Durable Effect of Alemtuzumab on MRI Lesion Outcomes Over
5 Years in Patients With Highly Active Relapsing-Remitting Multiple Sclerosis
Who Had an Inadequate Response to Prior Therapy
at Core Study Baseline (CARE-MS II)
Sven Schippling,1 Giancarlo Comi,2 Regina Berkovich,3 Alex Rovira,4 Daniel Pelletier,3 Anthony Traboulsee,5 Patrick Vermersch,6 David H Margolin,7
Karthinathan Thangavelu,7 Douglas L Arnold8,9; on behalf of the CARE-MS II and CAMMS03409 Investigators
1Neuroimmunology
4University
and Multiple Sclerosis Research, University Hospital Zürich and University of Zürich, Zürich, Switzerland; 2Vita-Salute San Raffaele University, Milan, Italy; 3University of Southern California, Los Angeles, CA, USA;
Hospital Vall d’Hebron, Barcelona, Catalonia, Spain; 5University of British Columbia, Vancouver, British Columbia, Canada; 6University of Lille, CHU Lille, LIRIC – INSERM U995, FHU Imminent, Lille, France;
7Sanofi Genzyme, Cambridge, MA, USA; 8NeuroRx Research, Montréal, Québec, Canada; 9Montréal Neurological Institute and Hospital, Montréal, Québec, Canada
OBJECTIVE
CONCLUSIONS
• To evaluate 5-year MRI outcomes in a subset of
patients with RRMS and highly active disease at
core study baseline who were treated with
alemtuzumab in CARE-MS II
• Efficacy of alemtuzumab on MRI outcomes, including BVL, was durable through Year 5 in patients with highly
active RRMS despite an inadequate response to prior therapy
• These results were observed with 97% of CARE-MS II extension patients with highly active disease remaining on
study, and 62% of patients receiving no additional alemtuzumab or other DMT treatment through 5 years
– The high retention rate compared with long-term studies of other DMTs in the highly active population
supports the robustness of these data
• These findings, along with improved clinical outcomes, suggest that alemtuzumab may provide a unique
approach for the treatment of RRMS patients with highly active disease, offering durable efficacy in the absence
of continuous treatment
MRI Analysis
• MRI scans were obtained at baseline and yearly thereafter, and
analyzed centrally at NeuroRx Research (Montréal, Canada) by
experts masked to treatment group assignment
• Assessments
– Proportion of patients free of MRI disease activity (no new
Gd-enhancing T1 and no new/enlarging T2 hyperintense
lesions), and proportion of patients free of new non-enhancing
T1 lesions
– NEDA was defined as absence of MRI disease activity and
clinical disease activity (relapses and 6-month confirmed
disability worsening, the latter defined as an increase from
core study baseline of ≥1.0 EDSS point [or ≥1.5 points if
baseline EDSS score=0])
– BVL was derived by brain parenchymal fraction (BPF) change,
and blinded scans were read by investigators at Cleveland
Clinic (Cleveland, OH, USA)
Statistical Analyses
• Treatment effect of the initial 2 courses in the core study was
assessed at Year 2; interim analyses for the extension study were
based on all available data through Year 5 (end of third year of the
extension study)
• Proportions of patients with lesions and MRI disease activity were
analyzed descriptively with percentages, and CIs were obtained
using the normal approximation to the binomial distribution
• Median percentage change from baseline BPF and annual
percentage change in BPF are presented
– Median annual change compares the BPF value of each year
to that of the previous year to compute percentage change
• Over half of patients (≥52%) achieved NEDA in Years 3, 4, and 5
(Figure 2)
• In each individual year through Year 5, ≥85% of patients were free
of Gd-enhancing T1 lesions (Figure 1A), ≥65% had no
new/enlarging T2 lesions (Figure 1B), and ≥65% were free of MRI
disease activity (Figure 1C)
• In Years 3, 4, and 5, 85%, 84%, and 89% of patients, respectively,
were also free of new non-enhancing T1 lesions
Figure 1. Durable Suppression of New Lesion and MRI
Disease Activity in the Core Study and the Extension
(A) Proportion Free of Gd-Enhancing T1 Lesions
62% of patients received no
alemtuzumab retreatment
100
80
87
85
87
92
100
Patients, % (95% CI)
New Lesion and MRI Disease Activity
Figure 2. Durable Efficacy of Alemtuzumab on NEDA in
the Core Study and the Extension
62% of patients received no
alemtuzumab retreatment
80
60
59
40
54
52
54
Y2
Y3
Y4
Y5
94
85
81
79
20
0
No. of Patients
Brain Atrophy
• BVL remained low in alemtuzumab patients through Year 5
(Figure 3A)
• Compared with the core study, patients had less yearly BVL in
Years 3–5 (Figure 3B)
Figure 3. Durable Slowing of BVL in the Core Study and
the Extension With Alemtuzumab
(A) BPF Change From Baseline
60
Alemtuzumab 12 mg
SC IFNB-1a 44 μga
40
20
0
No. of Patients
Y2
Y3
Y4
Y5
94
87
82
84
(B) Proportion Free of New/Enlarging T2 Hyperintense Lesions
100
80
60
71
65
68
Median BPF Change From
Baseline, % (95% CI)
• CARE-MS II was a phase 3, active-controlled, randomized,
head-to-head, rater-blinded, 2-year study of alemtuzumab versus
SC IFNB-1a (44 μg 3×/week) in patients with highly active RRMS
who had an inadequate response to prior therapy at baseline1
– Patients randomized to alemtuzumab 12 mg/day IV received
2 annual courses (on 5 consecutive days at baseline and on
3 consecutive days 12 months later)
• In the extension study, patients could receive additional treatment
with alemtuzumab (12 mg/day on 3 consecutive days ≥1 year after
the most recent course) as needed for relapse or radiological activity7
– Retreatment criteria were ≥1 protocol-defined relapse, or
≥2 new/enlarging T2 hyperintense and/or new gadolinium
(Gd)-enhancing T1 brain or spinal cord lesions on MRI
• Use of other licensed DMTs was permitted during the extension
per investigator discretion
• Highly active disease was defined as ≥2 relapses in the year prior
to randomization and ≥1 Gd-enhancing T1 lesion at core study
baseline
NEDA
• Of 435 patients treated with alemtuzumab 12 mg in CARE-MS II,
103 patients (24%) met the criteria for highly active disease at core
study baseline
• 92 (89%) of the 103 highly active patients entered the extension
study; of these, 89 (97%) remained on study through Month 60
(Year 5)
• Through 5 years, 57 (62%) patients did not receive alemtuzumab
retreatment or another DMT
– 57 (62%) patients did not receive retreatment with
alemtuzumab
– 89 (97%) patients did not receive another DMT
70
0.0
0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
-1.8
-2.0
40
0
No. of Patients
Y2
Y3
Y4
Y5
95
85
81
79
aHighly
100
80
65
67
70
40
20
0
No. of Patients
Y=year
71
Y2
Y3
Y4
Y5
94
85
81
79
-0.56
-0.54
-0.86
-0.99
-1.19
-1.19
-1.38
0
1
2
39
100
36
95
Year
3
4
5
–
87
–
81
–
81
active subgroup
(B) Median Annual BPF Change
(C) Proportion Free of MRI Disease Activity
60
62% of patients received no
alemtuzumab retreatment
No. of
41
Patients 102
20
Median Yearly BPF Change, %
(95% CI)
Study Design
Patients
Patients, % (95% Cl)
METHODS
RESULTS
Patients, % (95% Cl)
• Alemtuzumab is a humanized anti-CD52 monoclonal antibody
approved in >50 countries for the treatment of RRMS
• In patients with active RRMS who had an inadequate response
(≥1 relapse) to prior therapy at baseline (CARE-MS II;
NCT00548405), alemtuzumab demonstrated significantly greater
improvements on clinical and MRI outcomes versus SC IFNB-1a
over 2 years1
• The most frequent adverse events (AEs) observed with
alemtuzumab were infusion-associated reactions; other AEs of
interest included autoimmune AEs1
• Alemtuzumab demonstrated durable efficacy on clinical and MRI
outcomes and slowed brain volume loss (BVL) through 5 years in
an extension study (NCT00930553; 2-year core study plus 3 years
of extension) in the absence of continuous treatment; most
patients did not receive additional alemtuzumab 12 mg or other
disease-modifying therapy (DMT) during the follow-up period2,3
• Patients with highly active disease while on therapy present a
challenge for clinicians and should consider switching therapies,
so their response to alemtuzumab is of interest
• In the core CARE-MS II study, the subgroup of patients with highly
active disease at baseline who were treated with alemtuzumab
had significantly improved clinical and MRI outcomes versus
SC IFNB-1a, and greater proportions of patients showed no evidence
of disease activity (NEDA) over 2 years (24% vs 0%, P=0.0002)4-6
– Here we report their long-term (5-year) imaging outcomes
Patients, % (95% Cl)
INTRODUCTION
0.0
0
Y1
Y3
-0.01
-0.27
-0.2
-0.4
Y2
Alemtuzumab 12 mg
Y4
Y5
-0.20
-0.13
-0.56
-0.6
-0.8
-1.0
No. of Patients 100
95
86
References
Acknowledgments and Disclosures
1. Coles AJ, Twyman CL, Arnold DL, et al. Lancet
2012;380:1829-39. 2. Fox EJ, Arnold DL, Cohen JA,
et al. Mult Scler 2015;21(suppl 11):P1102.
3. Traboulsee A, Cohen JA, Coles AJ, et al. Mult Scler
2015;21(suppl 11):P1103. 4. Callegaro D, Krieger S,
Arnold DL, et al. Presented at LACTRIMS 2014;
November 26–29, 2014, Lima, Peru; Poster 124.00.
5. Krieger S, Arnold DL, Cohen JA, et al. Presented at:
CMSC; May 29–June 1 2013; Orlando, FL, DX01.
6. Confavreux C, Twyman CL, Arnold DL, et al.
Presented at: EFNS; September 8–11, 2012;
Stockholm, Sweden, SC345. 7. Fox EJ, Arnold DL,
Cohen JA, et al. Neurology 2013;80:S41.001.
CARE-MS II Steering Committee and CAMMS03409 Investigators. This poster was reviewed by Darren P Baker, PhD, and Colin Mitchell, PhD, of Sanofi Genzyme. Editorial support for the poster was provided by Karen Pemberton, PhD, Evidence
Scientific Solutions, and was funded by Sanofi Genzyme. CARE-MS II was funded by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals. SS: Consulting and/or speaking fees (Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva);
grant/research support (Novartis and Sanofi Genzyme). GC: Consulting fees (Actelion, Bayer Schering, Merck Serono, Novartis, Sanofi Genzyme, and Teva); lecture fees (Bayer Schering, Biogen, Dompé, Merck Serono, Novartis, Sanofi Genzyme,
Serono Symposia International Foundation, and Teva). RB: Consulting and/or speaking fees (Acorda, Avanir, Bayer, Biogen, Genentech, Novartis, and Teva). AR: Consulting and/or speaking fees (Bayer, Biogen, Bracco, Novartis, Sanofi Genzyme,
and Stendhal). DP: Consulting and/or speaking fees (Biogen, Novartis, Roche, Sanofi Genzyme, and Vertex) and grant/research support (Biogen). AT: Consulting fees (Biogen, Novartis, Roche, Sanofi Genzyme, Serono, and Teva Innovation); and
principal investigator on clinical trials (Roche and Sanofi Genzyme). PV: Honoraria and consulting fees (Almirall, Bayer, Biogen, GlaxoSmithKline, Merck Serono, Novartis, Sanofi Genzyme, and Teva); and research support (Bayer, Biogen, Merck
Serono, and Novartis). DHM and KT: Employees of Sanofi Genzyme. DLA: Compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support (Acorda, Bayer, Biogen, Canadian Institutes of Health
Research, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, MedImmune, Merck Serono, MS Society of Canada, NeuroRx Research, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi Genzyme, and Teva).
Previously presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 14−17, 2016; London, UK.
CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis
Rebif® is a registered trademark of Merck Serono Europe Ltd.
Alemtuzumab is approved in >50 countries around the world for treatment of adults with relapsing forms of MS. In the EU, it is approved to treat patients with relapsing-remitting MS with active disease defined by clinical or imaging features. In the
US, the indication provides that, because of its safety profile, the use of alemtuzumab should be reserved for patients who generally have had an inadequate response to 2 or more therapies indicated for the treatment of MS. This material may
contain information that is outside of the approved labeling in some countries.
Presented at the 24th Annual Meeting of the European Charcot Foundation, 24–26 November 2016, Baveno, Italy
Funding provided by Sanofi Genzyme
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