FormalPara Alemtuzumab in relapsing multiple sclerosis: a summary

More effective than subcutaneous interferon beta-1a in previously treated patients with regard to decreased relapse rate and disability progression

More effective than subcutaneous interferon beta-1a in treatment-naïve patients with regard to decreased relapse rate

Efficacy appears to continue over the long term

Has a generally acceptable tolerability profile, but is associated with an increased risk of autoimmunity and infections

Has a convenient dosing regimen; however, regular monitoring is necessary

1 Introduction

Multiple sclerosis, one of the leading causes of non-traumatic neurological disability in young adults, has an estimated global median prevalence of 30 (range 5–80) in 100,000 [1], and a total lifetime cost of US$1.2 million per patient [2]. Most patients (85–90 %) present with a relapsing-remitting form of multiple sclerosis [2].

Current first-line treatment for relapsing-remitting multiple sclerosis (RRMS) involves either interferon beta or glatiramer acetate [3, 4]; both have acceptable safety profiles, and reduce relapses by approximately 30 % [5]. However, there is a need for regular and ongoing subcutaneous or intramuscular treatment with these drugs, which is a potential disadvantage for quality of life and patient compliance, and neutralizing antibodies may develop. Recently, other treatments for multiple sclerosis have been developed, for example oral treatments (such as fingolimod, teriflunomide and dimethyl fumarate) and the monoclonal antibody alemtuzumab (Lemtrada™) [5].

Alemtuzumab is a humanized therapeutic monoclonal antibody, which has been approved for use in patients with B-cell chronic lymphocytic leukaemia for several years [6], and has recently become approved in the EU (and several other countries) for use in adult patients with active RRMS [7]. This article reviews the available pharmacological properties of intravenous infusions of alemtuzumab and its clinical efficacy and tolerability in adult patients with RRMS.

2 Pharmacodynamic Properties

Alemtuzumab is a recombinant, DNA-derived, humanised, monoclonal immunoglobulin (Ig)G1 kappa antibody, that targets the cell-surface glycoprotein CD52 [7]. It has a human variable framework and constant regions and complementary-determining regions from a murine monoclonal antibody. CD52 is a 21–28 kD cell-surface antigen which is present at high levels on T and B lymphocytes, and at lower levels on natural killer cells, monocytes and macrophages; neutrophils, plasma cells and bone marrow stem cells have little or no CD52 [7]. An in vitro study found that the cell-surface density of CD52 can influence the susceptibility of cells to alemtuzumab complement-dependent cytotoxicity, but that other factors, such as the level of expression of complement-inhibitory proteins, may also have an impact [8].

While the mechanism of therapeutic action of alemtuzumab is not fully elucidated, it likely exerts its action via antibody-dependent cellular cytolysis and complement-mediated lysis of T and B lymphocytes, leading to immunomodulatory effects as a result of depletion and repopulation of lymphocytes [7]. These effects include alterations in the number, proportions and properties of some lymphocyte subsets (e.g. proportionally increased regulatory T-cell and memory T- and B-lymphocyte levels), and transient effects on components of innate immunity (such as neutrophils, macrophages and natural killer cells). Ultimately, disease progression may be delayed by the resulting reduction in the potential for relapse [7].

In a transgenic mouse expressing human CD52, the transient increase in serum cytokines and depletion of peripheral blood lymphocytes observed in humans was replicated [9]. Both effects were largely independent of complement and potentially mediated by neutrophils and natural killer cells, implying antibody-dependent cell-mediated cytotoxicity is the predominant mechanism of action. In addition, lymphocyte depletion in lymphoid organs was less profound than in the blood [9].

Alemtuzumab was associated with a prolonged decrease in the secretion of pro-inflammatory cytokines, in particular interleukin (IL)17 and IL22 (produced by Th17 cells), in a study investigating ex vivo stimulation of T cells 12 months after alemtuzumab treatment in patients with multiple sclerosis [10]. This may be a mechanism of the therapeutic effect. In addition, alemtuzumab is associated with the acute induction of several serum cytokines, such as tumour necrosis factor-alpha, IL6 and interferon gamma (potentially due to cross-linking of natural killer cells, rather than cell lysis, and resulting in infusion-associated reactions), peaking within 2–6 h of infusion [11].

In general, total lymphocyte counts reached the lower limit of normal by month 6 in ≈ 40 % of patients and by month 12 in ≈80 % of patients [7]. One study found that CD4+ cells remained significantly decreased for 24 months [12]; another found that CD4+ and CD8+ cell counts were below baseline levels for a median of 61 and 30 months, respectively [13]. B cell numbers returned to baseline by 3 months (and rose beyond baseline levels at 27 months, although they rarely exceeded the upper limit of normal) [13].

In the phase III Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II trials (in treatment-naïve and previously treated patients with RRMS, respectively) (see Sect. 4.2 for trial details), alemtuzumab was associated with a decrease in circulating lymphocyte counts after each treatment course in both studies, but had few or transient effects on other leukocytes (neutrophils, monocytes, eosinophils, basophils and natural killer cells [7]) [14, 15]. B cells returned to normal levels within 6 months, while T cells approached the lower limit of normal within 12 months [14, 15]. The lowest observed levels of lymphocytes occurred one month after treatment (this was the earliest post-treatment time point investigated) [7].

With regard to lymphocyte subsets, data from CARE-MS I [16] and II [17] show that the relative proportion of CD4+ naïve T cells decreased (from 36 to 5 % [CARE-MS I] and from 37 to 2 % [CARE-MS II]) and the relative proportion of CD4+ memory T cells increased (from 63 to 94 % and from 63 to 97 %, respectively) by month 1 before returning to near-baseline levels by month 12, and the relative proportions of CD4+ regulatory T cells increased by month 1 (from 3 to 14 % and from 4 to 13 %, respectively), remaining elevated at month 12 [16, 17]. A similar pattern was observed in CD8+ T cells [16, 17]. The relative proportion of mature naïve B cells decreased and the relative proportion of immature B cells increased by month 1 before approaching baseline levels by month 6 [17].

Data suggest that early T-cell reconstitution occurs via the expansion of existing cells which have escaped depletion, rather than via generation of new T cells in the thymus [18]. This may be the cause of development of secondary autoimmunity following alemtuzumab treatment (see Sect. 5), as peripheral expansion favours immune populations that respond to self-antigens [18].

Alemtuzumab appears to protect against tissue damage, possibly by preventing new lesion formation [19]. In 20 patients with active RRMS, alemtuzumab treatment was associated with a stable mean magnetisation transfer ratio (MTR) over 36 months, both in normal-appearing grey and normal-appearing white matter, suggesting that tissue structure integrity is retained, according to data from the phase II Campath-1H® in Multiple Sclerosis (CAMMS223) study (see Sect. 4.1 for trial details). Conversely, the MTR fell significantly over the same time frame (p < 0.01 vs. baseline for both) in 18 historical controls. There was a significant difference between alemtuzumab recipients and historical controls with regard to grey matter (p < 0.001), but not white matter (following age adjustment).

In a post-hoc analysis of data from the CAMMS223 trial, the authors hypothesise that the improved disability observed following alemtuzumab but not interferon beta-1a treatment is not solely attributable to its anti-inflammatory effect, but that it may result, in part, from neuroprotection associated with increased lymphocytic delivery of neurotrophins such as brain-derived neurotrophic factor and ciliary neurotrophic factor [20].

Alemtuzumab does not appear to significantly affect immune responses to certain vaccines, according to data from a small, historically controlled, pilot study in patients with RRMS [21]. Alemtuzumab recipients retained humoral immunological memory and the ability to mount a humoral immune response against the diphtheria, tetanus and polio-myelitis vaccine, the Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and the pneumococcal polysaccharide vaccine [21].

3 Pharmacokinetic Properties

The pharmacokinetics of alemtuzumab were investigated in a study involving 216 patients with RRMS [7]. Patients received intravenous infusions of alemtuzumab 12 or 24 mg/day on 5 consecutive days, followed by the same dosage on 3 consecutive days 12 months later. The highest observed serum concentration of alemtuzumab occurred following the last infusion of each treatment course; serum concentration increased with each consecutive dose within the course [7].

The mean maximum serum concentration (C max) was 3014 ng/mL on day five of the initial treatment course, in recipients of alemtuzumab 12 mg; the mean C max was 2,276 ng/mL on day three of the second treatment course [7].

The expected metabolic pathway for alemtuzumab is degradation of the protein to small peptides and individual amino acids, by widely distributed proteolytic enzymes [7]. However, classical biotransformation studies have not been conducted for alemtuzumab, as yet.

The alpha elimination half-life was ≈4–5 days in both treatment courses, and low or undetectable serum concentrations occurred within ≈30 days of the end of each treatment course [7].

The pharmacokinetics of alemtuzumab have not been investigated in patients with renal or hepatic impairment, or in patients aged ≥55 years, and there are insufficient data to draw conclusion on the effect of race or sex on alemtuzumab pharmacokinetics [7].

No formal drug interaction studies have been conducted for alemtuzumab at the recommended dosage in patients with multiple sclerosis [7].

4 Therapeutic Efficacy

The efficacy of alemtuzumab in patients with active RRMS has been investigated in two randomized, rater-masked, active comparator-controlled, multinational, phase III trials (CARE-MS I [14] and CARE-MS II [15]), and one randomized, rater-blinded, active comparator-controlled, multinational, phase II trial (CAMMS223 [22]). Long-term data are available from the CAMMS223 trial (5 years’ follow-up) [23] and the CARE-MS I and II studies (3 years’ follow-up) [24].

4.1 Phase II CAMMS223 Trial

In CAMMS223, a total of 334 patients with treatment-naïve RRMS (2001 McDonald criteria) and symptom onset no more than 36 months prior to screening were randomized to treatment with an intravenous infusion of alemtuzumab 12 (n = 113) or 24 (n = 110) mg/day on 5 consecutive days, followed by a second treatment course at the same dosage on 3 consecutive days at months 12 and 24, or subcutaneous interferon beta-1a 44 μg three times per week (after dose titration; n = 111) [22]. All patients also received 1 g/day of intravenous methylprednisolone for 3 days at baseline and months 12 and 24. Endpoints were measured over 36 months. Data from patients receiving alemtuzumab 24 mg/day are not discussed, as this is not an approved dosage [7].

During the study, alemtuzumab treatment was suspended as a result of three cases of immune thrombocytopenic purpura, including one death [22]. At this time, 1 % of alemtuzumab recipients had not received the second course of treatment and 75 % had not received the third course. All safety and efficacy assessments and interferon beta-1a treatment continued as planned. The dosing suspension was lifted after ≈2.5 years [23]. A safety monitoring programme was subsequently implemented as a result of the ITP cases to ensure prompt identification and appropriate management [22].

In this phase II trial in patients with treatment-naïve RRMS, alemtuzumab 12 mg/day was significantly (p < 0.001) more effective than interferon beta-1a with regard to the coprimary endpoints of relapse rate (total number of events 34 vs. 89; patients with any event 21.4 vs. 40.5 %; hazard ratio [HR] 0.31 [95 % CI 0.18–0.52]) and rate of sustained disability accumulation for 6 months (26.2 vs. 8.5 % of patients; HR 0.25 [95 % CI 0.11–0.57]) [22].

4.2 Phase III CARE-MS Trials

Patients in CARE-MS I were randomized 2:1 to treatment with intravenously infused alemtuzumab 12 mg/day on days 1–5 at baseline and on days 1–3 in a second course 12 months later, or subcutaneous interferon beta-1a 44 μg three times per week (after dose titration) [14]. Patients in CARE-MS II were randomized 2 : 2 : 1 to treatment with intravenously infused alemtuzumab 12 or 24 mg/day on days 1–5 at baseline and on days 1–3 in a second course 12 months later, at the same dosage, or subcutaneous interferon beta-1a 44 μg three times per week (after dose titration) [15]. After a protocol amendment partway through the studies, alemtuzumab recipients also received oral aciclovir 200 mg twice daily during alemtuzumab infusion and for the 28 days following (as herpes infection prophylaxis) [14, 15]. Furthermore, following the protocol amendment, randomization to the alemtuzumab 24 mg/day group was discontinued in CARE-MS II, so as to accelerate enrolment in the other two treatment groups (no safety or efficacy data were reviewed for this decision; after this amendment, the principal efficacy comparison was between alemtuzumab 12 mg/day and interferon beta-1a) [15]. A total of 5 % [14] and 43 % [15] of alemtuzumab 12 mg/day recipients received aciclovir prophylaxis with the first course of alemtuzumab and 66 % [14, 15] received it with the second course. All patients in both studies also received intravenous methylprednisolone 1 g/day for 3 days at baseline and 3 days at 12 months, and concomitant treatment with antihistamines or antipyretics was permitted for management of infusion-associated reactions [14, 15]. Data from patients receiving alemtuzumab 24 mg/day in CARE-MS II are not discussed, as this is not an approved dosage [7].

Inclusion and exclusion criteria, patient baseline characteristics and the coprimary endpoints of the two phase III trials are outlined in Table 1 [14, 15]. Baseline characteristics did not significantly differ between treatment groups [14, 15]. Endpoints were measured over 24 months [14, 15].

Table 1 Baseline patient characteristics and trial design details for the CARE-MS I and CARE-MS II studies
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Intravenous alemtuzumab 12 mg/day was more effective than subcutaneous interferon beta-1a in the reduction of relapse rate (coprimary endpoint) in patients with treatment-naïve [14] or previously treated [15] RRMS (Table 2; Fig. 1). The rate ratio between alemtuzumab and interferon beta-1a recipients was significant (p < 0.0001) in both studies (Fig. 1), and alemtuzumab was associated with a risk reduction of 54.9 % in treatment-naïve [14] and 49.4 % in previously treated [15] patients compared with interferon beta-1a for this endpoint. Alemtuzumab 12 mg/day was also significantly (p < 0.0001) more effective than interferon beta-1a with regard to time to first relapse in both treatment-naïve (HR 0.45 [95 % CI 0.33–0.61]) [14] and previously treated patients (HR 0.53 [95 % CI 0.41–0.69]) [15].

Table 2 Clinical changes associated with intravenous alemtuzumab 12 mg/day versus subcutaneous interferon beta-1a treatment in patients with treatment-naïve (CARE-MS I [14]) or previously treated (CARE-MS II [15]) relapsing-remitting multiple sclerosis
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Fig. 1
figure 1

Efficacy of intravenous alemtuzumab 12 mg/day versus subcutaneous interferon beta-1a in patients with treatment-naïve (CARE-MS I [14]) or previously treated (CARE-MS II [15]) relapsing-remitting multiple sclerosis. a Relapse rate ratio and b 6-month sustained confirmed accumulation of disability rate hazard ratio (coprimary endpoints) in both studies. See main text for treatment details. *p = 0.0084, **p < 0.0001

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The number of patients who were relapse-free at 2 years was significantly (p < 0.0001) higher in the alemtuzumab 12 mg/day group than in the interferon beta-1a group in both studies [14, 15]. The number of patients with any relapse event, the total number of relapse events, and the yearly rate of relapses are presented in Table 2 [14, 15]. In previously treated patients, the specific previous treatment did not appear to affect the efficacy of alemtuzumab versus interferon beta-1a with regard to relapse rate [15].

Similarly, intravenous alemtuzumab 12 mg/day was more effective than subcutaneous interferon beta-1a in the reduction of 6-month confirmed sustained accumulation of disability rate (coprimary endpoint) in patients with previously treated RRMS [15], but there was no significant between-group difference in patients with treatment-naïve RRMS [14] (Table 2; Fig. 1). Alemtuzumab was associated with a risk reduction of 30 % (not significant) in treatment-naïve [14] and 42 % (p = 0.0084) in previously-treated [15] patients for this endpoint; the HR is presented in Fig. 1, and the rate by treatment group in Table 2. In previously treated patients, the specific previous treatment did not appear to affect the efficacy of alemtuzumab versus interferon beta-1a with regard to accumulation of disability [15].

In previously treated patients (CARE-MS II), significantly (p = 0.0002) more alemtuzumab 12 mg/day than interferon beta-1a recipients had a sustained reduction in disability (defined as a decrease of ≥1 point in Expanded Disability Status Scale [EDSS] score from baseline, confirmed over 6 months, in patients with baseline EDSS scores of ≥2.0) [HR 2.57 (95% CI 1.57–4.20)] [15].

While the between-group difference in improvements in Multiple Sclerosis Functional Composite (MSFC) score were not considered to be significant with the pre-specified significance models used (despite p-values of less than 0.05) in both treatment-naïve [14] and previously treated [15] patients, between-group differences in the change in EDSS score were significant (p < 0.0001) in previously treated patients [15], but not in treatment-naïve patients [14] (Table 2).

The differences between alemtuzumab 12 mg/day and interferon beta-1a recipients in the previously treated patients in CARE-MS II were significant (p < 0.05) within 4 months (for relapse reduction) [25] and from 6 months (for mean change from baseline EDSS score) [26], and were maintained through month 24 [25, 26].

Alemtuzumab 12 mg/day was significantly (p < 0.05) more effective than interferon beta-1a with regard to the proportion of patients with Gadolinium-enhancing lesions at 24 months or new or enlarging T2-hyperintense lesions, and the median change in brain parenchymal fraction in patients with treatment-naïve [14] or previously treated [15] RRMS (Table 3). No significant between-group difference was observed in the median change in volume of hyperintense lesions in either study (Table 3) [14, 15]. Significantly more recipients of interferon beta-1a had new T1 hypointense lesions than recipients of alemtuzumab 12 mg/day in previously treated patients; the difference was not significant in treatment-naïve patients [7].

Table 3 MRI changes associated with intravenous alemtuzumab 12 mg/day versus subcutaneous interferon beta-1a treatment in patients with treatment-naïve (CARE-MS I [14]) or previously treated (CARE-MS II [15]) relapsing-remitting multiple sclerosis [7, 14, 15]
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Alemtuzumab 12 mg/day was associated with a significantly (p < 0.01) greater proportion of patients who were clinically disease free (absence of both relapses and sustained accumulation of disability) and those who were both clinically disease free and MRI disease free (absence of both Gadolinium-enhancing lesions and new or enlarging T2 hyperintense lesions) than interferon beta-1a in both treatment-naïve [14] and previously treated [15] patients with RRMS (Fig. 2).

Fig. 2
figure 2

Efficacy of intravenous alemtuzumab 12 mg/day versus subcutaneous interferon beta-1a in patients with treatment-naïve (CARE-MS I [14]) or previously treated (CARE-MS II [15]) relapsing-remitting multiple sclerosis. Rates of a clinically disease-free survival and b MRI and clinically disease-free survival. These endpoints were investigated in a 376 [14] and 426 [15] alemtuzumab and 187 [14] and 202 [15] interferon beta-1a recipients and b 360 [14] and 396 [15] alemtuzumab and 172 [14] and 184 [15] interferon beta-1a recipients. MRI magnetic resonance imaging, OR odds ratio, *p = 0.006, **p < 0.0001 vs. IFN β-1a

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In a subanalysis of patients with highly-active RRMS in CARE-MS II (101 alemtuzumab 12 mg/day and 42 interferon beta-1a recipients), 33.3 and 0 %, respectively, were disease activity-free at 1 year (p < 0.0001) and 24.2 % of the alemtuzumab 12 mg/day recipients remained disease activity-free at 24 months [27]. At 24 months, 35.8 and 60.0 %, respectively, had relapses, 7.4 and 17.5 % had sustained accumulation of disability, 22.1 and 52.5 % had gadolinium-enhancing lesion activity, and 60.0 and 92.5 % had T2-lesion activity.

Supportive analyses demonstrated that significantly fewer alemtuzumab 12 mg/day than interferon beta-1a recipients had severe relapses (reduction of 61 and 48 %; both p < 0.05) or relapses leading to steroid treatment (reduction of 58 and 56 %; both p < 0.0001) in both treatment-naïve and previously treated patients, respectively, and relapses that led to hospitalization in previously treated patients (reduction of 55 %; p = 0.0045) [7].

4.2.1 Health-Related Quality of Life

Some measures of patient-reported health-related quality of life were improved to a greater extent with alemtuzumab 12 mg/day than with interferon beta-1a in both CARE MS-I [28, 29] and CARE-MS II [29, 30]. Functional Assessment of Multiple Sclerosis (FAMS) scores were consistently and significantly (p < 0.05) improved with alemtuzumab versus interferon beta-1a at all timepoints (every 6 months) [28, 30]. Alemtuzumab recipients had FAMS scores that significantly improved from baseline at all timepoints (p < 0.0001) in both studies [28, 30]; interferon beta-1a recipients had FAMS scores that differed significantly from baseline at months 6, 12 and 18 but not 24 in CARE-MS I [28], but did not differ significantly from baseline at any timepoint in CARE-MS II [30].

The change from baseline in scores on the Medical Outcomes Study 36-Item Short-Form Survey (SF-36) mental health component summary did not significantly differ between alemtuzumab 12 mg/day and interferon beta-1a recipients at any timepoint (months 12 and 24) in CARE-MS I, but was significantly greater with alemtuzumab 12 mg/day than interferon beta-1a at month 12 in CARE-MS II (p < 0.05) [29]. The change from baseline in scores on the SF-36 physical health component summary was significantly greater with alemtuzumab 12 mg/day than interferon beta-1a at month 12 (p < 0.001) in CARE-MS I and at both timepoints in CARE-MS II (p < 0.01) [29].

Furthermore, the change from baseline in EuroQol in Five Dimensions score did not significantly differ between treatment groups at any timepoint (months 6, 12, 18 and 24) in CARE-MS I, and was significantly greater in alemtuzumab 12 mg/day than interferon beta-1a recipients at month 18 (p < 0.05) in CARE-MS II [29]. The change from baseline in EuroQol Visual Analogue Scale score was significantly greater in alemtuzumab 12 mg/day than interferon beta-1a recipients at months 6 and 12 (p < 0.05), but not 18 and 24, in CARE-MS I, and at all four timepoints in CARE-MS II (p ≤ 0.05).

4.3 Long-Term Data

Data are available from 3 years of follow-up for both CARE-MS I and CARE-MS II; 349 and 386 alemtuzumab recipients, respectively, were enrolled in this blinded, ongoing extension study [31]. Patients were eligible for retreatment after 12 months if disease activity resumed (≥1 relapse or ≥2 new or enlarging brain or spinal lesions on MRI); retreatment consisted of intravenous alemtuzumab 12 mg/day for three days. Based on these retreatment criteria, ≈80 % of patients previously treated with alemtuzumab did not require additional treatment during the first year of the extension. While use of other disease-modifying therapies was permitted (based on investigators’ clinical decision), pooled data from both studies show that <2 % of patients previously treated with alemtuzumab received another disease-modifying therapy during the first extension year.

Efficacy was maintained through the first year of the extension period of both CARE-MS I and CARE-MS II [31]. At month 36, the annualized relapse rates in CARE-MS I and CARE-MS II, respectively, were 0.24 and 0.25; the respective annualized relapse rates at month 24 were 0.13 and 0.25 [31]. The mean EDSS scores at the beginning of the extension period were 1.8 and 2.5 and at the end of the extension period were 1.9 and 2.6, respectively. Moreover, the mean EDSS scores remained stable or improved from baseline through year 3 in approximately three quarters of patients previously treated with alemtuzumab.

In a rater-blinded extension study of the phase II CAMMS223 study [22], data are available from a 5-year follow-up [23]. Of the 334 patients who were originally randomized on CAMMS223, 198 (72 alemtuzumab 12 mg/day, 79 alemtuzumab 24 mg/day and 47 interferon beta-1a recipients) took part in the extension phase, and 183 (67, 74 and 42, respectively) patients reached 60 months of treatment [23]. As previously mentioned, data from patients receiving alemtuzumab 24 mg/day are not discussed, as this is not an approved dosage [7]. Retreatment was administered at least 12 months after the last alemtuzumab dose, and consisted of 3 days of alemtuzumab 12 mg/day, with methylprednisolone premedication [23]. However, most alemtuzumab recipients did not receive further treatment. The median duration of follow-up was 57.3 months (longest follow-up 80.6 months) [23].

Alemtuzumab 12 mg/day was more effective than interferon beta-1a over 60 months in patients with early, active, RRMS [23]. A total of 12 % of alemtuzumab 12 mg/day and 27 % of interferon beta-1a recipients had sustained accumulation of disability (measured from baseline to month 60). The hazard ratio for no sustained accumulation of disability was 0.31 (95 % CI 0.16–0.60; p = 0.0005). Moreover, the annualized relapse rate ratio was 0.34 (95 % 0.20–0.57; p < 0.0001); a total of 27 % of alemtuzumab 12 mg/day and 46 % of interferon beta-1a recipients had a relapse (measured from baseline to month 60) [23].

The mean change in EDSS score from baseline to month 60 was −0.15 in alemtuzumab 12 mg/day and +0.46 in interferon beta-1a recipients [23]. The odds ratio for improved disability (based on EDSS score) was 2.65 (95 % CI 1.22–5.76; p = 0.014). When investigating data from month 36 to month 60, there was no significant difference between alemtuzumab 12 mg/day and interferon beta-1a in mean change in EDSS score (+0.21 vs. +0.26), improved disability (odds ratio 1.14 [95 % CI 0.52–2.49]), or annualized relapse rate ratio (0.44 [95 % CI 0.17–1.14]) [23].

5 Tolerability

Alemtuzumab has a generally acceptable tolerability profile in patients with treatment-naïve [14, 22] or previously treated [15] RRMS, in both the initial studies [14, 15, 22] and their extensions [23, 24]. In the phase III, CARE-MS trials, adverse events occurred in 96 % of intravenous alemtuzumab 12 mg/day and 92 % of subcutaneous interferon beta-1a recipients in treatment-naïve patients (7.73 and 4.94 events per person-year) [14], and in 98 and 95 %, respectively, in previously treated patients (8.66 and 5.69 events per person-year) [15]. Most adverse events in both trials were mild to moderate in severity [14, 15]. A total of 1 and 6 % of treatment-naïve patients [14] and 3 and 7 % of previously treated patients [15] discontinued treatment as a result of adverse events.

Serious adverse events occurred in 18 and 14 % of treatment-naïve patients receiving alemtuzumab 12 mg/day or interferon beta-1a (0.13 and 0.09 events per person-year) [14], and in 20 and 22 % of previously treated patients (0.16 and 0.21 events per person-year) [15]. Of these, 5 and 7 % (treatment-naïve) [14] and 8 and 12 % (previously treated) [15] were multiple sclerosis relapses. Less than 1 % of patients in both alemtuzumab 12 mg/day groups and 0 % of patients in both interferon beta-1a groups died [14, 15] (two treatment-naïve patients [car accident and sepsis after the study] [14] and two previously treated patients [car accident and aspiration pneumonia] [15]). All individual serious adverse events occurred in ≤1 % of patients [14, 15]. When grouped by type, the most common serious adverse events (≥3 % of patients) were infusion-associated reactions (3% of alemtuzumab 12 mg/day recipients) in treatment-naïve patients [14] and infusion-associated reactions (3 % of alemtuzumab 12 mg/day recipients) and infections (4 % of alemtuzumab 12 mg/day and 1 % of interferon beta-1a recipients) [15] in previously treated patients.

The incidence of adverse events was highest in the first month after treatment initiation in both CARE-MS I and CARE-MS II [32, 33]. These were mainly due to infusion-associated reactions, in the alemtuzumab groups [32, 33]. Overall, the rate of adverse events with alemtuzumab versus interferon beta-1a was balanced over time in both studies [32, 33].

The incidences of adverse events in CARE-MS I and II, grouped by type, are presented in Fig. 3 [14, 15]. The most common adverse events in the alemtuzumab 12 mg/day groups were infusion associated (this type of adverse event does not apply to interferon beta-1a recipients), the most common of which (≥15 % of patients) were headache (43 %), rash (41 %) and pyrexia (33 %) in treatment-naïve patients [14] and headache (43 %), rash (39 %), nausea (17 %), pyrexia (16 %) and urticaria (15 %) in previously treated patients [15]. Infusion-associated reactions were less common during the second treatment course [14, 32].

Fig. 3
figure 3

Tolerability of intravenous alemtuzumab 12 mg/day versus subcutaneous interferon beta-1a in patients with a treatment-naïve [14] and b previously treated [15] relapsing-remitting multiple sclerosis. Incidence of adverse events, grouped by event type, in the CARE-MS I [14] and CARE-MS II [15] studies. NA not applicable for interferon beta-1a recipients

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Infections were also common (mostly mild to moderate), and included nasopharyngitis (20 % of alemtuzumab 12 mg/day and 13 % of interferon beta-1a recipients), urinary tract infections (17 and 4 %) and herpes viral infections (16 and 2 %; most commonly herpes simplex) in treatment-naïve recipients [14] and nasopharyngitis (29 and 24 %), urinary tract infections (21 and 11 %), upper respiratory tract infection (16 and 12 %) and herpes viral infections (16 and 4 %; most commonly herpes simplex) in previously treated patients [15]. An analysis of lymphocyte counts and infection risk in patients from CARE-MS II found that low on-treatment lymphocyte counts did not correlate with the increased infection risk [34]. Overall, in controlled clinical trials, infections occurred in 71 % of alemtuzumab 12 mg/day and 53 % of interferon beta-1a recipients, and most were of mild to moderate severity (serious infections occurred in 2.7 and 1 %) [7]. Infections worthy of note in these pooled analyses include serious varicella zoster virus infections (including primary varicella and varicella zoster re-activation) [0.3 % of alemtuzumab 12 mg/day and 0 % of interferon beta-1a recipients], cervical human papilloma virus infections (including cervical dysplasia) [2 % of alemtuzumab 12 mg/day recipients], tuberculosis (active and latent) [0.3 % of alemtuzumab 12 mg/day recipients], and superficial fungal infections (particularly oral and vaginal candidiasis) [12 % of alemtuzumab 12 mg/day and 3 % of interferon beta-1a recipients] [7].

The second course of alemtuzumab treatment did not increase the risk of infection [32, 33]. In treatment-naïve patients receiving alemtuzumab 12 mg, in the month after the 12-month alemtuzumab course, the incidence of herpetic infection was 1 % in patients receiving concomitant aciclovir, compared with 3 % of patients not receiving aciclovir [14]. In previously treated patients receiving alemtuzumab 12 mg, the respective incidence of herpes infection was 0.5 and 2.8 % in the month after the first course and 0.4 and 2.1 % in the month after the second course [15].

Administration-site reactions and liver toxicity occurred in a numerically greater proportion of interferon beta-1a than alemtuzumab 12 mg/day recipients in both studies (see Fig. 3), whereas infections and thyroid disorders occurred in a numerically greater proportion of alemtuzumab 12 mg/day than interferon beta-1a recipients [14, 15]. Blood and lymphatic system disorders appeared to occur in similar proportions in both groups [14, 15].

Other events (not infusion-associated) affecting ≥20 % of patients in either treatment group included headache (23 % of alemtuzumab 12 mg/day and 19 % of interferon beta-1a recipients), multiple sclerosis relapse (21 and 39 %), influenza-like illness (3 and 23 %), and injection-site erythema (0 and 25 %) in treatment-naïve patients [14], and headache (53 and 18 %), rash (44 and 5 %), multiple sclerosis relapse (33 and 49 %), pyrexia (22 and 9 %), and influenza-like illness (7 and 23 %) in previously treated patients [15].

Alemtuzumab treatment may result in autoantibody formation, increasing the risk of autoimmune disorders, such as immune thrombocytopenia, thyroid disorders or nephropathies [7]. Autoimmune disorders have been previously reported with alemtuzumab treatment [22]. A correlation between higher baseline levels of serum IL21 and serum CCL21, and lower baseline levels of serum IL7, and the incidence of autoimmunity following alemtuzumab treatment has been reported; however, the predictive value of these trends remains to be confirmed [35, 36].

Thyroid disorders occurred in numerically more alemtuzumab 12 mg/day recipients than interferon beta-1a recipients (Fig. 3); these were rarely classified as serious (≤1 % of alemtuzumab 12 mg/day recipients vs. 0 % of interferon beta-1a recipients) in either phase III study [14, 15]. The incidence of thyroid disorders increased from year 1 to year 2 [33]. Thyroid disorders pose special risks in women who are pregnant [7].

The overall incidence of serious immune thrombocytopenia was approximately 1 % in alemtuzumab recipients in the controlled clinical trials of patients with multiple sclerosis [7]. Onset usually occurred between 14 and 36 months after first exposure [7]. The overall incidence of nephropathies was 0.3 % in alemtuzumab recipients in clinical trials, and onset occurred within 39 months of the last administration [7]. In treatment-naïve patients in CARE-MS I, three alemtuzumab12 mg/day recipients developed serious immune thrombocytopenia, one alemtuzumab recipient developed glomerulonephritis, and one developed presumed autoimmune pancytopenia [14]. In previously treated patients in CARE-MS II, three alemtuzumab 12 mg/day recipients developed serious immune thrombocytopenia, and one patient developed membranous nephropathy [15].

Suspected autoimmune cytopenias (e.g. neutropenia, haemolytic anaemia and pancytopenia) have been reported (infrequently) in clinical trials involving patients with multiple sclerosis receiving alemtuzumab [7].

Two treatment-naïve patients (both alemtuzumab 12 mg/day recipients) developed malignant disease (both thyroid cancer) [14]; of the previously treated patients, two alemtuzumab 12 mg/day and two interferon beta-1a recipients developed malignant disease (basal cell carcinoma and thyroid cancer, and basal cell carcinoma and acute myeloid leukaemia, respectively) [15].

Data from a substudy involving 13 male alemtuzumab 12 mg/day (n = 10) or 24 mg/day (n = 3) recipients in the CARE-MS studies imply that alemtuzumab has no significant adverse effect on sperm quality, quantity or motility [37]. None of the patients investigated developed aspermia, azoospermia, or a consistently depressed sperm count, and there was no evidence of motility disorders or an increase in sperm morphological abnormalities. One patient had sperm-binding antibodies; this did not impact sperm parameters adversely.

In animal studies of alemtuzumab, reproductive toxicity was demonstrated, although it is currently unknown whether alemtuzumab can cause foetal harm in humans [7]. Human immunoglobulin G is known to cross the placental barrier, meaning that alemtuzumab may also have that ability [7]. As previously mentioned, thyroid disease (a possible adverse event with alemtuzumab) poses special risks in pregnant women, and can lead to miscarriage or foetal effects such as mental retardation and dwarfism [7].

Alemtuzumab overdosage has been observed in two patients with multiple sclerosis in clinical trials, who accidentally received up to 60 mg in a single infusion [7]. Serious reactions occurred (headache, rash, and either hypotension or sinus tachycardia) [7].

5.1 Longer-Term Tolerability

In the 5-year follow-up (median duration 57.3 months) of patients in the phase II CAMMS223 study [23], the tolerability profile of alemtuzumab continued to be generally acceptable. A total of 27.8 and 27.1 % of patients had serious adverse events, and 0.9 and 0.9 % died. Adverse events leading to withdrawal from treatment occurred in 4.6 and 12.1 % of alemtuzumab 12 mg/day and interferon beta-1a recipients, respectively.

Infusion-associated reactions occurred in 98.1 % of alemtuzumab 12 mg/day recipients; 3.7 % of patients had serious infusion-associated reactions [23]. A total of 71.3 % of alemtuzumab 12 mg/day and 50.5 % of interferon beta-1a recipients had infections, 33.3 and 3.7 % had thyroid-associated events, and 1.9 and 0.9 % had protocol-defined immune thrombocytopenia. With regard to serious adverse events, 5.6 and 2.8 % of patients had serious infections, 0.9 and 0 % had serious thyroid-associated events, and 0.9 and 0 % had serious immune thrombocytopenia.

In alemtuzumab recipients, the incidence of infections was highest in the month immediately following an infusion [23]. Infections were mostly mild to moderate in severity, and none were life-threatening or fatal. The most common was upper respiratory tract infection. The number of courses of alemtuzumab treatment (2 or 3) did not significantly affect the rates of infection.

The incidence of first autoimmune events decreased after year 3 [23]. The most common autoimmune event was thyroid disease; patients with this disease responded to conventional therapy. All cases of immune thrombocytopenia occurred during the initial study; no new cases occurred during the extension period, and all surviving patients with immune thrombocytopenia maintained normal or near-normal platelet counts, without additional treatment or clinical sequelae, for ≥41 months. One patient in the alemtuzumab 12 mg/day group developed anti-glomerular basement membrane disease during the extension period, and was successfully treated; this patient had stable mild renal impairment which did not require treatment.

Overall, autoimmune thyroid disorders occurred in 36 % of alemtuzumab 12 mg/day recipients over 48 months in controlled clinical trials of patients with multiple sclerosis [7]. Most were mild or moderate in severity, and most were managed with conventional medical therapy, although some required surgery [7]. The incidence was higher in patients with a medical history of thyroid disorders [7].

A pooled analysis of data from the core and extension studies of CAMMS223, CARE-MS I and CARE-MS II (mean follow-up of 2.9 years), involving 1216 alemtuzumab 12 mg/day recipients, found that thyroid adverse events occurred in 23.1 % of alemtuzumab 12 mg/day recipients (1.4 % were serious); thyroid adverse events peaked during the fourth year [38]. Thyroid events were mostly managed with conventional medication. Immune thrombocytopenia occurred in 1.1 % of alemtuzumab 12 mg/day recipients (0.6 % were serious). Other autoimmune cytopenias occurred in 0.2 % of patients.

A further pooled analysis of the core and extension studies of CAMMS223, CARE-MS I and CARE-MS II, involving 1486 patients treated with alemtuzumab 12 or 24 mg, found that a total of five patients, all recipients of alemtuzumab 12 mg, developed nephritis; four had glomerular disease [39]. While these events are rare, they may occur months or years after treatment, and safety monitoring is recommended.

5.2 Immunogenicity

The presence of alemtuzumab-binding antibodies was observed in 29 and 86 % of alemtuzumab 12 mg/day recipients immediately before and 1 month after the second course of treatment in treatment-naïve patients [14] and 29 and 81 %, respectively, in previously treated patients [15]. Efficacy, safety, and lymphocyte depletion and repopulation were not affected by the presence and level of anti-alemtuzumab antibodies in either study [14, 15]. The development of alemtuzumab-binding antibodies occurred within 15 months of initial exposure [7].

A total of 13 % of 175 [14] and 13 % of 178 [15] interferon beta-1a recipients tested positive for anti-interferon beta neutralizing antibodies at 24 months (18 % of 193 previously treated interferon beta-1a recipients tested positive at baseline [15]). In the study including treatment-naïve patients, the presence of anti-interferon beta neutralizing antibodies did not affect the relapse rate; alemtuzumab remained more effective than interferon beta-1a regardless of the presence (p = 0.0047) or absence (p < 0.0001) of neutralizing antibodies at 24 months [14].

6 Dosage and Administration

Alemtuzumab is indicated in the EU for adult patients with relapsing remitting multiple sclerosis with active disease defined by clinical or imaging features [7]. The recommended dosage is an initial treatment course of intravenous infusion of alemtuzumab 12 mg/day on 5 consecutive days, followed by a second treatment course at the same dosage on 3 consecutive days, 12 months after the initial treatment course, and a recommended safety follow-up of 48 months after the final infusion [7].

Patients should also be pretreated with corticosteroids (e.g. methylprednisolone) immediately prior to administration of alemtuzumab on each of the first 3 days of each treatment course, and pretreatment with antihistamines and/or antipyretics prior to alemtuzumab administration should be considered [7]. Starting on the first day of each treatment course, patients should receive oral prophylaxis for herpes infection (e.g. aciclovir); this treatment should continue for at least 1 month following alemtuzumab treatment [7].

Patients should be monitored for safety risks before treatment initiation and regularly throughout treatment and for at least 48 months after treatment [7]. The EU summary of product characteristics recommends that patients complete local immunisation requirements at least 6 weeks before treatment with alemtuzumab [7].

The safety and efficacy of alemtuzumab in patients aged 0–18 years have not been established, and alemtuzumab treatment is not approved in these patients [7]. Alemtuzumab treatment is not recommended in patients who have inactive disease or who are stable on current therapy [7]. Women of childbearing age should use effective contraception during treatment and for 4 months after each treatment course, as placental transfer and potential alemtuzumab pharmacological activity were observed in animal studies during gestation and after delivery [7]. Moreover, breastfeeding should be discontinued during treatment and for 4 months following each treatment course, as it is unknown whether alemtuzumab is excreted in human breast milk [7].

Local prescribing information should be consulted for further, detailed information, including contraindications, precautions, drug interactions, and use in special patient populations.

7 Place of Alemtuzumab in the Management of Relapsing Multiple Sclerosis

The current first-line treatments for relapsing multiple sclerosis, interferon beta and glatiramer acetate, are associated with reductions in relapses and are generally well tolerated, with the main adverse events being transient flu-like reactions at administration and (less commonly) hepatotoxicity and depression for interferon beta and mild injection site reactions and transient post-injection symptoms for glatiramer acetate [5]. However, both drugs require regular, ongoing subcutaneous or intramuscular administration, which may affect quality of life and may lead to compliance issues. Furthermore, there is a risk of neutralizing antibodies with interferon treatment, reducing efficacy [5]. As a result of these limitations, several new treatments have been developed, including oral treatments and monoclonal antibodies, of which alemtuzumab is one.

Current guidelines for the treatment of multiple sclerosis were developed several years ago, and thus do not include the most recently approved disease modifying therapies [3, 4]. They emphasize the use of such treatments as interferon beta-1a and -1b and glatiramer acetate, under certain criteria, for prevention of multiple sclerosis relapse. Other treatments discussed in these guidelines include azathioprine, mitoxantrone, intravenous immunoglobulin, plasma exchange and methylprednisolone [3, 4]. New guidelines for the treatment of multiple sclerosis [40] and a separate technology appraisal of alemtuzumab in multiple sclerosis [41] are expected from NICE in 2014.

Alemtuzumab, initially approved for the treatment of B-cell chronic lymphocytic leukaemia, has been in development for the treatment of multiple sclerosis for decades [11]. It was initially investigated in patients with progressive disease, as it was theorized at the time that this form of the disease was due to repeated waves of cerebral inflammation, and was a more aggressive form of relapsing-remitting disease. However, upon the discovery that, while relapse rate decreased, disability continued to deteriorate, it was concluded that progressive disease is not due to inflammation (which would be successfully suppressed by alemtuzumab treatment) but rather to progressive cerebral atrophy as a result of noninflammatory mechanisms associated with previous inflammation [11].

This conclusion led to the initial research in patients with relapsing-remitting disease, which found that both relapse rate and disability scores decreased with alemtuzumab treatment [11]. The researchers concluded that, unlike progressive disease, early multiple sclerosis disability accumulation is driven by inflammation, allowing for successful treatment with immunotherapies [11].

It is believed that alemtuzumab exerts its therapeutic action by the depletion and subsequent repopulation of lymphocytes, effectively rebalancing the immune system (see Sect. 2); this theory is consistent with the durable effects associated with alemtuzumab, which occur despite its infrequent and finite administration. Researchers have hypothesized that alemtuzumab treatment creates a “tolerogenic environment” during lymphocyte repopulation; in the initial 6 months following treatment in patients with relapsing-remitting multiple sclerosis, there is a predominance of peripheral blood regulatory T cells, implying that these cells are relatively spared the depletion associated with alemtuzumab [42]. This hypothesis is supported by the lower than expected incidence of opportunistic infections and the higher incidence of novel autoimmunity with alemtuzumab treatment [11]. Moreover, lymphocyte depletion in lymphoid organs in a transgenic animal model was less profound than the depletion in the serum (see Sect. 2).

Alemtuzumab treatment is more effective than interferon beta-1a with regard to relapse rate reduction and disability accumulation rate reduction in patients with previously treated RRMS; in treatment-naïve patients, alemtuzumab was more effective than interferon beta-1a in relapse rate reduction, but there was no significant between-group difference in disability accumulation rate reduction (see Sect. 4.2). It has been hypothesised [14] that the lack of superiority of alemtuzumab over interferon beta-1a in disability activity in treatment-naïve patients was in part a result of the low number of patients in the interferon beta-1a group with confirmed EDSS worsening; this was less than the anticipated rate based on the phase II study. It is as yet unclear whether the reduction in disability observed in previously treated patients was a result of the anti-inflammatory actions of alemtuzumab or whether it was due to direct repair-promoting actions.

Several MRI outcomes were more favourable in patients receiving alemtuzumab than in those receiving interferon beta-1a, and alemtuzumab was associated with a significantly greater proportion of patients who were clinically disease free and both clinically and MRI disease free (see Sect. 4.2). Health-related quality of life was also improved to a greater extent with alemtuzumab than with interferon beta-1a in both treatment-naïve and previously treated patients (see Sect. 4.2.1).

The efficacy of alemtuzumab was maintained during the first year of the extension periods of the phase III trials; moreover, ≈80 % of patients did not require re-treatment with alemtuzumab. Alemtuzumab remained significantly more effective than interferon beta-1a over 60 months in sustained accumulation of disability and relapse rate, in the phase II trial (see Sect. 4.3).

Aside from the promising efficacy of alemtuzumab, it has a highly favourable treatment regimen, which requires hospital or outpatient-clinic attendance for an intravenous infusion on a handful of days on two consecutive years, with no treatment required in between (see Sect. 6). This may be a tempting treatment offer for patients who don’t wish to undergo frequent injections or daily oral dosing. However, further compliance and patient satisfaction studies would be of interest to determine whether this is indeed the case.

As the phase III trials were only rater blinded (the patients were aware which treatment, if not which dosage, they were receiving), by necessity, there is the potential for bias in clinical outcome assessments. However, as the administration regimens for the two drugs are so different, the only other option would be to carry out a double-dummy trial, which creates a much more complicated protocol. Moreover, the authors of both CARE-MS I and CARE-MS II conducted sensitivity analyses on the effect of rater blinding, and found that the results of the studies were supported [14, 15].

The tolerability profile of alemtuzumab in patients with previously treated or treatment-naïve RRMS is generally acceptable (see Sect. 5). Most adverse events in the phase III trials were of mild to moderate severity, and serious adverse events occurred at a similar incidence among alemtuzumab recipients as among interferon beta-1a recipients. The most common adverse events (and among the most common serious adverse events) were infusion-associated reactions; infections were also common and occurred numerically more frequently in alemtuzumab-treated patients, but were mostly mild to moderate in severity. This tolerability profile has been demonstrated to remain generally acceptable with longer-term treatment of up to ≈60 months (based on an extension study of the phase II trial; see Sect. 5.1).

As alemtuzumab treatment may result in autoantibody formation, the risk of autoimmune disorders is increased (see Sect. 5). Autoimmunity is a recognised risk associated with reconstitution from lymphopenia. Thyroid disorders were the most common autoimmune event; most were of mild to moderate severity, and were treatable. Serious immune thrombocytopenia and thyroid disorders each occurred in ≤1 % of alemtuzumab recipients, but the risk requires monitoring; this should occur before treatment initiation and regularly throughout treatment and for at least 48 months after treatment. Prophylactic treatment for the increased risk of infusion reactions and infection is also necessary. In the long-term follow-up of the phase II trial, the incidence of first autoimmune events decreased after year 3. However, there have been rare cases of glomerulonephritis reported in the phase II and III extension trials, and these events may occur months or even years after treatment; thus, safety monitoring is required.

While the convenient dosing schedule of alemtuzumab is certainly attractive, the convenience may be counterbalanced by the need for detailed monitoring for the safety concerns outlined above. Monitoring will need to continue for several years after the last treatment course (the EU summary of product characteristics requires 48 months [7]), requiring patient compliance of a different kind.

There appears to be a potential correlation between higher baseline levels of serum IL21 and serum CCL21, and lower baseline levels of serum IL7, and the incidence of autoimmunity following alemtuzumab treatment (see Sect. 5). It is thought that pretreatment monitoring of these (or other) biomarkers may provide a useful screening model to help identify patients at an increased risk of developing autoimmunity following alemtuzumab treatment, thus allowing for a more individualized treatment.

The efficacy, safety and lymphocyte depletion and repopulation associated with alemtuzumab were not affected by the presence and level of anti-alemtuzumab antibodies in the phase III studies. Moreover, alemtuzumab remained more effective than interferon beta-1a regardless of the presence or absence of anti-interferon beta-1a neutralizing antibodies, although the studies were not powered to detect an interaction.

Further information is required with regard to the long-term effects of alemtuzumab; i.e. whether alemtuzumab treatment should be repeated at a later date following the initial treatment regimen, or whether the effects observed so far (with data from up to 5 years) continue without the need for retreatment. There is also a great need to discover ways of providing individualized treatment, as each patient’s disease course is different, and treatments that are appropriate for some are less appropriate for others. More research that sheds further light on the course of the disease itself would clearly be of great use in determining the appropriate treatment, as would examination of whether early intensive intervention has long-term advantages, over standard treatment followed by second-line intensive treatments. In addition, alemtuzumab has to date largely been administered to patients with chronic lymphocytic leukaemia, who have a time-limited survival. Therefore, given that treated patients with multiple sclerosis are likely to have an almost full life expectancy, it will be necessary to determine what long-term effects on immunity and lymphoid organs there are with alemtuzumab treatment in these patients. And, naturally, trials directly comparing the efficacy and tolerability of alemtuzumab with other multiple sclerosis treatments, such as the newer oral drugs or natalizumab, would be of great interest.

On the assessments of effectiveness, tolerability and convenience, there is as yet no treatment that rates highly on all three. Alemtuzumab itself is both effective and convenient, but its risk of autoimmunity development is worthy of consideration; however, if pretreatment assessment of biomarkers associated with the development of autoimmune disease following alemtuzumab treatment proves to be accurate, this may even out.

Given the risk-benefit profile of alemtuzumab, it appears it may be most appropriate for patients with active disease, and when administered earlier rather than later in the disease course. Of particular note, alemtuzumab, unlike most multiple sclerosis drugs, does not appear to be associated with the reversion to previous clinical disease activity once treatment is stopped; as mentioned above, time will tell if this continues past the follow-up duration so far investigated.

In December 2013, the US FDA stated that the evidence submitted for the efficacy of alemtuzumab was not sufficient for approval, and that further data from one or more additional active comparator clinical trials of different design and execution are required before alemtuzumab can be approved [43]. Genzyme intends to appeal this decision; however, as a result, alemtuzumab is not yet approved for the treatment of RRMS in the US.

In conclusion, alemtuzumab is an effective treatment for patients with active RRMS, and has a generally acceptable tolerability profile. In phase III trials, it was shown to be more effective than a current first-line treatment, interferon beta-1a, in decreasing relapse rate in treatment-naïve and previously treated patients and in decreasing disability progression in previously treated patients. Of note, these results appear to have extended into the long-term follow-up, despite no further treatment in the majority of patients. There was an increased risk of autoimmunity and infection associated with alemtuzumab in these trials; while these adverse events were generally mild to moderate, some were severe. Alemtuzumab is a highly convenient treatment, requiring an intravenous infusion on a handful of days on two consecutive years, with no treatment required in between; however, this convenience is counterbalanced by the need for regular monitoring for the increased risk of autoimmunity. More investigation is required before final conclusions can be drawn on the correct placement of alemtuzumab in multiple sclerosis treatment; however, it is of a certainty a welcome addition to the treatment options for these patients.

Sources:

Medical literature (including published and unpublished data) on alemtuzumab in patients with relapsing multiple sclerosis was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 31 January 2013], bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug

Search terms: alemtuzumab, multiple sclerosis

Study selection: Studies in patients with relapsing multiple sclerosis who received alemtuzumab. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included

Keywords: Alemtuzumab, multiple sclerosis, therapeutic efficacy, tolerability, pharmacodynamics, pharmacokinetics