Active RRMS Patients Show Disability Improvements in Each Functional System Following - PowerPoint Presentation

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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

Rebif® 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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Background 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

CARE-MS II Core and Extension Studies: Design and Disposition for the Alemtuzumab Treatment Arm

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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

Analysis 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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76

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

32

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

17

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

Patients 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

95

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

CDI 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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CDI 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

ConclusionsAlemtuzumab 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

The 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

CARE-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

)

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