prior therapy METHODS Study Design Core Study 7 • CARE-MS II was a randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial of 24 months’ duration • Entry criteria included age 18–55 years, baseline Expanded Disability Status Scale (EDSS) score ≤5, MS symptom onset within 10 years, active RRMS (≥2 relapses in prior 2 years and ≥1 in the prior year), and relapse on prior therapy (≥1 relapse during treatment with IFNB or glatiramer acetate, after receiving that therapy for ≥6 months [prior treatment with other therapies was also permitted]) • Patients were randomized 2:1 to receive alemtuzumab 12 mg/day via intravenous (IV) infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later, or SC IFNB-1a 44 µg 3 times weekly Extension Study 9 • Patients who had received alemtuzumab in the core study received re-treatment as needed in the extension (12 mg/day IV on 3 consecutive days) – Re-treatment criteria were one of the following, based on the investigator’s clinical decision: ■ ≥1 protocol-defined relapse ■ ≥2 new or enlarging T 2 and/or gadolinium-enhancing brain or spinal lesions on magnetic resonance imaging – Use of other disease-modifying therapies (DMTs) was allowed based on investigators’ clinical decisions – All data presented here are from patients who received alemtuzumab in the core CARE-MS II study Disability Assessment • EDSS was assessed by blinded raters at core study baseline and every 3 months • Disability outcomes – Change from core study baseline on EDSS – Proportion of patients improved, remained stable, or worsened on EDSS ■ Improvement and worsening were defined as ≥0.5-point decrease or increase, respectively, from core study baseline EDSS score – Sustained reduction in disability: decrease from core study baseline by ≥1 EDSS point confirmed over 3, 6, or 12 months for patients with baseline EDSS scores ≥2.0 Statistical Analysis • Analyses were based on Year 3 follow-up data on patients who had received alemtuzumab 12 mg in the core CARE-MS II study • Data from CARE-MS II patients who transitioned into the extension study were analyzed from the time of first treatment • Kaplan-Meier analysis of time to 3-, 6-, and 12-month sustained reduction in disability • Analyses were undertaken for all patients in the extension and for patients who received only 2 courses over 3 years RESULTS Patients • More than 90% (393 of 423) of patients who had received alemtuzumab 12 mg in CARE-MS II and completed the core study entered the extension • Approximately 80% did not receive re-treatment during Year 3 • Fewer than 3% of former alemtuzumab-treated patients received another DMT in Year 3 Disability Improvement • Mean EDSS scores were 2.7 at core study baseline, 2.5 at Year 2, and 2.6 at Year 3 (Figure 1) • Mean EDSS scores remained below pre-treatment values during the third year – Year 2 mean EDSS score change from core study baseline: −0.21 – Year 3 mean EDSS score change from core study baseline: −0.06 • At Year 3, 70% of alemtuzumab-treated patients had either stable or improved EDSS scores from core study baseline (Figure 2), similar to the results seen over Years 0–2 Acknowledgments and Disclosures CARE-MS II steering committee: Douglas L Arnold, Jeffrey A Cohen, Alasdair J Coles, D Alastair S Compston, Christian Confavreux*, Edward Fox, Hans-Peter Hartung, Eva Havrdova, Tamara Miller, Krzysztof W Selmaj, Cary L Twyman, and Howard Weiner. Genzyme: Aji Nair; Linda Kasten. CARE-MS II was sponsored by Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals. Editorial support for this poster was provided by Richard Hogan, Evidence Scientific Solutions, and was funded by Genzyme. G.G. reports receiving compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen-Idec, Five Prime Therapeutics, Genzyme, GW Pharma, Merck-Serono, Novartis, Roche, Synthon, Teva, and Vertex Pharmaceuticals. G.G. received compensation for serving as a journal editor for Multiple Sclerosis and Related Disorders and research support from Serono. D.H.M and J.P. report receiving personal compensation as employees of Genzyme. J.H. reports receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen Idec. Alemtuzumab is approved in Australia, the European Union, and Mexico for treatment of active RRMS defined by clinical or imaging features, in Brazil for treatment of relapsing forms of MS, and in Canada for patients with inadequate response to interferon beta or other DMTs. Rebif ® is a registered trademark of EMD Serono, 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, 1 DH Margolin, 2 J Palmer, 2 J Herbert 3 1 Queen Mary University of London, Barts and The London School of Medicine, London, UK; 2 Genzyme, a Sanofi company, Cambridge, MA, USA; 3 New York University Medical Center, New York, 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 • At Year 3, 66% of alemtuzumab-treated patients had either stable or improved EDSS scores from extension study baseline (data not shown) • Among patients whose EDSS score remained stable from baseline to Year 2, 75% either continued to remain stable or experienced improvement from Years 2–3 (Figure 3) • Among patients whose EDSS score improved from baseline to Year 2, 58% remained stable or improved further from Years 2–3 (Figure 3) Sustained Reduction in Preexisting Disability • At Year 3, more than one third of patients who had received alemtuzumab 12 mg in the core study attained improvement in preexisting disability sustained for 6 months, as measured by 6-month sustained reduction in disability (Figure 4) – About one quarter of the patients achieved 12-month sustained reduction in disability at Year 3 Durability of Effect • Mean EDSS score at Year 3 was 2.5 for patients who received 2 courses of alemtuzumab over 3 years – Year 3 mean EDSS score change from core study baseline was −0.16 in this patient subgroup • At Year 3, EDSS score was improved from core study baseline in 48% of patients who received 2 courses of alemtuzumab over 3 years and stable in a further 28% of patients (data not shown) • Among patients whose EDSS score remained stable from baseline to Year 2, 79% either continued to remain stable or experienced improvement from Years 2–3 (Figure 5) • Among patients whose EDSS score improved from baseline to Year 2, 61% remained stable or improved further from Years 2–3 (Figure 5) Sustained Reduction in Preexisting Disability • For patients who received only 2 courses of alemtuzumab over 3 years, the proportions achieving 3-, 6-, and 12-month sustained reduction in disability were 45%, 37%, and 28% at Year 3 (data not shown) CARE-MS=Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis; EDSS=Expanded Disability Status Scale. EDSS=Expanded Disability Status Scale Figure 1. EDSS Score over Time in the Core Study and Extension 0 6 12 18 24 30 36 3 9 15 21 27 33 426 419 422 410 416 373 370 419 419 415 413 367 364 0 2.00 2.40 2.60 2.20 2.80 Baseline EDSS 3.00 Follow-up Month No. of Patients EDSS Score Alemtuzumab 12 mg CARE-MS II Core Study Extension (N=423) Years 0–2 (N=369) Years 0–3 Proportion of Patients (%) 60 Improved Remained stable Worsened 50 40 30 20 10 0 46 30 25 24 30 45 (N=178) Improved Years 0–2 EDSS Shift Category (Baseline through Year 2) (N=112) Remained stable Years 0–2 Proportion of Patients at Year 3 (%) 60 70 80 Improved from Year 2 to Year 3 Remained Stable from Year 2 to Year 3 50 40 30 20 10 0 11.8 46.6 51.8 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=Expanded Disability Status Scale 35% 43% 0 6 12 18 24 30 36 0 10 20 30 40 50 Follow-up Month CARE-MS II Core Study Extension 321 280 241 222 200 172 162 3-Month SRD Proportion of Patients with Sustained Reduction in Disability (%) 29% 35% 321 290 262 245 221 190 182 6-Month SRD 22% 27% 321 294 275 263 245 215 207 12-Month SRD No. at Risk Figure 4. Percentage of Patients with 3-, 6-, and 12-Month Sustained Reduction in Disability CARE-MS=Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis; SRD=sustained reduction in disability 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=Expanded Disability Status Scale (N=148) Improved Years 0–2 EDSS Shift Category (Baseline through Year 2) (N=96) Remained stable Years 0–2 Proportion of Patients at Year 3 (%) 60 70 80 Improved from Year 2 to Year 3 Remained Stable from Year 2 to Year 3 50 40 30 20 10 0 12.2 48.6 54.2 25.0 CARE-MS=Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis; EDSS=Expanded Disability Status Scale
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Transcript of AAN 2014: Alemtuzumab Sustainded Improvement
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
kaups
Highlight
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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
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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
kaups
Highlight
kaups
Highlight
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
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) 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
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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
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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
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) 60
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80 Improved from Year 2 to Year 3
Remained Stable from Year 2 to Year 3
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012.2
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CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
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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
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Sco
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Alemtuzumab 12 mg
CARE-MS II Core Study Extension
(N=423)Years 0–2
(N=369)Years 0–3
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60 Improved
Remained stable
Worsened50
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30
20
10
0
46
302524
30
45
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ImprovedYears 0–2
EDSS Shift Category (Baseline through Year 2)(N=112)
Remained stableYears 0–2
Prop
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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
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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
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n of
Pat
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s w
ith S
usta
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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
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012.2
48.654.2
25.0
CARE-MS=ComparisonofAlemtuzumabandRebif®EfficacyinMultipleSclerosis;EDSS=ExpandedDisabilityStatusScale
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