Results From the CAREMS II Extension Samuel F Hunter 1 Rany A Aburashed 2 Raed Alroughani 3 Steven M Bromley 45 Dominique Dive 6 Guillermo Izquierdo 7 Ho Jin Kim ID: 830022
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Slide1
Active RRMS Patients Show Disability Improvements in Each Functional System Following Treatment With Alemtuzumab: Results From the CARE-MS II Extension
Samuel F Hunter1, Rany A Aburashed2, Raed Alroughani3, Steven M Bromley4,5, Dominique Dive6, Guillermo Izquierdo7, Ho Jin Kim8, Jan Lycke9, Richard AL Macdonell10, Carlo Pozzilli11, Basil Sharrack12, Patrick Vermersch13, Andreas Lysandropoulos14, Luke Chung15, Nadia Daizadeh15, Heinz Wiendl16on behalf of the CARE-MS II and CAMMS03409 investigators
1Advanced Neurosciences Institute, Franklin, TN, USA; 2Institute for Neurosciences and Multiple Sclerosis, Owosso, MI, USA; 3Amiri Hospital, Sharq, Kuwait; 4South Jersey MS Center, Audubon, NJ, USA; 5Bromley Neurology PC, Linwood, NJ, USA; 6University Hospital Centre of Liège, Liège, Belgium; 7Virgen Macarena University Hospital, Seville, Spain; 8Research Institute and Hospital of National Cancer Center, Goyang, Korea; 9University of Gothenburg, Gothenburg, Sweden; 10Austin Health and Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia; 11Sapienza University of Rome, Rome, Italy; 12Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 13University of Lille, Lille, France; 14Sanofi, Naarden, The Netherlands; 15Sanofi, Cambridge, MA, USA; 16University of Münster, Münster, Germany
Presented by Samuel F Hunter
CMSC 2018
Presentation DX66
Slide2Rebif® is a registered trademark of EMD Serono Inc.CARE-MS=Comparison of
Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis.DisclosuresSamuel F Hunter: Consulting agreements, speaker honoraria, and grant/research financial support (AbbVie, Acorda, Actelion, ADAMAS, Avanir, Bayer HealthCare, Biogen Idec, Novartis, Osmotica, Questcor, Roche, Sanofi, Synthon, and Teva)Rany A Aburashed: Consulting and/or speaker honoraria, and scientific advisory boards (Bayer, Biogen, Genentech, Novartis, Sanofi, and Teva); research grants (Novartis)Raed Alroughani: Speaker honoraria, scientific advisory boards, and research grants (Bayer, Biogen, Biologix, Genpharm, GSK, Lundbeck, Merck Serono, Novartis, and Sanofi)
Steven M Bromley: Consulting and/or speaker honoraria (Acorda, Avanir, Biogen, Novartis, Sanofi, Teva, and UCB); research support (Biogen, Novartis, Sanofi)Dominique Dive: Institutional honoraria for advisory board participation and travel grants (Bayer, Merck Serono, Novartis, Sanofi, and Teva)Guillermo Izquierdo: Speaking and advisory fees (Almirall, Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva)Ho Jin Kim: Consulting and/or speaking fees (Bayer Schering Pharma, Biogen, Celltrion, Eisai, Genzyme, HanAllBioPharma, MedImmune, Merck Serono, Novartis, Teva-Handok, and UCB); research support (Genzyme, Merck Serono, Ministry of Science and ICT, Teva-Handok, and UCB); steering committee member (MedImmune); co-editor (Multiple Sclerosis Journal –Experimental, Translational, and Clinical); and associate editor (Journal of Clinical Neurology)Jan Lycke: Travel support and/or lecture honoraria (Biogen, Novartis, Sanofi, and Teva); scientific advisory boards (Almirall, Biogen, Novartis, Sanofi, and Teva); editorial board (Acta Neurologica Scandinavica); and unconditional research grants (Biogen, Novartis, and Teva
)
Richard
AL
Macdonell
:
Compensation for advisory boards and/or speaking fees (Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva); research support (Biogen, Merck, Novartis, Sanofi, and Teva)Carlo Pozzilli: Consulting and/or speaking fees, research, and travel grants (Actelion, Biogen, Merck, Novartis, Sanofi, and Teva)Basil Sharrack: Nothing to disclose Patrick Vermersch: Consulting fees and/or speaking fees, and research support (Almirall, Bayer, Biogen, Celgene, Merck Serono, Novartis, Sanofi, Servier, and Teva)Andreas Lysandropoulos, Luke Chung, Nadia Daizadeh: Compensation as employees of SanofiHeinz Wiendl: Consulting and/or speaking fees (Bayer, Biogen, Behring, EMD Serono, Fresnius Medical Care, Merck Serono, Novartis, Sanofi, Roche, and Teva); license fee payments (Huber-Verlag); grant/research support (Neotope Bioscience, Novartis, and PML Consortium)CARE-MS II (NCT00548405), and its extension study, CAMMS03409 (NCT00930553), were funded by Sanofi and Bayer HealthCare PharmaceuticalsEditorial and scientific support was provided by Darren P Baker, PhD, Ericka M Bueno, PhD, Steven J Cavalier, MD, Colin Mitchell, PhD, and Laura Saltonstall, MD, of Sanofi. Additional editorial support for this presentation was provided by Jaya Kolipaka, and Valerie P Zediak, PhD, of Envision Scientific Solutions, and was funded by Sanofi
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Slide3Background and ObjectiveDisability and neurologic impairments associated with MS manifest as changes in the individual functional systems (FS) of the EDSS
In CARE-MS II, patients with RRMS who had an inadequate response to prior therapy received 2 annual courses of alemtuzumab 12 mg/day IV (on 5 consecutive days at baseline and on 3 consecutive days 12 months later)Alemtuzumab significantly improved clinical outcomes, including mean EDSS scores, versus SC IFNB-1a over 2 years1 A significantly greater percentage of alemtuzumab-treated patients achieved 6-month confirmed disability improvement (CDI), possibly due to improved remyelination or plasticity after treatment with alemtuzumab1-3Evaluation of improvements in specific FS may provide further insights into the overall treatment effect with alemtuzumab
EDSS=expanded disability status scale; RRMS=relapsing-remitting multiple sclerosis; SC IFNB-1a=subcutaneous interferon beta-1a1. Coles AJ et al. Lancet 2012;380:1829-39; 2. Giovannoni G, et al. Neurology 2016;87:1985-92; 3. Bielekova B, et al. Neurology 2016;87:1966-67. CMSC 2018
Slide4CARE-MS II Core and Extension Studies: Design and Disposition for the Alemtuzumab Treatment Arm
CMSC 2018
Alemtuzumab
12
mg IV
n=435
a
C1
C2
As-needed
additional alemtuzumab courses
(≥12 months
after
previous course
) or other DMT
Core Study
48
12
0
36
60
Y1
Y2
Y3
Y4
Y5
Y6
72
24
Month
n=393
b
CARE-MS Extension
Study
Completed
c
n=338
Study Duration
1,2
78
% of patients remained in the study from core study baseline through Year 6
50% of patients received
no additional alemtuzumab courses and no other DMTs in the extension through Year 6
DMT=disease-modifying
therapy;
a
As-treated population;
b
Criteria
for treatment with additional alemtuzumab courses
:
≥
1 protocol-defined relapse, or ≥2 new/enlarging T2 hyperintense and/or new Gd-enhancing T1 lesions; other DMT permitted per investigator
discretion;
c
Data cutoff date: September 15, 2015
1.
Coles AJ et al. Lancet 2012;380:1829-39; 2. Fox EJ et al. Mult Scler 2016;22 (Suppl 3):1-917, P1160
Slide5Analysis of EDSS and FS ScoresChanges in EDSS and FS scores were analyzed in two different cohorts:
Overall populationImprovement: ≥1.0-point decrease from core study baselineStability:EDSS: ≤0.5-point change from core study baseline in either directionFS: 0-point change from core study baselinePatients with 6-month confirmed disability improvement (CDI) defined as those achieving a stringent criterion of ≥1.0-point EDSS decrease from core study baseline confirmed over 6 monthsAssessed in patients with an EDSS score of ≥2 at core study baselineFS change was assessed from the score obtained just prior to CDI onset date (re-baseline)Improvement: ≥1.0-point decrease from re-baselineStability: 0-point change from re-baseline
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Slide676
778085
772956255524
5325
51
24
53
Overall Population Over 6 Years: Improvements in EDSS Scores
Occurred in 24%–29% of Patients Overall population N=435; EDSS change from core study baseline was categorized as improved (≥1.0-point decrease) or stable (≤0.5-point change in either direction); Sum of percentages may differ due to roundingCore StudyExtension StudyPatients, %ImprovedStableCMSC 2018
Slide732
56315428
5329533349
77
79
82
85
75
Sensory30552755275230472846Pyramidal30
54
27
53
28
50
31
47
27
48
78
78
81
84
75
Patients, %
83
82
85
88
83
Cerebellar
Patients, %Core StudyExtension Study
Patients, %Overall population N=435; FS change from core study baseline was categorized as improved (≥1.0-point decrease) or stable (0-point change); Sum of percentages may differ due to rounding CMSC 2018
Overall Population Over 6 Years: While Majority of Patients Remained Stable in Each FS, 27%–33% Achieved ImprovementsCore StudyExtension StudyCore StudyExtension Study
ImprovedStable
Slide817
69176518
6419622161
18
67
20
62
18
612158195925662461236322632362
15
72
15
67
16
67
18
63
16
66
Patients, %
81
84
82
88
82
Brainstem
85
86
86
9185
81
83828682Visual7879
828578Bowel/BladderPatients, %Cerebral
Patients, %Patients, %CMSC 2018Overall population N=435; FS change from core study baseline was categorized as improved (≥1.0-point decrease) or stable (0-point change); Sum of percentages may differ due to rounding Overall Population Over 6 Years: While Majority of Patients Remained Stable in Each FS, 15%–25% Achieved Improvements
ImprovedStableCore StudyExtension Study
Core StudyExtension Study
Slide9Patients were more than twice as likely to achieve CDI with alemtuzumab compared with SC IFNB-1a in the core study Year 2The percentage of alemtuzumab-treated patients achieving CDI continued to increase from Year 2 to Year 6
aBased on n=435 (as-treated population); CDI was assessed only in patients with an EDSS score of ≥2.0 at core study baseline (alemtuzumab, n=297; SC IFNB-1a, n=111); CDI was defined as ≥1.0-point EDSS decrease from baseline confirmed over 6 months; Kaplan-Meier estimates were used to assess percentages of patients with 6-month CDICMSC 2018
Y1
Y2
Y3
Y4
Y5
Y6
0
19%
30%
36%
41%
42%
43%
10%
14%
Core Study
Extension Study
Patients,
%
Alemtuzumab 12 mg
SC IFNB-1a 44 µg
CDI Over 6 Years: 43
% of Alemtuzumab-Treated Patients
Achieved 6-Month
CDI on
EDSS
162% relative increase
a
with alemtuzumab vs SC IFNB-1a
Slide1095
94979297
9493CDI Over 6 Years: Improvements Occurred in Each Functional System Among Patients With 6-Month CDI
44
52
48
47
44
527022257272212469Analysis was performed at 6 months after CDI onset; FS change was assessed from the score obtained just prior to CDI onset date (re-baseline); Change from re-baseline in each FS score was categorized as improved (≥1.0-point decrease) or stable (0-point change); Sum of percentages may differ due to roundingCMSC 2018
Improved
Stable
Slide11CDI Over 6 Years: 71% of Patients With 6-Month CDI Achieved Improvements in Multiple Functional Systems
Analysis was performed at 6 months after CDI
onset; FS change was assessed from the score obtained just prior to CDI onset date (re-baseline); Improvement in FS score was defined as ≥1.0-point decrease from re-baseline29251417
Number of Improved Functional Systems
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Slide12CDI Over 6 Years: An Increase in the Percentage of Patients With an EDSS Score <4 After CDI Onset
a
EDSS score was obtained just prior to CDI onset date (re-baseline); Re-baseline n=126 (EDSS <4, n=96; EDSS ≥4, n=30)7624
96
4
EDSS <4
EDSS ≥4
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Baselinea6-Months After CDI OnsetIt is notable that improvements occurred after CDI onset even among patients with an EDSS score of ≥4 at baseline
Slide13ConclusionsAlemtuzumab stabilized or improved all FS of
the EDSS over 6 years in patients with RRMS who had an inadequate response to prior therapyWhile a majority of patients had stable FS scores over 6 years, 15%–33% of patients achieved a ≥1.0-point improvement from core study baselinePatients were more than twice as likely to achieve the stringent criterion of CDI after treatment with alemtuzumab vs SC IFNB-1a in the core study Year 2Percentage of patients achieving CDI with alemtuzumab continued to increase from Year 2 to Year 6Patients with CDI after alemtuzumab showed improvements in each FS 71% showed improvements in >1 FSA higher percentage of patients had an EDSS score <4 after CDI onset The robustness of these results is supported by the high retention rate (78%) from core study baseline
Improvement in multiple aspects of disability indicates a broad therapeutic effect with alemtuzumab in the absence of continuous treatmentCMSC 2018
Slide14The authors and Sanofi would like to thank
the patients for their participation in the trials, as well as the CARE-MS II Steering Committee and CAMMS03409 InvestigatorsCMSC 2018
Slide15CARE-MS and CAMMS03409 Study Group and Acknowledgments
ArgentinaDeriAustraliaBoundyBroadleyDreyerHodgkinsonKingMacdonell
McCombeNeilPaineReddelSchwartzVucicAustria
LeutmezerVass
Belgium
Dive
DuboisSindicEl SankariBrazil CallegaroFerreiraMartins (Marcio)Martins (Maurer)Tilbery CanadaAyotteBrunetFreedmanGrand’MaisonJacquesKremenchutzkyTraboulseeYeungIsraelAchironKarniVaknin-Dembinsky
Italy
Bertolotto
Capra
Durelli
Ghezzi
Mancardi
Marrosu
Pozzilli
Zaffaroni
Mexico
Santos
Venzor
Violante
Netherlands
Hupperts
van Munster
Poland
Członkowska
Kozubski
SelmajStelmasiakSzczudlik
Russia BarantsevichBelovaBoykoGusevMagzhanovMalkovaPerfiliev PoverennovaSazonovSokolovaSkorometsStolyarov
CroatiaAntonelliBrinarHabek
JankuljakKidemet-PiskaćTrkanjecVladicCzech RepublicBrichtaKovarovaRektorTalab
TalabovaDenmarkPetersenRavnborgSørensenFranceClanetDe SezeEdanLubetzkiMoreauVermerschGermany
BaumFörchHaasHemmerHerrlingerKöhlerMüllerOchsStangelTumaniUrbanZettl
ZiemannZiemssen United States (cont)Krieger
KrolczykLaGanke LallanaLathiLavaLynchMachanicMarkovic-PleseMattsonMillerMinagarMitchellMosesMuley
NegrosPachnerPardoPelletierPharrPiconeRemmelRiskindRizviRobertsonRossenRothsteinRoweSchaefferSheppardShubin
Silliman
Singer
SpikolStein
Steingo
Thadani
ThoitsThrowerTwymanVaishnav
Russia (cont
)YakupovZavalishin
SerbiaDinčićDrulovićNadj
ToncevVojinović
SpainArroyoIzquierdo AyusoMontalban
Oreja-GuevaraSanchezSwedenLyckeSvenningssonUkraineKobysMartsynkevychNehrychOrzheshkovskyiVoloshinaUnited Kingdom
ColesCompstonGiovannoniRobertsonRogScoldingSharrackUnited StatesAbou ZeidAgiusBassBigleyBomprezzi
United States (cont)BosterBowenBraleyCarterCascioneCohen CooperCraytonDunnEdwardsEliasEvansFabianFletcherFordFox
FrohmanGazda GiancarloGittGoodmanGottesmanGottschalkGrazioliGudesblattGuptaHerbertHoneycuttHughesHunterHuttonIoneteJanusJavedJonesJubeltJung
KaufmanKhan
KisterKitaUnited States (cont)VincentVollmerWaldmanWeinerWendtWingerchukWrayWynnNeurology Steering CommitteeCompston (UK)Arnold (CA)Cohen (US)Coles (UK)
Confavreux (FR) (in memoriam)Fox (US)
Hartung (DE)Havrdova (CZ)Selmaj (PL)Weiner (US)Data Monitoring Committee
Clifford (US)Barkhof (ND)Snydman (US)DeGroot (US)Cines (US)D’Agostino (US)
Antel (CA)
Panitch (US)
(in memoriam)
Relapse Adjudication Panel
Greenberg (US)
Kraus (AT)
Limmroth (DE)
Markowitz (US)
Naismith (US)
Tabby (US)
MRI Analyses
Arnold; NeuroRX (CA)
Fisher; CCF (US
)
CMSC 2018