International Journal of Clinical Medicine, 2013, 4, 459-471
http://dx.doi.org/10.4236/ijcm.2013.410082 Published Online October 2013 (http://www.scirp.org/journal/ijcm)
Alemtuzumab: A Place in Therapy for Treatment of
Multiple Sclerosis*
Teya M. Tietje1,2, Douglas R. Allington1,2, Michael P. Rivey1,2
1Skaggs School of Pharmacy, University of Montana, Missoula, USA; 2Pharmacy Department, Community Medical Center, Mis-
soula, USA.
Received August 24th, 2013; revised September 23rd, 2013; accepted October 4th, 2013
Copyright © 2013 Teya M. Tietje et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Alemtuzumab is a humanized mononclonal antibody known to cause rapid depletion of B- and T-cell lymphocytes.
Subsequent repletion of these lymphocytes leads to changes in adaptive immunity. Alemtuzumab is approved by the
United States Food and Drug Administration (FDA) for the treatment of B-cell lymphocytic leukemia but has been in-
vestigated off-label in recent years for treatment of autoimmune diseases, including multiple sclerosis (MS). In MS
treatment, alemtuzumab is administered as pulsed therapy, given once daily initially for 5 consecutive days and then for
3 consecutive days at 12-month intervals. Alemtuzumab has recently been compared to interferon beta 1-a in one phase
II and two phase III trials in patients with relapsing-remitting MS. Results from the studies show alemtuzumab com-
pared to interferon beta 1-a is associated with a greater reduction in the risk of sustained accumulation of disability and
is more effective in reducing disease relapse rates. The treatment of MS continues to be a healthcare challenge due to
the modest clinical benefit and adverse effect profiles of available disease modifying treatment options. Available data
suggest alemtuzumab may offer better efficacy outcomes compared to traditional disease modifying therapies in pa-
tients with MS. However, the agent has not been compared to other new disease modifying medications that have been
recently introduced.
Keywords: Alemtuzumab; Multiple Sclerosis; Monoclonal Antibody; Lymphocyte Depletion
1. Introduction
Multiple Sclerosis (MS) is a chronic, progressive in-
flammatory disease affecting the central nervous system
(CNS), resulting in demyelination and irreversible axonal
damage of nerves in the CNS. Abnormal activation of the
immune system against antigens results in disruption of
the blood-brain barrier (BBB) allowing inflammatory
mediators access to the CNS, leading to widespread in-
flammation and subsequent neurodegeneration. A result
of the destruction of myelin and central neurons is nerve
conduction abnormalities.
The clinical presentation of MS varies widely between
patients as well as during the disease course in individual
patients. Depending on the area of the brain and spinal
cord damage, symptomatic disease presentation consists
of a wide range of symptoms including weakness, fatigue,
paresthesias, ataxia, speech dysfunction, and cognitive
changes. Magnetic resonance imaging (MRI) evidence of
CNS plaques and dissemination of brain lesions is an
objective sign of possible MS [1,2]. The diagnosis of MS
incorporates a combination of clinical symptomatology
that cannot be attributed to another disease state or illness,
as well as MRI evidence. However, a symptomatic dis-
ease episode or a positive MRI scan is not independently
diagnostic and must be evaluated with other evidence
after consideration of differential diagnoses, thus making
MS a diagnosis of exclusion.
There are several subtypes of MS classified based on
clinical disease course, with the preponderance (ap-
proximately 85%) of patients experiencing a MS disease
course characterized by symptomatic episodes lasting at
least twenty-four hours followed by remission, or a
symptom-free period, lasting at least thirty days. This
clinical disease course is referred to as relapsing-remit-
ting multiple sclerosis (RRMS). Another MS subtype is
secondary progressive (SPMS) described as accrual of
disability with or without relapses; many patients with
RRMS eventually develop SPMS. Other disease subtypes
*The authors report no conflicts of interest in this work.

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 460
are primary progressive (PPMS), described as a slowly
progressive disease that begins at disease onset without
defined relapses, and progressive relapsing (PRMS) de-
scribed as a progressive disease starting at onset but with
relapses [1,3].
An optimal pharmacotherapeutic treatment plan has
not yet been determined for MS, and there is no cure.
Current MS pharmacotherapy is targeted at disease modi-
fication while incorporating acute and chronic treatment
of symptoms. Disease modifying therapies (DMT) used
in MS include interferon beta 1-a, immune modulators,
immunosuppressants, and monoclonal antibodies [4].
Monoclonal antibodies used in the treatment of MS tar-
get specific immune molecules on the surface of cells to
interfere with the inflammatory pathophysiological dis-
ease process.
Epidemiology of MS
An increase in prevalence of MS is seen above the 37th
latitude in Northern or Southern Hemisphere countries
including Australia, Europe, countries of the Mediterra-
nean, New Zealand and the United States, with the high-
est prevalence seen in Scotland at 145 - 193 cases per
100,000 people. Epidemiologic studies in the United
States have not been extensive; however, a north-to-
south gradient is seen with MS occurring in >50 indi-
viduals and ≤30 individuals per 100,000 people living
above and below the 37th parallel, respectively [5,6]. Mi-
gration studies have shown that persons who migrate
from an area of high to an area of low MS prevalence
have a risk intermediate to their habitation origin, whereas
persons who migrate from an area of low to high MS
prevalence maintain the low risk of their origin [7-9].
Several potential environmental risk factors for MS
including infection, physical environment, climate, diet,
and stress have been assessed for causality. Viral infec-
tions have long been an area of interest as precipitating
factors of MS. Studies have evaluated an association with
childhood viral infections including measles, mumps,
rubella and varicella, but data have failed to demonstrate
a link to MS development [10]. Epstein-Barr virus (EBV)
has gained the most interest as a potential environmental
factor for MS. An increased EBV antibody seropreva-
lence has been found to occur in MS patients compared
to controls [11,12]. While current evidence is not suffi-
ciently robust to confirm an increased risk of developing
MS in patients with prior EBV infection, research of the
association remains plausible [11,13-15]. More recently
Chlamydia pneumonia and viruses such as herpes sim-
plex and retroviruseshave drawn attention as potential
candidates for increasing the risk of developing MS but
conclusive data are lacking [10,16-18].
Studies evaluating exposure to sunlight and related vi-
tamin D concentrations have been mostly consistent in
their findings and suggest a decreased risk of MS devel-
opment in subjects with high levels of sun exposure be-
tween the ages of 6 and 15 years [19]. It has been sug-
gested that ultraviolet light may have immunosuppres-
sive effects and increases production of vitamin D in the
skin. Nevertheless, specific environmental risk factors
involved in the etiology of MS remain difficult to isolate
and quantify due to many other factors that contribute to
the development of MS, as well as confounding factors
expressed by genetically susceptible individuals [10].
Several genes are suspected to be associated with MS
development including human leukocyte antigen (HLA)
class I and II alleles, T-cell receptor alpha, and cytotoxic
T-lymphocyte antigen 4 (CTLA4). Results of studies
have shown an increased risk for first, second, and third
degree relatives of MS patients when compared to the
0.1% general population risk [20]. The greatest risk is
observed in an offspring of both parents with MS, with
30.5% of individuals developing the disease, compared
to 2.49% in offspring of a single parent with MS [21,22].
Additionally, the disease concordance rate is near 30% in
monozygotic twins compared to 4% in dizygotic twins. It
is interesting that the increased risk of developing MS in
the offspring of two MS positive parents is comparable to
that observed in monozygotic twins, independent of pa-
rental MS status [23,24].
2. Pathophysiology of MS
Our knowledge regarding the cellular responses and im-
munobiology associated with MS has benefitted substan-
tially by tissue sample analysis obtained from MS lesions
[25] and from over 70 years of animal research, primarily
using experimental autoimmune encephalomyelitis (EAE)
models [26]. Histologic examination of MS plaques has
documented CD4+ T-lymphocytes in perivascular spaces
and meninges and CD 8+ T-lymphocytes in the main
body of the MS lesion [27]. The specific type and num-
ber of cells differs between patients and within a given
patient as the MS lesion progresses from an acute to
chronic stage [28,29]. B-lymphocytes may act as antigen
presenting cells (APC) in the CNS, similar to their
known role in the peripheral immune system [30]. Oligo-
clonal bands of immunoglobulin (IgG) found in the cere-
bral spinal fluid (CSF) of MS patients and directly from
MS plaques indicate B-lymphocytes have an important
role in the escalated inflammatory response.
The demyelinating plaques of MS are dependent upon
the recruitment and entry of inflammatory cells into the
CNS. Once activated, CD4+ and CD8+ T-lymphocytes
and B-lymphocytes from the periphery cross the BBB.
Cellular migration from the periphery to the CNS is as-
sisted by integrin receptors on lymphocyte membranes

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 461
(VLA-4) and itsup-regulatedepithelial vascular cell ad-
hesion molecule ligand, VCAM-1 [31]. In the CNS,
APCs such as dendrites, B-lymphocytes, or macrophages
express major histocompatibility complexes (MHC Class
I or II) thatamplify inflammatory responses directed at
myelin basic protein (MBP), myelin oligodendrocyte
glycoprotein (MOG), and proteolipid protein (PLP).
T-cell phenotypes, primarily TH1 and TH17, produce cell
line specific chemokines, cytokines, interleukins, matrix
metalloproteinases (MMP), tumor necrosis factor-α and
other inflammatory components capable of causing direct
myelin injury [32]. B-lymphocyte directed antibodies
assist in demyelination through several proposed path-
ways that include direct antibody-dependent cell-medi-
ated cytotoxicity (ADCC), complement activation and Fc
receptor stimulation of macrophages, mast cells, or natu-
ral killer cells [33] (Figure 1).
3. Alemtuzumab
Alemtuzumab is a CD52 surface protein specific IgG1k
humanized monoclonal antibody. Alemtuzumab was
originally marketed under the brand name Compath-1H®
for the treatment of B-cell chronic lymphocytic leukemia
unresponsive to first-line therapy [34]. It was later evalu-
ated for use in autoimmune diseases such as autoimmune
hemolytic anemia (AIHA) and MS [35]. The remainder
of this article discusses alemtuzumab and its potential
role in the treatment of RRMS.
3.1. Mechanism of Action
Alemtuzumab exerts immunomodulatory effects in MS
through prolific T and B lymphocyte depletion and sub-
sequent repletion, resulting in long term changes in adap-
tive immunity [36-38]. The site of action for alemtuzu-
mab is human CD52 antigen, a surface protein expressed
on T and B lymphocytes, natural killer cells, dendritic
cells and monocytes. Interestingly, the exact biological
function of CD52 is unknown. During the differentiation
of leukocytes, CD52 antigen is expressed on peripheral T
and B lymphocytes; this occurs in both normal and
Figure 1. Immunopathogenesis of multiple sclerosis. R. C. Selter, B Hemmer, “Update on Immunopathogenesis and Immu-
notherapy in Multiple Sclerosis,” Immunotargets and Therapy, 2013, Vol. 2, pp. 21-30. Abbreviations: Treg, regulatory T cell;
NK cell, natural killer cell; IL, interleukin.

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 462
malignant cells, thereby explaining the development of
alemtuzumab as a chemotherapeutic agent [39,40]. Alem-
tuzumab adherence to the CD52 protein induces cell lysis
via complement deposition and formation of the mem-
brane attack complex [40]. Lymphocyte lysis and deple-
tion is proposed to promote removal of malignant lym-
phocytes and eliminate the involvement of normal lym-
phocytes in the inflammatory process.
As noted, several subtypes of T lymphocytes have
been implicated in the release of inflammatory mediators
in MS [41]. Specifically, subtype TH1 lymphocytes re-
lease proinflammatory cytokines associated with MS
relapses, thereby providing a pharmacotherapeutic target
for DMT. Moreover, there is a limited amount of CD52
antigen expressed on the surface of CD34+ hematopoietic
cells, which are parent stem cells to CD52+ lymphocytes
[40,42]. Decreased CD52 expression on the parent stem
cells allows for eradication of mature lymphocytes after
alemtuzumab administration without severe depletion of
bone marrow cells, allowing for subsequent reconstitu-
tion of lymphocytes [40].
3.2. Pharmacokinetics and Pharmacodynamics
The pharmacokinetics of alemtuzumab are intertwined
with the pharmacodynamics since pharmacokinetic pa-
rameters change as lymphocytes that express the CD52
antigen target of the drug are depleted [43]. Basically, the
clearance of the drug is dependent on CD52 availability.
This relationship contributes to large intersubject vari-
ability in alemtuzumab pharmacokinetics that is common
for monoclonal antibody agents that target antigens [44].
Alemtuzumab pharmacokinetics have been character-
ized in B-cell chronic lymphocytic leukemia and post
stem-cell transplant patients receiving the drug for cancer
chemotherapy, usually in combination with other anti-
neoplastic drugs [43-45]. No similar data are available in
the MS population and caution should be used when ex-
trapolating existing information. On the other hand,
alemtuzumab in some chemotherapy studies was given
by intravenous infusion in doses and regimens similar to
those utilized in the MS studies. Limited pharmacoki-
netic information is available from late 1990s studies in
rheumatoid arthritis patients, although doses used in
those studies were typically much larger than MS doses
[46].
It is believed that alemtuzumab serum concentrations
of 1 - 10 mcg/ml are associated with cellular processes
that mediate lymphocyte lysis. Results of studies in bone
marrow transplant patients have shown that 10 gm doses
given over 5 or 10 consecutive days resulted in mean
peak alemtuzumab concentrations of 2.5 mcg/ml and 6.1
mcg/ml, respectively; the drug could still be detected 11 -
23 days after the last dose [45]. Mould et al. [44] deter-
mined that the best pharmacokinetic model to describe
alemtuzumab was a two-compartment model with zero
order input and non-linear Michaelis-Menten elimination
strongly influenced by the covariate of the white blood
cell count [44].
While the half-life of a drug varies with concentration
and time in nonlinear kinetics (i.e. elimination slows with
subsequent doses), the elimination of alemtuzumab after
repeated doses is clearly prolonged. A half-life range of 5
- 9 days was determined in rheumatoid arthritis patients
receiving 100, 250, or 400 mg doses divided over 5 - 10
days [46]. A more prolonged half-life range of 15 - 21
days was measured after alemtuzumab 10 mg given for 5
or 10 days to patients in preparation for stem-cell trans-
plant [45]. Large interpatient variability has also been
seen for the volume of distribution (approximately 0.2
L/kg) of alemtuzumab in B-cell chronic leukemia pa-
tients; this is likely attributable to patient status but also
is caused by changes in CD52 antigen availability [44].
Since the mechanism of clearance of alemtuzumab from
the body is not completely understood, dosage adjust-
ments based on gender, age, or hepatic or renal function
are not available [43]. Furthermore, the clearance of
alemtuzumab has been correlated with clinical outcome
by Hale et al. [47] who found that chronic lymphocytic
leukemia patients who responded to treatment also had
slower clearance of the drug [47].
The pharmacodynamics of alemtuzumab are primarily
centered on lymphocytes that express the CD52 antigen.
Interindividual variability of pharmacodynamic proper-
ties of alemtuzumab is also great since baseline white
blood cell counts vary between patients and a wide range
of plasma concentrations of CD52 have been determined
in patients [43,44]. Lymphocyte depletion & reconstitu-
tion have been investigated in the MS studies. Consistent
with cancer studies, lymphocytes were rapidly depleted
days after and slowly reconstituted only months after
alemtuzumab treatment in the MS studies [45].
Hill-Cawthorne et al. [48] recently described lympho-
cyte reconstitution in 36 SPMS or PPMS patients treated
with alemtuzumab between1991-1997 and followed for
384 total person-years. The mean recovery time to the
lower end of the normal range was 7.1 months for B-cell
and 12.7 months for total lymphocyte counts. T-cell sub-
sets CD4+ and CD8+ counts had median recovery times
of 20 and 35 months, respectively, but did not return to
baseline levels in approximately 70% of patients. In the
Phase II and III trials, B-cell lymphocytes reconstituted
within 6 months, whereas T-cell lymphocyte recovery
was slower and only approached the lower limit of nor-
mal after one year [49-51].
Finally, alemtuzumab-binding antibodies can be de-
tected in about 30% of treated MS patients before the
second course of therapy and increases to over 80% one

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 463
month following that course. However, no association
has been determined for the appearance of the antibodies
and effects on alemtuzumab clinical efficacy, safety, or
lymphocyte effects [49-51].
4. Clinical Trials of Alemtuzumab
Alemtuzumab has been studied in comparison to inter-
feron beta-1a as an initial DMT treatment option in
RRMS, and for treatment of RRMS patients who have
relapsed despite previous first-line treatment. Results are
available from open-label and clinical phase II and phase
III trials (Table 1).
4.1. Open Label, Non-Controlled Trials
Cautious treatment of patients with SPMS began in 1991
when a trial was initiated to investigate alemtuzumab’s
effect [52]. This continued through 1999, with a total of
36 patients with SPMS being treated. Evidence of re-
duced annualized relapse rate (ARR) in patients (0.7 -
0.001, P < 0.001) was seen, as well as an absence of new
lesions identified on MRI; however, accumulation of
disability and cerebral atrophy continued in the patients.
This prompted a change in strategy to treat RRMS pa-
tients prior to onset of SPMS.
The subsequent cohort consisted of 22 RRMS patients
Table 1. Clinical trial summaries for alemtuzumab in MS.
ARR Mean EDSS
Study & duration Subject Characteristics Regimen nBefore
tx
Following tx
(reduction %)
Before
tx
Following tx
(Δ EDSS)
Comments
Coles et al. [52]
Follow-up:
29 months
RRMS
77% female
Alemtuzumab
20 mg 22 2.940.19 (94%) 4.83.6 (−1.2)
Hirs et al. [53]
Follow-up:
22 months
RRMS
Mean age: 34 years
62% female
Alemtuzumab
12 - 30 mg 392.440.19 (92%)4.454.09 (−0.36)
Fox et al. [36]
Follow-up:
24 months
RRMS
Mean age: 37 years
76% female
Alemtuzumab
24 mg 451.60.17 (94%)2.31.92 (−0.38)
CAMMS223 [49]
Phase II first-line
therapy
Follow-up:
36 months
Untreated RRMS
Mean age: 32 years
64% female
Alemtuzumab
12 mg
Alemtuzumab
24 mg
IFNβ1a
44 mcg
112
110
111
≥ 2.3
≥ 2.2
≥ 2.2
0.11 (69%)
0.08 (79%)
----
1.9
2.0
1.9
1.58 (−0.32)
1.55 (−0.45)
2.28 (0.38)
6 month SAD: 75% TE in 12 mg
group (P < 0.001); 67% TE in 24
mg group (P < 0.003)
Median change in lesion load on
T2-weighted MRI: −17.7 in 12 mg
group and −19.2 in 24 mg group vs
−12.1 in IFNβ1a group (P = 0.01)
CAMMS223 [54]
five-year extension
Follow-up:
60 months
Patients from
CAMMS223
Alemtuzumab
12 mg
Alemtuzumab
24 mg
IFNβ1a
44 mcg
112
110
111
0.12 (66%)
0.11 (71%)
0.35
1.19
2.0
1.9
1.04 (−0.15)
1.56 (−0.44)
0.46
SAD from baseline to month 60:
69% TE in 12 mg (P = 0.0005);
75% TE in 24 mg (P = 0.0001)
CARE-MS I [50]
Phase III
first-line therapy
Follow-up:
2 years
Untreated RRMS
Mean age: 33 years
65% female
Alemtuzumab
12 mg
IFNβ1a
44 mcg
376
187
1.8
1.8
0.18
0.39
2.0
2.0
1.6 (−0.14)
1.6 (−0.14)
SAD: Rates did not differ
between groups (P = 0.22)
MRI: gadolinium-enhancing
lesions: 7% in alemtuzumab group
vs 19% in IFNβ1a group (P < 0.0001);
new or enlarged T2-hyperintense
lesions: 48% in alemtuzumab group
vs 58% in IFNβ1a group (P = 0.04)
CARE-MS II[51]
Phase III – previous
use of DMT
Follow-up:
2 years
RRMS post-tx relapse
Mean age: 35 years
67% female
Mean # of previous
MS drugs used: 1
Alemtuzumab
12 mg
Alemtuzumab
24 mg
IFNβ1a
44 mcg
435
161
202
1.7
1.6
1.5
0.26
----
0.52
2.7
2.7
2.7
2.53 (−0.17)
----
2.94 (0.24)
SAD vs IFNβ1a: 13% in
alemtuzumab groups vs 20%
in IFNβ1a group; 42% RR in
alemtuzumab group (P = 0.0084)
MRI: New or enlarging
T2-hyperintense lesions: 46% of
patients in alemtuzumab group vs
68% in IFNβ1a group (P < 0.0001);
gadolinium-enhancing lesions: 9%
in alemtuzumab group vs 23%
in IFNβ1a group (P < 0.0001)
Abbreviations: ARR – annualized relapse rate; DMT – disease modifying therapy; EDSS – expanded disability status scale; IFNβ1a – interferon beta-1a; ITP –
immune thrombocytopenic purpura; MRI – magnetic resonance imaging; RR – risk reduction; RRMS – relapsing remitting multiple sclerosis; SAD – sustained
ccumulation of disability; TE – treatment effect; tx – treatment; vs – versus (compared to). a

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 464
who had previously failed treatment or had high relapse
rates, indicating rapidly progressing disease and poor
prognosis. Patients received 20 mg of intravenous alem-
tuzumab daily for five consecutive days, with the option
of a three-day re-treatment after 12 - 18 months and
again after 12 - 30 months. Nineteen (86%) patients re-
ceived a second course, and three (14%) patients re-
ceived a third course of alemtuzumab following disease
relapses. Relapse rates were compared using ARR, and
changes in expanded disability status scale (EDSS)
scores were used to assess accumulation of disability.
After a mean 29-month follow-up, a 94% improvement
in ARR (P < 0.001) was seen and EDSS scores had im-
proved by an average of 1.2 points. The difference in
disability outcomes between the SPMS and RRMS pa-
tients suggested the optimal time for alemtuzumab treat-
ment was earlier in the disease process, prior to progres-
sion to SPMS [52].
The promising results in the Coles et al. [52] RRMS
trial prompted another trial of alemtuzumab in 39 pa-
tients with aggressive RRMS and a poor prognosis [53].
Thirty-two (82%) patients were treatment-naïve and
seven (18%) had previously failed DMT. Alemtuzumab
doses were not consistent for all trial subjects due to
changesas new information became available. However,
all subjects received five consecutive days of 12 - 30 mg
alemtuzumab and three consecutive days of 1 g methyl-
prednisolone at the beginning of treatment. Retreatment
occurred in 13 (33%) patients an average of 17 months
after the first treatment, and three (8%) patients received
a third treatment an average of 19 months later. Com-
parison of pre- and post-treatment ARRs demonstrated a
mean difference of 2.27 (P < 0.0001), representing a 92%
overall reduction in ARR. The mean change in EDSS
after 23 months of follow-up was 0.2 for patients with
stable EDSS scores prior to treatment and 0.6 in patients
with unstable baseline EDSS scores [53].
In 2012, Fox et al. [36] published results of a study
conducted in 45 RRMS patients who previously received
interferon beta (IFNβ) for at least six months within two
years prior to the study and had two confirmed relapses
during IFNβ treatment. All patients received an initial
five consecutive days of alemtuzumab therapy and a
three-day retreatment 12 months later. At the 24-month
follow-up, a 94% reduction in ARR (P < 0.0001) and a
mean improvement in EDSS of 0.38 (P = 0.0542) were
determined for the alemtuzumab compared to prior treat-
ment period [36].
4.2. Active Comparator Trials
4.2.1. CAM MS223
The CAMMS223 study was a randomized, blinded,
phase II trial to compare the effects alemtuzumab and
interferon beta 1-a on ARR and sustained accumulation
of disability (SAD) in previously untreated RRMS pa-
tients. This study enrolled patients from December 2002
to July 2004. Patients assigned to receive alemtuzumab
were administered either 12 mg (n = 113) or 24 mg (n =
110) intravenously per day for five consecutive days
during the first month of therapy, then subsequently for
three consecutive days at 12 and 24 months. The inter-
feron beta 1-a patients (n = 111) were titrated up to a
dose of 44 mcg subcutaneously three times a week dur-
ing the study. A disease relapse was defined as the ap-
pearance of new or worsening MS symptoms accompa-
nied by a change in the neurologic examination lasting at
least 48 hours and having been preceded by at least 30
days of clinical stability. The EDSS was used to assess
disability, with SAD being defined as an EDSS score
increase of ≥1.5 points for patients with a baseline score
of 0 and ≥1 for patients with a baseline score of 1 or
above. SAD was recorded from the date of qualifying
increase in EDSS, and confirmed by EDSS scores twice
during a six-month period. Patients had a mean follow-up
of 36 months [49].
Alemtuzumab ARRs compared to the interferon beta
1-a group were significantly reduced by 69% and 79% (P
< 0.001 with a NNT of 3.1 and 3.9) in the 12 mg and 24
mg groups, respectively. At 36 months, the ARR in the
pooled alemtuzumab groups was 0.10 compared to 0.36
for the interferon beta 1-a group. Compared to interferon
beta 1-a, alemtuzumab therapy was associated with re-
ductions in risk of SAD after six months of 75% (P <
0.001) and 67% (P < 0.001) in the 12 mg and 24 mg
groups, respectively. The number needed to treat (NNT)
with alemtuzumab compared to interferon beta 1-a to
avoid one patient progression to SAD in a 36-month
study period was 5.6 in the 12 mg and 6.0 in the 24 mg
alemtuzumab groups. The mean EDSS scores signifi-
cantly improved by 0.32 and 0.45 in the alemtuzumab
groups, compared to a worsening of 0.38 in the interferon
beta 1-a group. Finally a reduction in the volume of le-
sions on T2-weighted MRI was seen in all study groups,
but was significantly more marked after alemtuzumab
compared to interferon beta 1-a treatment (P = 0.005).
Two notable aspects regarding alemtuzumab dosage
emerged in the CAMMS223. First, outcomes for the two
alemtuzumab dosage groups were not significantly dif-
ferent. Second, in September 2005 during the study,
alemtuzumab dosing was temporarily suspended after
three subjects were diagnosed with immune thrombocy-
topenia (ITP), an antibody and cell mediated suppression
and destruction of platelets. The suspension caused two
(1%) patients in the trial to not receive alemtuzumab
therapy at month 12 and 155 (75%) patients to not re-
ceive alemtuzumab at the 24-month dosing time. The
study protocol was amended to include formal monitor-

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 465
ing for ITP, and alemtuzumab was resumed. But notably,
no significant differences in treatment effect on disability
or safety were seen between patient subgroups who re-
ceived two cycles and those who received three cycles of
alemtuzumab.
Adverse events occurred in >99% of all study partici-
pants with the most common being infusion-related reac-
tions in all groups. Serious infusion reactions occurred in
three alemtuzumab patients with one patient discontinu-
ing the drug as a result, whereas two interferon beta 1-a
patients discontinued treatment due to infusion reactions.
Mild to moderate infections and thyroid dysfunction
were more frequent in patients receiving alemtuzumab
than those receiving interferon beta 1-a. Infection rates
were highest during the month following an infusion, but
no infections were life-threatening or fatal. Thyroid dys-
function occurred up to 30 months after the last dose of
study medication, with serious thyroid events occurring
in three alemtuzumab-treated patients. Six alemtuzumab
and 1 interferon beta 1-a patients developed ITP over a
mean follow-up period of 4.5 years; the difference was
not statistically significant. The overall incidence rate of
ITP for all patients treated with alemtuzumab was 6.2 per
1000 person-years, with 4.2 per 1000 person-years in the
12 mg group and 8.0 per 1000 person-years in the 24 mg
group, respectively. In comparison, the rate of ITP in the
interferon beta 1-a treated patients was 2.7 per 1000 per-
son-years. Study dropouts occurred not only due to ad-
verse events but also due to lack of DMT efficacy; 83%
of all alemtuzumab and 59% of interferon beta 1-a pa-
tients completed the 36-month study.[49]
An extension to the CAMMS223 study was initiated in
August 2006, four years after initial enrollment into the
first study. [54] The extension study was composed of
198 of the original 334 participants and included patients
from each of the three treatment (alemtuzumab 12 mg
and 24 mg and interferon beta 1-a 44 mcg) groups. Of
the original study groups, 47 patients (42%) who contin-
ued interferon beta 1-a and 151 patients (68%) who re-
ceived alemtuzumab 36 to 48 months earlier were as-
sessed in the extension study. Outcomes were assessed
from baseline of the original trial period to 60 months.
During the extension period, all patients were permitted
to use other DMTs for MS including interferon beta 1-a.
In 2008, patients in the alemtuzumab groups were given
the option to receive additional alemtuzumab 12 mg per
day for 3 consecutive days, but the majority of patients
did not receive additional alemtuzumab.
Results of the extension study showed that, compared
with interferon beta 1-a, alemtuzumab decreased the risk
of SAD by 69% (p < 0.0001) in the 12 mg group and
75% in the 24 mg group (p < 0.0001) and decreased the
ARR by 66% (p < 0.0001) in the 12 mg group and 71%
(p < 0.0001) in the 24 mg group [54]. The ARR in the
pooled alemtuzumab groups compared to the interferon
beta 1-a group was significantly (P < 0.0001) lower for
the baseline to the 5-year assessment (0.11 versus 0.35)
and was lower, although not statistically significant for
the 3-year to 5-year time period (0.14 versus 0.28, P =
0.072). The mean EDSS score decreased in both alemtu-
zumab groups while an increased mean EDSS score was
experienced in the interferon beta 1-a group [54].
Adverse effects of alemtuzumab were similar to those
seen in the original study. Infections due to alemtuzumab
decreased in frequency as the extension study progressed
and no life-threatening or fatal infections occurred; only
herpes zoster infections occurred more commonly in the
alemtuzumab compared to interferon beta 1-a patients at
the end of the extension study. Similarly, autoimmune
adverse effects decreased during the extension study,
with thyroid autoimmunity being the most common event
[54].
4.2.2. C AR E-MS I
Results of the CARE-MS I study, a phase III trial com-
paring alemtuzumab to interferon beta 1-a as first line
therapy, were released in 2012 [50]. The study enrolled
563 patients with confirmed, active, and untreated RRMS
who had the disease less than five years and had suffered
at least two relapses in the previous two years, with the
most recent relapse being within the previous year. Pa-
tients also had an EDSS score of no greater than 3. Pa-
tients were randomized in a 2:1 ratio to receive a 12 mg
of alemtuzumab intravenous infusion for five days at
study initiation and three days at 12 months, or were ti-
trated to interferon beta 1-a 44 mcg administered subcu-
taneously three times a week. All patients also received
methylprednisolone 1 g daily by the intravenous route for
3 consecutive days at study enrollment and at 12 months.
Patients were excluded if they previously received MS
DMT, including immunosuppressive, investigational, or
monoclonal antibody therapy, or if they had a progres-
sive MS disease course or other clinically significant
autoimmune disorder. Because of concern for an in-
creased herpes virus infection rate, the study protocol
was amended and alemtuzumab patients received oral
acyclovir 200 mg twice daily as prophylaxis. Acyclovir
was given on alemtuzumab infusion days and for the next
28 days [50].
Primary efficacy outcomes assessed were MS RR and
time to SAD confirmed over a 6-month period. MS re-
lapse and SAD were defined the same as in CAMM223.
Patients who did not experience a MS relapse or suffer
SAD were defined as free of clinical disease activity.
Secondary study outcomes included aspects of changes
in the primary efficacy outcomes, brain MRI changes
including the presence of both gadolinium-enhancing
lesions and new or enlarging T2-hyperintense lesions,

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 466
and safety reflected by adverse events [50].
Alemtuzumab reduced the MS RR at 2 years when the
study concluded, with 77.6% of patients who received
alemtuzumab relapse-free, compared to 58.7% of inter-
feron beta 1-a patients (P < 0.0001). However, there was
no difference between treatment groups for SAD rates,
observed in 8% of alemtuzumab compared to 11% of
interferon beta 1-a patients (P = 0.22). Interestingly, the
SAD rate in the interferon beta 1-a group was less than
half the rate that had been determined in the CAMMS223
study. A significant difference was seen for the secon-
dary outcome of 2-year clinically disease-free prevalence,
occurring in 279 (74%) alemtuzumab compared to 104
(56%) interferon beta 1-a patients (P < 0.0001).
Mixed results were observed for the MRI radiological
outcomes. There was no difference (P = 0.31) in the me-
dian change in volume of T2-hyperintense lesions be-
tween groups, although alemtuzumab compared to inter-
feron beta 1-a was associated with a decreased propor-
tion of patients with new or enlarging T2-hyperintense
lesions(48% versus 58%, p = 0.04). Moreover, there
were significantly fewer patients in the alemtuzumab
group with gadolinium-enhancing lesions at 24 months
(7% versus 19%, P < 0.0001), as well as a significantly
smaller median change in brain parenchymal fractions
(−0.867% alemtuzumab and −1.488% interferon beta 1-a,
P < 0.0001). When the clinical and MRI disease-free
results were combined, the joint outcome was found in
139/360 (39%) alemtuzumab and 46/172 (27%) inter-
feron beta 1-a patients, respectively (P = 0.006) [50].
At least one adverse event occurred in 96% of patients
receiving alemtuzumab and 92% of patients receiving
interferon beta 1-a. As seen in the CAMMS223 study,
the most frequently observed adverse events in alemtu-
zumab patients were infusion-related reactions (90%)
and of these, 3% were serious reactions. Infections (67%
versus 45% of patients) and thyroid dysfunction (18%
versus 6% of patients) occurred more frequently in
alemtuzumab compared to interferon beta 1-a treated
patients, but the occurrences were predominantly mild to
moderate in severity. Acyclovir prophylaxis was not
found to lessen the risk of herpetic infection in alemtu-
zumab patients. Three alemtuzumab patients developed
ITP, of which two were successfully treated and one re-
solved spontaneously [50].
4.2.3. C ARE-MS II
Nearly concurrent with CARE-MS I, the phase III
CARE-MS II study was conducted in RRMS patients
who had MS relapse despite treatment with first line
DMT [51]. Trial design mirrored that of the CARE-MS I
study, but patients admitted to the CARE-MS II study
had MS no longer than 10 years, an EDSS score less than
5, and must have suffered a MS relapse after at least 6
months of treatment with interferon beta 1-a or glati-
ramer. Approximately 70% of patients had previously
used a single MS medication, 23% had used two MS
medications, and less than 7% had used more than two
MS medications [51].
Patients were randomized in a 2:2:1 ratio to receive
alemtuzumab 12 mg or 24 mg or interferon beta 1-a 44
mcg given in the same regimen used for other studies. In
December of 2008 after 14 months of subject recruitment,
randomization to the alemtuzumab 24 mg arm was ter-
minated to facilitate more rapid recruitment into the other
two groups. As such, final subject groups were composed
of 436 patients in the alemtuzumab 12 mg, 173 patients
in the alemtuzumab 24 mg, and 231 patients in the inter-
feron beta 1-a groups. Follow-up for the study was 24
months, and 755 (90%) of participants completed the
study. Primary and secondary outcomes assessed were
the same as those in the MS-CARE I study, using the RR
and time to 6-month SAD as primary endpoints [51].
Results of the CARE-MS II demonstrated superiority
of alemtuzumab compared to interferon beta 1-a for pri-
mary study outcomes [see Table 1]. Due to the ran-
domization change, only the alemtuzumab 12 mg group
was included for the primary endpoint comparisons with
interferon beta 1-a. Alemtuzumab reduced the ARR
49.4% (P < 0.0001) over that observed in the interferon
beta 1-a group, with relapses occurring in 35% of alem-
tuzumab and 53% of interferon beta 1-a patients, respec-
tively. A 42% (P = 0.0084) reduced risk of SAD was
observed with alemtuzumab, affecting 13% alemtuzumab
versus 20% interferon beta 1-a patients. Significant
benefits associated with alemtuzumab were also found
for the mean change in EDSS score during the study and
the percentages of patients who were relapse-free, had
sustained reduction in disability for 6 months, had new or
enlarging lesions on MRI, and were clinically plus MRI
disease-free. When the alemtuzumab 12 mg and 24 mg
groups were compared for clinical outcomes, only new
MRI lesion formation was improved with the larger dos-
age [51].
A subgroup analysis was conducted in patients with
highly active RRMS (≥2 relapses in the year prior to
randomization and ≥1 gadolinium enhancing lesion at
baseline) who had relapsed while receiving DMT. The
subgroup consisted of 101 patients (23.7%) in the alem-
tuzumab 12 mg group and 42 patients (20.8%) in the
interferon beta 1-a group. After two years, 24.2% of 101
patients treated with alemtuzumab were disease-activity
free compared to 0% of 42 patients treated with inter-
feron beta 1-a (P = 0.0002); 35.8% of patients in the
alemtuzumab subgroup had relapses compared to 60% in
the interferon beta 1-a subgroup, 7.4% had SAD com-
pared to 17.5% in the alemtuzumab and interferon beta
1-a subgroups, respectively [55].

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 467
Adverse events occurred in 98% of alemtuzumab
treated patients and 95% of patients treated with inter-
feron beta 1-a [51]. The alemtuzumab 24 mg group was
separately included in the safety analysis and more
commonly caused infusion-related adverse events, al-
though serious infusion-related events occurred in only
3% of patients in each group. As seen in other studies,
alemtuzumab at either dose compared to interferon beta
1-a was associated with a greater incidence of infections
(78% versus 66%), thyroid disorders (17% versus 5%),
and autoimmune thrombocytopenia (7 versus no patients);
all of the adverse effects were slightly more common in
the alemtuzumab 24 mg group [51].
5. Safety and Tolerability
Safety issues consistently observed in studies of alemtu-
zumab include common infusion-related reactions, in-
creased risk of mild to moderate infections, and autoim-
munity that is primarily directed at the thyroid, but in
some cases causes ITP (Table 2). Autoimmunity is
thought to be the result of a combination of alemtuzu-
mab-induced lymphopenia and increased IL-21 levels
[56,57]. Lymphopenia is induced after a single dose of
alemtuzumab and persists for several years after a five-
day course. Repopulation of lymphocytes leads to a
change in lymphocyte proportions and altered functional-
ity of T cells, resulting in highly proliferative self-reac-
tive T cells. IL-21 was found to induce T cell prolifera-
tion and apoptosis, [56] making the combination of al-
tered T cell functionality and overproduction of IL-21 a
feasible cause of alemtuzumab-induced autoimmunity
[56,57].
The occurrence of adverse events per person-year
ranged from 7.2 - 8.66 in alemtuzumab 12 mg groups
compared to 4.94 - 5.69 in interferon beta 1-a groups in
the three primary studies; the incidence for alemtuzumab
12 mg dropped to 5.67 compared to 4.49 with interferon
beta 1-a in the CAMMS223 extension study. However,
the incidence of serious adverse effects was not different
between treatment groups. Moreover, drug discontinua-
tion due to adverse effects was notably decreased in the
alemtuzumab (1% - 3%) compared to interferon beta 1-a
(6% - 12.1%) groups; this was a statistically significant
(p < 0.001) finding in the CAMMS223 study.
Infusion reactions due to alemtuzumab can largely be
controlled using methylprednisolone, antihistamines, and
antipyretics. The overall infection rate with alemtuzumab
compared to interferon beta 1-a was increased by ap-
proximately 20% in DMT treatment-naïve and 10% in
DMT treatment-experienced patients. Predominant infec-
tions encountered in the studies were upper and lower
respiratory tract, urinary tract, and herpes viral infections.
Most infections were mild-to-moderate in severity,
Table 2. Adverse events in alemtuzumab clinical trials.
Event Incidence (%)
Alemtuzumab IFNβ1a
Infusion-associated event 90 - 99 NA
Headache 43 - 63 NA
Rash 39 - 60 NA
Pyrexia 16 - 33 NA
Nausea 14 - 24 NA
Urticaria 11 - 27 NA
Chills 7 - 14 NA
Infections 67 - 83 45 - 66
Nasopharyngitis 20 - 32 13 - 24
Urinary tract infection 17 - 23 4 - 12
Herpes viral infection 16 3 - 4
URTI 15 - 21 12 - 27
Autoimmune-associated events 16 - 26 3 - 6
Hyperthyroidism 7 - 16 1 - 2
Hypothyroidism 5 - 7 1 - 2
ITP 1 - 3 <1
Other
Fatigue 13 - 30 9 - 30
Flu like illness 2 - 8 23 - 27
Headache 23 - 63 18 - 28
Rash 12 - 60 4 - 14
Insomnia 9 - 14 15
Anxiety 9 - 12 11
Depression 13 - 16 18
Abbreviations: ITP: immune thrombocytopenic purpura; URTI: upper res-
piratory tract infection.
although the occurrence of serious adverse events com-
pared to interferon beta 1-a also was increased by about
1% with alemtuzumab. Increased herpes viral infections
were mostly local and were not decreased by the use of
prophylactic acyclovir.
Of greatest concern are the autoimmune adverse ef-
fects of alemtuzumab. The drug-related autoimmunity
most commonly results in thyroid dysfunction that occurs
in 17% - 22.7% of alemtuzumab compared to 2.8% - 6%
of interferon beta 1-a patients. The observed thyroid dys-
function included a full spectrum of effects including
hyper- and hypothyroidism, thyroiditis, and goiter; al-
most all episodes were mild or moderate in severity and

Alemtuzumab: A Place in Therapy for Treatment of Multiple Sclerosis 468
managed with conventional therapy. Comprehensive mo-
nitoring uncovered many of the thyroid adverse events
and also provided for early detection and treatment of
ITP. ITP occurred in 0.8% - 2.8% of alemtuzumab pa-
tients but most were classified as a serious adverse event
[49-51]. Alemtuzumab currently carries a black box
warning for fatal cytopenias, infusion reactions and in-
fections and is classified as pregnancy category C by the
FDA [58].
6. Conclusions
MS is a lifelong illness and as such requires lifelong
treatment. Current first-line DMTs for MS offer modest
clinical benefit and have considerable adverse effects
associated with their use. Previous parenteral therapies
for treatment of MS require at least weekly administra-
tion, whereas alemtuzumab administration is necessary
only five days in the first 12 months and three days in the
following 12 months, with evidence of sustained clinical
benefit up to 60 months and possibly beyond.
When available alemtuzumab studies are evaluated
together, consistent benefit from the investigational agent
compared to conventional therapy has been seen in both
previously untreated RRMS patients and those who have
relapsed on first-line conventional therapy. Significant
decreases in the primary outcome of MS RR have been
associated with alemtuzumab in each study and a reduced
risk of SAD is observed in both the CAMMS223 and the
CARE-MS II trials. Safety outcomes for both the 12 mg
and 24 mg alemtuzumab doses were similar, and efficacy
of the 24 mg dose was evaluated only in the CAMMS223
trial, with no differences seen between doses for clinical
or MRI efficacy outcomes.
Adverse effects associated with alemtuzumab infu-
sions usually occur within one month of administration
and can be screened for and effectively managed or
treated. Nevertheless, the drug has been associated with
an increased frequency of adverse effects compared to
interferon beta 1-a-based therapy. Specifically, increased
vigilance for infections and autoimmune diseases, in-
cluding mainly thyroid dysfunction but also immune
thrombocytopenia, appears to be required for alemtuzu-
mab therapy.
Current trials have shown sustained benefit up to 60
months when alemtuzumab therapy is administered at 0,
12, and 24 months. However, continued dosing of alem-
tuzumab beyond the 24th month has not been evaluated.
This is an area for continued research and will require an
extended duration of study.
Alemtuzumab, marketed under the trade name Lem-
trada™, gained support from the European Medicines
Agency’s (EMA) Committee for Medicinal Products for
Human Use (CHMP) in June 2013 [59] and was approved
for the treatment of RRMS by the European Commission
in September 2013 [60]. Alemtuzumab is currently under
review by the US FDA for the treatment of RRMS [59].
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