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 Thompson et al. return to baseline by 3 months. BAFF levels elevated 201060 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 and reduced blood lymphocytes similar to human
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.
refractory cases of relapsing MS, but mitoxantrone is decreasingly used.14,15,34,35
Evaluation of pooled clinical trial data has shown that, compared with placebo, approximately 0.1% of patients treated with natalizumab for 18 months developed the rare but potentially fatal progressive multifocal leukoencephalopathy (PML),38
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
1.63 PML cases per 1,000 patients treated.39
However, both of these drugs are associated with serious adverse events (AE) and therefore are generally used as second-line options, although use as first-line therapy may be warranted in selected cases.14,15,36,37
and this risk
More recent data indicate a global incidence of 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 leukemia was 0.74% in one retrospective study,41 observed in clinical studies.40
which is much higher than the rate
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
84
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
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 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. In a recently completed phase III trial one such treatment, teriflonomide, has been shown to have a benign safety profile similar to that of placebo.50
However, most other oral DMDs
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
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
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 leukemia.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 humanized 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 US NEUROLOGY
Hu et al. 200958
Reference Jones et al. 200968
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