Alemtuzumab in the treatment of multiple sclerosis

Figures & data

Table 1 Eligibility criteria for the CARE-MS-1 and CARE-MS-2 trials

CARE-MS-1 (alemtuzumab as first-line treatment)^Citation16

CARE-MS-2 (alemtuzumab after failure of disease-modifying therapy)^Citation17

Inclusion criteria • Age 18–50 years, either sex • Diagnosis of MS and cranial MRI scan demonstrating white matter lesions attributable to MS within 5 years • Onset of MS symptoms within 5 years • EDSS score 0.0–3.0 • ≥2 MS relapses within 24 months, with ≥1 relapse within 12 months Main exclusion criteria • Prior therapy for MS other than corticosteroids • Exposure to immunosuppressive or immunomodulatory agents other than systemic corticosteroid treatment • Previous treatment with a monoclonal antibody for any reason • Any progressive form of MS

Inclusion criteria • Age 18–55 years, either sex • Diagnosis of MS and cranial MRI scan demonstrating white matter lesions attributable to MS • Onset of MS symptoms within 10 years • EDSS score 0.0–5.0 • ≥2 MS relapses within 24 months, with ≥1 relapse within 12 months • ≥1 MS relapse during treatment with a beta interferon therapy or glatiramer acetate after having been on that therapy for at least 6 months within 10 years Main exclusion criteria • Previous treatment with alemtuzumab • Previous treatment with any investigational drug • Treatment with natalizumab, methotrexate, azathioprine or cyclosporine in the past 6 months • Previous treatment with mitoxantrone, cyclophosphamide, cladribine, rituximab, or any other immunosuppressive or cytotoxic therapy (other than steroid treatment) • Any progressive form of MS

Note: Data from Cohen et al¹⁶ and Coles et al.¹⁷

Abbreviations: EDSS, expanded disability status scale; MRI, magnetic resonance imaging; MS, multiple sclerosis; CARE-MS, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis.

Table 2 Baseline characteristics of patients enrolled in the CARE-MS-1 and CARE-MS-2 trials

	CARE-MS-1 (alemtuzumab as first-line treatment)^Citation16		CARE-MS-2 (alemtuzumab after failure of disease-modifying therapy)^Citation17,a
	IFN beta-1a (n=187)	Alemtuzumab 12 mg (n=376)	IFN beta-1a (n=202)	Alemtuzumab 12 mg (n=426)
Age, years	33.2±8.5	33.0±8.0	35.8±8.8	34.8±8.4
Sex, female	122 (65%)	243 (65%)	131 (65%)	281 (66%)
Mean EDSS	2.0±0.8	2.0±0.8	2.7±1.2	2.7±1.3
Mean disease duration	2.0±1.3	2.1±1.4	4.7±2.9	4.5±2.7
Mean number of relapses in previous year	1.8±0.8	1.8±0.8	1.5±0.8	1.7±0.9
Mean number of Gd-enhancing T1-weighted lesions	2.2±4.9	2.3±5.1	2.1±5.0	2.3±6.0
Mean number of T2-hyperintense lesions	7.3±9.9	7.4±9.0	9.0±10.4	9.9±12.3

Notes: Data presented as mean ± standard deviation unless otherwise stated;

a Alemtuzumab 24 mg arm not shown, as not included in primary efficacy analysis. Data from Cohen et al¹⁶ and Coles et al.¹⁷

Abbreviations: EDSS, expanded disability status scale; Gd, gadolinium; IFN, interferon; CARE-MS, Comparison of Alemtuzumab and Rebif® efficacy in Multiple Sclerosis.

Table 3 Efficacy outcomes of patients enrolled in the CARE-MS-1 and CARE-MS-2 trials

	CARE-MS-1 (alemtuzumab as first-line treatment)^Citation16			CARE-MS-2 (alemtuzumab after failure of disease-modifying therapy)^Citation17
	IFN beta-1a (n=187)	Alemtuzumab 12 mg (n=376)	P	IFN beta-1a (n=202)	Alemtuzumab 12 mg (n=426)	P
Relapses
Patients with relapse	75 (40%)	82 (22%)		104 (53%)	147 (35%)
Rate ratio (95% CI)		0.45 (0.320.63)	<0.0001		0.51 (0.39–0.65)	<0.0001
Risk reduction		55%			49%
Yearly relapse rate (95% CI)	0.39 (0.29–0.53)	0.18 (0.13–0.23)		0.52 (0.41–0.66)	0.26 (0.21–0.33)
Relapse-free patients (95% CI)	58.7% (51.1%–65.5%)	77.6% (72.9%–81.6%)	<0.0001	46.7% (39.5%–53.5%)	65.4% (60.7%–69.7%)	<0.0001
Disability
Patients with sustained accumulationa	20 (11%)	30 (8%)		40 (20%)	54 (13%)
Percentage of patients (95% CI)b	11.1% (7.3%–16.7%)	8.0% (5.7%–11.2%)	0.22	21.1% (16.0–27.7)	12.7% (9.9%–16.3%)
Hazard ratio (95% CI)		0.70 (0.40–1.23)			0.58 (0.38–0.87)
Risk reduction		30%			42%	0.0084
Mean change in EDSS from baseline (95% CI)	−0.14 (−0.29–0.01)	−0.14 (−0.25–0.02)	0.97	0.24 (0.07–0.41)	−0.17 (−0.29 to −0.05)	<0.0001
Mean change in MSFC from baseline	0.07	0.15	0.01	−0.04	0.08	0.002
MRI
Patients with new or enlarging T2-hyperintense lesions	99/172 (58%)	176/363 (48%)	0.04	127/187 (68%)	186/403 (46%)	<0.0001
Patients with Gd-enhancing lesions at 24 months	34/178 (19%)	26/366 (7%)	<0.0001	44/190 (23%)	38/410 (9%)	<0.0001

Notes:

a Confirmed over 6 months

b Kaplan–Meier estimation. Data from Cohen et al¹⁶ and Coles et al.¹⁷

Abbreviations: CI, confidence interval; EDSS, expanded disability status scale; Gd, gadolinium; IFN, interferon; MRI, magnetic resonance imaging; MSFC, multiple sclerosis functional composite; P, P-value; CARE-MS, Comparison of Alemtuzumab and Rebif® efficacy in Multiple Sclerosis.

Table 4 Comparison of selected adverse events across randomized studies with alemtuzumab

	CAMMS223^Citation15		CARE-MS-1^Citation16		CARE-MS-2^Citation17		Total
	IFN beta-1a (n=107)	Alemtuzumaba (n=216)	IFN beta-1a (n=187)	Alemtuzumab (n=376)	IFN beta-1a (n=202)	Alemtuzumaba (n=596)	IFN beta-1a (n=496)	Alemtuzumab (n=1,188)
Patients with adverse event	107 (100%)	215 (100%)	172 (92%)	361 (96%)	191 (95%)	587 (99%)	470 (95%)	1,163 (98%)
Discontinuation due to adverse event	13 (12%)	3 (1%)	11 (6%)	5 (1%)	15 (7%)	20 (3%)	39 (8%)	28 (2%)
Infusion-associated reactions	NA	213 (99%)	NA	338 (90%)	NA	549 (92%)	NA	1,100 (93%)
Infections	50 (47%)	142 (66%)	85 (45%)	253 (67%)	134 (66%)	468 (79%)	269 (54%)	863 (73%)
Serious infections	2 (2%)	9 (4%)	2 (1%)	7 (2%)	3 (1%)	22 (4%)	7 (1%)	38 (3%)
Thyroid disorders	3 (3%)	49 (23%)	12 (6%)	68 (18%)	10 (5%)	100 (17%)	25 (5%)	217 (18%)
Serious thyroid disorders	0	3 (1%)	0	4 (1%)	0	4 (0.7%)	0	11 (9%)
Blood and lymphatic system disorders	Not reported	Not reported	36 (19%)	66 (18%)	28 (14%)	84 (14%)	64 (17%)b	150 (15%)c
Serious immune thrombocytopenic purpura	0	5 (2%)d	0	3 (1%)	0	5 (<1%)	1 (<1%)	13 (1%)
Serious agranulocytosis	0	0	0	2 (1%)	0	0	0	2 (<1%)
Serious thrombocytopenia	0	0	0	0	0	1 (<1%)	0	1 (<1%)
Serious anemia	0	0	0	0	0	1 (<1%)	0	1 (<1%)
Serious febrile neutropenia	0	0	0	0	0	1 (<1%)	0	1 (<1%)
Malignant disease	0	0	0	2 (1%)	2 (1%)	5 (<1%)	2 (<1%)	7 (<1%)

Notes:

a 12 mg and 24 mg dose arms combined;

b percentage calculated for n=389;

c percentage calculated for n=972;

d one death attributed to serious immune thrombocytopenia. Data from CAMMS223 Trial Investigators et al,¹⁵ Cohen et al¹⁶ and Coles et al.¹⁷

Abbreviations: CAMMS, Campath-1H in Multiple Sclerosis; IFN, interferon; NA, not available; CARE-MS, Comparison of Alemtuzumab and Rebif® efficacy in Multiple Sclerosis.

Table 5 Comparison of the labeling for new generation multiple sclerosis treatments (as of September 29, 2013)

	Natalizumab	Fingolimod	Alemtuzumab	Teriflunomide
Indication	High disease activity despite treatment with a beta interferon or glatiramer acetatea Adult patients aged ≥18 years with rapidly evolving severe relapsing-remitting multiple sclerosisb	High disease activity despite treatment with a beta interferona Patients with rapidly evolving severe relapsing-remitting multiple sclerosisb	Relapsing-remitting multiple sclerosis with active disease defined by clinical or imaging features (ie, not recommended for patients with inactive disease or those stable on current therapy)	Relapsing-remitting multiple sclerosis
Posology	300 mg is administered by intravenous infusion once every 4 weeks. Careful reassessment daily of risk of PML required after 24 months of treatment	One 0.5 mg capsule taken orally once daily	12 mg/day administered by intravenous infusion for two treatment courses • Initial treatment course: 12 mg/day for 5 consecutive days (60 mg total dose) • Second treatment course: 12 mg/day for 3 consecutive days (36 mg total dose) administered 12 months after the initial treatment course	One 14 mg tablet taken orally once
Main special warnings and precautions for use	PML	Bradyarrhythmia, QT interval, infections	Autoimmunity (immune thrombocytopenic purpura, nephropathies, thyroid disorders, cytopenias)	Hepatic effects (monitoring of alanine aminotransferase recommended)
Date of approval by the European Medicines Agency	June 2006	March 2011	September 2013	August 2013

Notes:

a Defined as patients who have failed to respond to a full and adequate course (normally at least 12 months of treatment) of beta interferon or glatiramer acetate. Patients should have had at least one relapse in the previous year while on therapy and have at least nine T2-hyperintense lesions in cranial magnetic resonance imaging (MRI) or at least one gadolinium-enhancing lesion. A “nonresponder” could also be defined as a patient with an unchanged or increased relapse rate or on-going severe relapses as compared to the previous year

b two or more disabling relapses in 12 months, and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a recent MRI.

Abbreviation: PML, progressive multifocal leukoencephalopathy.

CohenJAColesAJArnoldDLCARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trialLancet201238098561819182823122652

 PubMed Web of Science ®Google Scholar

ColesAJTwymanCLArnoldDLCARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trialLancet201238098561829183923122650

 PubMed Web of Science ®Google Scholar

CAMMS223 Trial InvestigatorsColesAJCompstonDAAlemtuzumab vs interferon beta-1a in early multiple sclerosisN Engl J Med2008359171786180118946064

 PubMed Web of Science ®Google Scholar