Multiple Sclerosis

Table 2: Alemtuzumab Mechanism of Action and Autoimmunity Studies Mechanism of Action Study

Study Methods

Genetics, T-cell apoptosis IL-21 levels in T-cell apoptosis, serum IL-21 and RRMS patients treated with alemtuzumab genetic studies determined in groups from a population of 232 patients with RRMS

B-cell reconstitution after alemtuzumab treatment

B-cell levels and serum BAFF

(measured in 78 patients with RRMS receiving alemtuzumab and 13 healthy controls)

Transgenic human CD52 mouse model Transgenic mouse model expressing human CD52 to study effect of alemtuzumab on immune function

Study Findings

IL-21 expression is genetically pre-determined. Greater levels of T-cell apoptosis, T-cell cycling and serum IL-21 in patients who develop autoimmunity

after alemtuzumab treatment. High IL-21 levels may facilitate autoimmunity

B-cell reconstitution is rapid after alemtuzumab, levels return to baseline by 3 months. BAFF levels elevated for 12 months. Most abundant cell types

1 month after treatment: immature transitional 1 B cells. High BAFF levels may have a role in autoimmunity

Alemtuzumab transiently increased serum cytokines Hu et al. and reduced blood lymphocytes similar to human

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response. Lymphocyte depletion was lower in lymphoid organs. Eliminating natural killer cells and neutrophils reduced effects of alemtuzumab; removal of complement factor had no effect – alemtuzumab is believed to mediate lymphocyte depletion primarily through ADCC versus complement cytotoxicity

ADCC = antibody-dependent cell-mediated cytotoxicity; BAFF = B-cell activating factor; IL = interleukin; RRMS = relapsing–remitting multiple sclerosis. fatal progressive multifocal leukoencephalopathy (PML),38 and this risk

increases with time on the drug. Post-marketing data indicate a similar risk, with 11 reported cases of PML in 18,000 patients receiving at least 18 months of therapy.2

of 1.63 PML cases per 1,000 patients treated.39

More recent data indicate a global incidence Mitoxantrone is

associated with cardiotoxicity; in one analysis of 1,378 patients with no history of congestive heart failure (CHF), the risk of CHF in patients with MS was <0.20% (mean cumulative dose of mitoxantrone 60.5mg/m2). In the same study, 2.2% of patients experienced an asymptomatic reduction in left ventricular ejection fraction of <50%, although this was not correlated with cumulative mitoxantrone dose.40 Furthermore, the risk of developing mitoxantrone-therapy-related acute leukaemia was 0.74% in one retrospective study,41 much higher than the rate observed in clinical studies.40

which is

Injection anxiety and injection-site reactions can discourage patients resulting in low adherence, particularly during the first few months of treatment, leading to suboptimal health outcomes.42–44

In addition, some patients may have difficulty following the correct dosing regimen or injection technique.43

Finally, a lack of

perceived efficacy is the main reason for discontinuation of therapy despite the fact that some therapies require longer courses to show health benefits.43

New Treatment Options for Relapsing–Remitting Multiple Sclerosis are Being Developed

Recently, a series of oral DMDs have entered late-stage development: cladribine, dimethyl fumarate, laquinimod and teriflunomide. Data from phase II and III trials suggest that these have similar or improved efficacy compared with existing DMDs, although properly designed head-to-head comparative studies are lacking. However, the option of an oral therapy and the elimination of injections could represent an

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With the exception of the recently approved oral medication, fingolimod, the other approved DMDs for use in MS require regular administration (daily, every other day, weekly or monthly [in the case of natalizumab]) by injection for indefinite periods to allow optimal outcomes.42

attractive option to MS patients.2,18,42,45–49 The approval of oral DMDs

may improve patient adherence to therapy, particularly for patients who have concerns with frequent injections. One such treatment, teriflonomide, has been shown in a recently completed phase III trial to have a benign safety profile, similar to that of placebo.50

However,

most other oral DMDs have been shown to have significant side effects such as increased rates of malignancy and infections and these may outweigh the benefits for some patients.42

In addition

to these oral preparations, there are a number of mAbs undergoing phase II and III trials for the treatment of MS, including rituximab (anti-CD20 on B-lymphocytes), daclizumab (anti-CD25 on T cells), alemtuzumab (anti-CD52 on both T and B cells), ofatumumab and ocrelizumab (newer anti-CD-20 types).51

See Table 1 for an overview of

the efficacies of novel treatments relative to placebo or active comparator. Of these, alemtuzumab is the furthest developed and has been used in the most extensive clinical trials of these agents in MS therapy. Alemtuzumab is already approved for first-line treatment of B-cell chronic lymphocytic leukaemia.52

In early studies, alemtuzumab

has shown remarkable efficacy in the treatment of MS, with significant improvements in disability. Alemtuzumab is administered in short courses at 12-month intervals, making dosing regimens entirely different from the available injectable DMDs.53,54

Mode of Action of Alemtuzumab

Alemtuzumab is a humanised mAb that targets CD52, a glycoprotein on the surface of various blood cell types (T- and B-lymphocytes, monocytes and eosinophils).55

CD52 antigens are expressed at high

density on T- and B-lymphocytes but at lower density on cells of the innate immune system and not on haematological precursor cells.53,56 Once bound to CD52, alemtuzumab triggers antibody-mediated cytotoxicity and complement fixation;57

subsequent lymphocyte

depletion and cytokine induction appear to be mediated by neutrophils and natural killer cells.58

alemtuzumab and the exact function of CD52 are not fully understood.

The distribution of CD52 may account for the selective and beneficial mode of action of alemtuzumab and for the transient depletion of

EUROPEAN NEUROLOGICAL REVIEW However, the exact mode of action of

Thompson et al. 201060

Reference Jones et al. 200968