touchNEUROLOGY touchNEUROLOGY
Multiple Sclerosis
Read Time: 4 mins

Alemtuzumab—A New Efficacy Benchmark in Relapsing–Remitting Multiple Sclerosis?

Copy Link
Published Online: Jun 4th 2011 US Neurology, 2010;6(2):82-90 DOI: http://doi.org/10.17925/USN.2010.06.02.82
Authors: Omar A Khan
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

The disease-modifying drugs (DMDs) available for the treatment of multiple sclerosis (MS) have been used effectively for nearly two decades. These treatments delay the neurorodegenerative process, but do not restore lost neurological function. New oral DMDs are becoming available that offer improved convenience over existing injectable DMDs. Recently, several monoclonal antibody treatments have been developed for MS; the furthest developed is alemtuzumab (Campath-1H). In a landmark phase II clinical trial (CAMMS223) on patients with relapsing–remitting MS (RRMS), short cycles of alemtuzumab given at baseline, at 12 months, and optionally at 24 months, demonstrated superior and sustained efficacy in terms of relapse rates and magnetic resonance imaging (MRI) findings over the comparator compound, interferon beta-1a (IFNβ-1a), which was given subcutaneously and continuously. Most notably, the mean disability score for patients receiving alemtuzumab showed an unprecedented improvement, whereas for IFNβ-1a it deteriorated. Alemtuzumab in treating RRMS is the subject of two ongoing phase III trials, the results of which have the potential to change future treatments and prognoses for many patients.
Support: Editorial assistance was provided by Touch Briefings and funded by Genzyme. The views and opinions expressed are those of the author and not necessarily those of Genzyme.

Keywords

Alemtuzumab, monoclonal antibody, multiple sclerosis, disease-modifying drugs, disability, clinical trials

Article:

The introduction of disease-modifying drugs (DMDs) during the 1990s made chronic therapies that inhibit the disease process in multiple sclerosis (MS) available to patients for the first time.1,2 While the currently available DMDs decrease the number of relapses, delay the onset of disabilities, improve quality of life (QoL), and allow increased participation in work and social activities,3–7 they only modestly delay disease progression and none has the capacity to restore lost neurological function. Therefore, improvement in motor and cognitive ability in MS has remained a substantially unmet clinical need. This deficiency has prompted the search for and development of better alternatives, some of which are now pending regulatory approval. The treatment landscape in MS treatment will soon see a rapid transition; many promising new DMDs are currently in development, including a number of oral medications and parenteral monoclonal antibodies (mAbs). The arrival of these new treatments will profoundly increase the number of options available to the neurologist and may change the prognosis for many patients with MS. This article will outline the currently available MS treatments and consider the potential benefits of investigative agents. It will then focus on the fully humanized mAb: alemtuzumab (Genzyme). The clinical development program of this drug, its potential lymphocyte modulatory role, its potential advantages over existing injection-based, newer oral therapies, and investigative agents will also be discussed.

Current Treatments for Relapsing–Remitting Multiple Sclerosis
Eight DMDs have been approved for treating MS: interferon beta-1a ([IFNβ-1a], Rebif® subcutaneously [SC] and Avonex® intramuscular [IM]), IFNβ-1b (Betaseron® SC and Extavia® SC), glatiramer acetate (Copaxone® SC), natalizumab (intravenous [IV] infusion humanized monoclonal antibody against the α4 subunit of α4β1 integrin on leukocytes, Tysabri®), mitoxantrone (an immune suppressor and antineoplastic, Novantrone® IV infusion), and fingolimod (a sphingosine 1-phosphate receptor [S1PR] modulator, Gilenya®, an oral capsule that was approved by the US Food and Drug Administration [FDA] in September 2010). Clinical trials conducted over the past 20 years have investigated the efficacy, safety, and tolerability of these medications.8–19 Recent head-to-head trials comparing different IFNβs and comparing IFNβs with glatiramer acetate have shown comparative efficacy between the products.20–23 However, one study demonstrated that IFNβ-1a SC was significantly more effective than IFNβ-1a IM in reducing relapse rate and activity on magnetic resonance imaging (MRI) and increasing time to relapse.24,25 Another study, the Independent Comparison of Interferon (INCOMIN) trial, also showed superiority of IFNβ-1b SC during two years of treatment over IFNβ-1a IM in terms of the proportion who were relapse-free, the relative risk of relapse and the proportion remaining free from new T2 lesions detected by MRI.26 A disadvantage with IFNβ therapy in some patients is the development of neutralizing antibodies and this is associated with reduced efficacy,27–32 particularly in patients with persistently high titres of antibodies. Such patients often benefit from switching to a non-IFNβ therapy.33For patients who relapse despite using IFNβs or glatiramer acetate, the next treatment options are natalizumab or mitoxantrone. Both natalizumab and mitoxantrone can be highly effective in treating refractory cases of relapsing MS, but mitoxantrone is decreasingly used.14,15,34,35 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 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 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 More recent data indicate a global incidence of 1.63 PML cases per 1,000 patients treated.39 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 which is much higher than the rate observed in clinical studies.40

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 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.43Finally, 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 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 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 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.53,54Mode 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 density on T- and B-lymphocytes but at lower density on cells of the innate immune system and not on hematological 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 However, the exact mode of action of 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 both T- and B-lymphocytes. Importantly, because CD52 is found less frequently on innate immune cells, such as natural killer cells and phagocytes, alemtuzumab does not appear to disrupt other immune system functions. This could explain the relatively low rates of serious infections reported for alemtuzumab in clinical trials. Pre-clinical mechanism of action studies on alemtuzumab have been limited by a lack of cross-reactivity between human and mouse CD52. However, significant insights into alemtuzumab’s mechanism of action have been gained via studies in the recently developed transgenic mouse that expresses human CD52 (hCD52) under control of the hCD52 promoter.58

The tissue distribution of hCD52 and immune function in the transgenic mice were normal. Treating the mice with alemtuzumab transiently increased serum cytokines and reduced blood lymphocytes in a manner that was similar to the response seen in humans. However, lymphocyte depletion was not as marked in lymphoid organs including the spleen, thymus, and lymph nodes; this could explain why patients receiving alemtuzumab show a lower incidence of infection than might be anticipated. In mice, eliminating populations of natural killer cells and neutrophils with antibodies to Gr-1 or asialo-GM-1, respectively, markedly reduced the effects of alemtuzumab but removal of complement using cobra venom factor had no effect. These findings indicate that lymphocyte depletion resulting from alemtuzumab therapy relies primarily on antibody-dependent cell-mediated cytotoxicity as opposed to complement-dependent cytotoxicity. An overview of these potential mechanisms of action is shown in Table 2.

After alemtuzumab treatment, immune reconstitution follows a unique characteristic pattern in which B cells return towards baseline levels within three months while T cells take up to five years to recover.59,60

Following peripheral lymphocyte depletion, it has been postulated that naïve myelin-specific T cells could be tolerized, preventing their neurodegenerative activity.56 This property could provide alemtuzumab with immunomodulatory properties in addition to depleting lymphocytes.59 Furthermore, in vitro analysis has shown that alemtuzumab may increase the lymphocytic delivery of neurotrophins to the central nervous system promoting survival of neurons and increased axonal length.54 This potential neurorestorative action may partly explain the observed improvement in disability after alemtuzumab administration, although much work is required to further elucidate this effect. Overall, it appears that the benefits of alemtuzumab therapy in MS rest not on lymphocyte depletion per se, but rather in a long-term shift in the lymphocyte repertoire.

Alemtuzumab Clinical Trial Data
Initial pilot studies (1991–2002) comprising 58 patients with MS showed that alemtuzumab significantly reduced relapse rates in both RRMS and secondary progressive MS (SPMS) (2.2–0.19 and 0.7–0.001 relapses per year, respectively, both p<0.001).61 Moreover, in alemtuzumab-treated patients with either RRMS or SPMS there was no new lesion formation. It also produced sustained and significant reductions in disability progression in RRMS, but not in SPMS where disability accumulation was sustained.61 Data from these pilot studies suggest that alemtuzumab may be more effective in treating MS in early active patients.The phase II Campath-1H in Multiple Sclerosis (CAMMS223) trial provided the first well-designed controlled trial evidence in favor of alemtuzumab treatment in MS. This randomized study compared two doses of alemtuzumab with a current standard DMD treatment (IFNβ-1a SC) in a total of 334 DMD-naïve patients with early, active RRMS. Patients had an expanded disability status scale (EDSS) ≤3 and at least two clinical episodes during the previous two years.62 Patients received intravenous alemtuzumab 12 (n=108) or 24mg per day (n=108, both doses were administered initially as a five-day course then as a three-day course at 12 months and an optional 24 months) or IFNβ-1a 44μg SC three times weekly throughout the study (n=107). In CAMMS223, alemtuzumab showed markedly superior efficacy compared with IFNβ-1a in both the time to sustained accumulation of disability and the rate of relapse.62 An analysis at 36 months demonstrated that the annualized relapse rates for patients receiving IFNβ-1a or alemtuzumab 12 or 24mg per day and the pooled alemtuzumab analysis were 0.36, 0.11, 0.08, and 0.10, respectively (see Figure 1). Compared with IFNβ-1a, alemtuzumab 12 and 24mg per day reduced the rate of relapse by 69 and 79%, respectively (p<0.001 for both comparisons). For six-month sustained accumulation of disability (SAD), greater improvements were observed for alemtuzumab-treated patients compared with those treated with IFNβ-1a. An estimated 26.2, 8.5, 9.5, and 9% of patients had SAD in the IFNβ-1a, the alemtuzumab 12 and 24mg per day groups and the pooled alemtuzumab analysis, respectively. Compared with IFNβ-1a, the alemtuzumab 12 and 24mg per day and pooled groups reduced the risk of sustained accumulation of disability (six-months’ criteria) by 75, 67, and 71, respectively (p<0.001, p=0.003, and p<0.001). From baseline to 36 months, all treatment groups were observed to have a lower volume of lesions, as measured by T2-weighted MRI. In addition, significant reductions in lesion load from baseline were observed at 12 months (p=0.01) and 24 months (p=0.005) in patients receiving alemtuzumab compared with IFNβ-1a. The changes in mean EDSS score from baseline at 36 months were -0.32, -0.45, and -0.39 for alemtuzumab 12 and 24mg per day and the pooled alemtuzumab analysis, respectively (p=0.006, p<0.001 and p<0.001 for changes from baseline) but was +0.38 for IFNβ-1a (p<0.001 for comparisons between alemtuzumab and IFNβ-1a). This indicates an unprecedented improvement in disability status for patients receiving alemtuzumab but a deterioration for patients receiving IFNβ-1a. In addition, the proportion of patients observed to have improvements in disability scores was greater with alemtuzumab 12 and 24mg per day and pooled (54.2, 60.2, and 57.2%, respectively) than IFNβ-1a (33.7%) (see Figure 2). The four-year follow-up of CAMMS223 patients show that the efficacy advantages of alemtuzumab compared with IFNβ-1a were sustained over long-term durations despite the fact that no further doses of alemtuzumab were given after two years and that the majority had not received a dose for three years.63 In the pooled alemtuzumab groups, there was a 72% reduction in the risk of relapse and the proportion experiencing a relapse was approximately halved relative to the IFNβ-1a group. Annualized relapse rates were 0.1 for the pooled alemtuzumab groups and 0.34 for the IFNβ-1a group. With alemtuzumab there was a 73% reduction in the risk of SAD, which is supported by the Kaplan–Meier analysis of SAD during the CAMMS223 study and through four-years of follow-up given in Figure 3. The percentage of patients with SAD was 9% for pooled alemtuzumab groups and 32% for the IFNβ-1a group. The significant improvement in disability for alemtuzumab was also maintained during four years of follow-up; the EDSS scores in the pooled alemtuzum
b-treated patients improved by -0.43 (standard deviation [SD]=1.04) whereas for IFNβ-1a the EDSS scores deteriorated by +0.25 (SD=0.96) (p<0.001). Therefore, the four-year data provide further evidence of the durability of benefit derived from alemtuzumab in producing clinically disease-free status and preventing clinical progression in a substantial majority of RRMS patients. This treatment effect is observed even in those patients who completed only two annual cycles of alemtuzumab during the first 12 months.64Three-year data for the CAMMS223 trial show that the overall proportion of patients receiving alemtuzumab who reported AEs was greater than the proportion receiving IFNβ-1a. In the alemtuzumab groups, the most common AEs reported were infusion-associated reactions (98.6%). These reactions were confined to the alemtuzumab group due to the method of administration. These reactions included rash (91.7%), headache (61.1%), pyrexia (37.5%), fatigue (27.8%), pruritus (25.0%), and nausea (24.1%).

Notable AEs occurring in both the alemtuzumab (pooled analysis) and IFNβ-1a groups were: autoimmune thyroid disorders (23 and 3%), idiopathic thrombocytopenic purpura (ITP) (3 and 1%), and infections (66 and 47%).62 Among the other events, the most frequent were influenza-like illness (4 versus 27%; p<0.001), fatigue (31 versus 30%), headache (31 versus 28%), pyrexia (11 versus 10%), and rash (26 versus 14%). Apart from influenza-like symptoms, the differences in incidence in these events between alemtuzumab- and IFNβ-1a-treated groups were not significant.62

The first case of ITP went unrecognized and following several weeks of typical symptoms, presented with a fatal cerebral hemorrhage. However, the other ITP cases were self-limiting or responsive to treatment, all patients achieved durable remission and no ITP was reported >16 months after treatment.65 It was previously hypothesized that patients who had autoimmune AEs following alemtuzumab had a fundamentally different immune reconstitution and may be less likely to respond to treatment compared with patients without such events. The study data show that this is not the case; patients with autoimmune events through 36 months showed a 66% reduction in the risk of SAD (p=0.03) and a 78% reduction in risk of relapse (p<0.0001) compared with patients receiving IFNβ-1a.66 Therefore, patients who experienced autoimmunity were equally likely to benefit from alemtuzumab efficacy as those without such events.

In the CAMMS223 trial, one patient developed antiglomerular basement membrane (anti-GBM, Goodpastures syndrome). The patient developed hypothyroidism at month 24 (day 733) and at month 51 (39th month after the second alemtuzumab cycle), showed increased serum creatinine (1.9mg/dl at diagnosis and peaking at 2.8mg/dl) with hematuria. A renal biopsy showed anti-GBM. The patient also had an upper respiratory infection and rash, which are typical of anti-GBM, just prior to the onset of hematuria. The patient was treated with a course of plasmapheresis, cyclophosphamide, and steroids. Seventeen months after diagnosis, the patient remains in remission with elevated but stable serum creatinine and is MS relapse-free. In CAMMS223 to date, only one patient has developed anti-GBM disease (frequency 0.5%, event rate one per 981 patient-years).63,67

In MS patient populations treated with alemtuzumab to date, the incidence of any serious opportunistic infections has been low and the infections that have occurred were mostly of mild to moderate severity.62,65 However, the immunosuppressive effects of alemtuzumab may be selective with relative sparing of the lymphoid organs including the spleen, thymus, and lymph nodes. These observations demonstrate a favorable safety profile but larger phase III trial safety data are awaited.

Hypotheses Concerning Delayed or Secondary Autoimmunity
The mechanism of action of alemtuzumab and the process by which it might induce secondary autoimmunity in a subset of MS patients have received attention in several studies. Recent clinical data on a subset of 94 of the 232 patients in the CAMMS223 trial who had RRMS and received alemtuzumab has shown that those who develop lymphopenia-associated autoimmunity (mainly to the thyroid gland) have greater levels of T-cell apoptosis and T-cell cycling driven by substantially higher baseline levels (two-fold) of interleukin 21 (IL-21) than patients who do not develop autoimmunity.68 The study also showed that IL-21 expression is genetically pre-determined. It was proposed that following lymphocyte depletion by alemtuzumab, overproduction of IL-21 in some individuals results in excess T-cell cycling and apoptosis and thereby increases the stochastic opportunities for T-cells to encounter self antigen and break tolerance and for autoimmunity to develop. Increased IL-21 levels may also act to promote B-cell differentiation and antibody production.56 Therefore, IL-21 levels could be used as a biomarker prior to alemtuzumab treatment, to indicate which patients may be at increased risk of developing secondary autoimmunity.Other immunological studies have shown that although lymphocytes are repeatedly depleted during cycles of alemtuzumab treatment, the capacity of the immune system to regenerate remains unimpaired. After exposure to alemtuzumab, B-cell reconstitution is rapid, with levels returning to baseline by three months and to higher levels by 12 months.60 The most abundant B-cell subtype one month after treatment are immature transitional B cells. At the same time, there is an increase (33%) in serum levels of B-cell activating factor (BAFF) that is sustained for at least 12 months. BAFF is essential for transition of immature B cells to a mature naïve B-cell phenotype and has been associated with the development of autoimmunity by an as yet, incompletely understood mechanism.60 A potential factor contributing to autoimmunity following alemtuzumab treatment is the delayed proliferation of T-cell populations, including T-regulatory cells, at a time of rapid proliferation of unregulated B-cells.54,60,69

An Ongoing Clinical Development Program for Alemtuzumab
The development program for alemtuzumab consists of two large ongoing phase III trials with active comparators (i.e. no placebo arm) and an extension study. These will include both previously untreated patients and those who have relapsed on therapy. The first of the phase III trials is the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS-I) trial, which is a randomized, rater-blinded, multicentre study comparing one dose level of alemtuzumab with IFNβ-1a in treatment-naïve patients with early active RRMS.70 In this trial, a total of 581 patients have been randomized and alemtuzumab (12mg per day IV) was initially administered for five days and then for a three-day course at 12 months. The comparator (IFNβ-1a, 44μg SC) is to be given three times weekly throughout (randomized 2:1) (see Figure 4). The end-points include time to SAD, relapse rates, change from baseline in MRI-T2-detected hyperintense lesions, change from baseline EDSS, and acquisition of disability as assessed by the multiple sclerosis functional composite (MSFC) over a two-year period.

The parallel study, CARE-MS II, includes patients with active RRMS who have relapsed at least once in the past 10 years while receiving either IFNβ or glatiramer acetate and have an EDSS score of 0.0–5.71 A total of 840 patients have been enrolled in the trial. CARE-MS II includes two dose levels of alemtuzumab (12mg per day and an exploratory 24mg per day) and IFNβ-1a (44μg), (randomized 2:2:1) (see Figure 4). The end-points are similar to CARE-MS I. Together, the results from these trials will further define the clinical profile of alemtuzumab in RRMS. An open-label extension study is also in progress for all patients from CAMMS223 and those completing CARE-MS I and II.72 Alemtuzumab-treated patients will receive further alemtuzumab based on protocol-specified criteria of disease activity that include relapse or a minimum of two new lesions on cranial/spinal MRI consisting of any combination of gadolinium-enhancing lesions or new or enlarging T2 lesions. This treatment approach is innovative as it represents the first time where patients would receive MS therapy only on an as-needed basis. IFNβ-1a-treated patients will receive annual courses of alemtuzumab (12mg per day for five days initially then for three days after 12 months) and then will have the option of further treatment based on the same criteria for the patients previously treated with alemtuzumab. The extension study is designed to assess the long-term efficacy and safety of alemtuzumab, define criteria for additional as needed alemtuzumab therapy, and determine the safety and effectiveness of the alemtuzumab in patients who switch from IFNβ. As with the phase III studies, the extension study will include risk-monitoring programs for autoimmune disease.

Implications of Study Data
Efficacy data from the phase II CAMMS223 trial provide strong evidence that alemtuzumab represents a major advance in the treatment of RRMS. Improvements over IFNβ-1a were seen in terms of reducing relapse rates, reducing both the number of lesions and new lesions, and decreasing progression of disability in patients with RRMS. Most surprisingly, the majority of patients treated with alemtuzumab in the CAMMS223 trial showed an improvement in disability scores compared with worsening scores with IFNβ-1a. This could indicate that for some patients in the early phase of the disease, treatment with alemtuzumab may reverse deficits by its potent immune modulating effect and allow physiologically effective repair in the central nervous system to occur. The potential finite treatment duration of alemtuzumab could fulfil a substantially unmet clinical need in MS and free patients from the necessity of constant DMD treatment. This administration regimen helps patients to forget about their diseases and achieves high levels of adherence resulting in durable remission. As the disease transitions into SPMS, neuronal damage and axonal loss become more extensive and with such high levels of damage repair mechanisms appear unable to restore function. Alemtuzumab could potentially delay or prevent the onset of the secondary progressive phase.

Future Developments
In the future, there will be a greater choice of DMDs available to the neurologist for MS treatment. Choosing either of the current injectable agents, new oral agents, or existing and new monoclonal antibody therapies will require an understanding of the therapeutic role of these medications and the development of guidelines. Immunomodulators have made great progress in the last few years, but it will be important for patients to be carefully monitored to ensure ongoing therapeutic effect. A patient must have a decreased number of relapses and reduced relapse severity compared with the pre-therapeutic phase, slowed disease progression and a lack of severe side effects that reduce QoL. The order in which MS treatments are used and methods for optimal dosing in individual patients will also need to be defined. As more clinical data become available, escalating immunotherapy options will need to be redefined.33,73 The role of biomarkers in therapeutic monitoring and clinical outcomes is also likely to emerge in the near future, providing further guidance to the clinician.7,74 The completion of the first decade of this century is heralding a new era of MS therapeutics. In this context, alemtuzumab offers great promise for MS patients. If the phase II data are replicated in the ongoing phase III trials, alemtuzumab may set the bar for therapeutic efficacy. If the long-term safety of this agent is acceptable and manageable, alemtuzumab may present itself as a potent and reasonable first choice in a long list of therapeutic options.

Article Information:
Disclosure

Omar A Khan, MD, is a consultant to and has received research support from Genzyme.

Correspondence

Omar A Khan, MD, Multiple Sclerosis Center and MR Image Analysis Laboratory, Department of Neurology, Wayne State University School of Medicine, 4201 St Antoine, 8D-UHC, Detroit, MI 48201. E: okhan@med.wayne.edu

Received

2010-10-04T00:00:00

References

  1. Goodin DS, Bates D, Treatment of early multiple sclerosis: the value of treatment initiation after a first clinical episode, Mult Scler, 2009;15:1175–82.
  2. Lim SY, Constantinescu CS, Current and future disease-modifying therapies in multiple sclerosis, Int J Clin Pract, 2010;64:637–50.
  3. Goodman AD, Brown TR, Krupp LB, et al., Sustainedrelease oral fampridine in multiple sclerosis: a randomized, double-blind, controlled trial, Lancet, 2009;373:732–8.
  4. Gusev EI, Boiko AN, Multiple sclerosis at the time of world-wide use of disease modifying treatment, Zh Nevrol Psikhiatr Im S S Korsakova, 2009;109:4–9.
  5. Katrych O, Simone TM, Azad S, et al., Disease-modifying agents in the treatment of multiple sclerosis: a review of long-term outcomes, CNS Neurol Disord Drug Targets, 2009;8:512–9.
  6. Jongen PJ, Sindic C, Carton H, et al., Improvement of health-related quality of life in relapsing remitting multiple sclerosis patients after 2 years of treatment with intramuscular interferon-beta-1a, J Neurol, 2010;257:584–9.
  7. Rudick RA, Miller DM, Health-related quality of life in multiple sclerosis: current evidence, measurement and effects of disease severity and treatment, CNS Drugs, 2008;22:827–39.
  8. IFNB Multiple sclerosis Study Group, Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group, Neurology, 1993;43:655–61.
  9. PRISMS Study Group, Randomized double-blind placebo-controlled study of interferon beta-1a in relapsing/ remitting multiple sclerosis, Lancet, 1998;352:1498–504.
  10. Cocco E, Marchi P, Sardu C, et al., Mitoxantrone treatment in patients with early relapsing-remitting multiple sclerosis, Mult Scler, 2007;13:975–80.
  11. Cohen JA, Barkhof F, Comi G, et al., Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis, N Engl J Med, 2010;362:402–15.
  12. Comi G, O'Connor P, Montalban X, et al., Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results, Mult Scler, 2010;16:197–207.
  13. Galetta SL, Markowitz C, Lee AG, Immunomodulatory agents for the treatment of relapsing multiple sclerosis: a systematic review, Arch Intern Med, 2002;162:2161–9.
  14. Hartung HP, Gonsette R, Konig N, et al., Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomized, multicentre trial, Lancet, 2002;360:2018–25.
  15. Hyde R, Bozic C, Belcher G, Utilization and safety of natalizumab in patients with relapsing multiple Sclerosis in the post-marketing setting, Congress of Neurology, Bangkok, Thailand, 24–30 October 2009.
  16. Jacobs LD, Cookfair DL, Rudick RA, et al., Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG), Ann Neurol, 1996;39:285–94.
  17. Johnson KP, Brooks BR, Cohen JA, et al., Copolymer 1 reduces relapse rate and improves disability in relapsingremitting multiple sclerosis, Neurology, 1995;45:1268–76.
  18. Kappos L, Radue EW, O'Connor P, et al., A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis, N Engl J Med, 2010;362:387–401.
  19. Polman CH, O'Connor PW, Havrdova E, et al., A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis, N Engl J Med, 2006;354:899–910.
  20. Cadavid D, Cheriyan J, Skurnick J, et al., New acute and chronic black holes in patients with multiple sclerosis randomized to interferon beta-1b or glatiramer acetate, J Neurol Neurosurg Psychiatry, 2009;80:1337–43.
  21. Comi G, Martinelli V, Rodegher M, et al., Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomized, double-blind, placebo-controlled trial, Lancet, 2009;374:1503–11.
  22. Mikol DD, Barkhof F, Chang P, et al., Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study), Lancet Neurol, 2008;7:903–14.
  23. O'Connor P, Filippi M, Arnason B, et al., 250 microg or 500 microg interferon beta-1b versus 20mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomized, multicentre study, Lancet Neurol, 2009;8:889–97.
  24. Schwid SR, Thorpe J, Sharief M, et al., Enhanced benefit of increasing interferon beta-1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE Study, Arch Neurol, 2005;62:785–92.
  25. Panitch H, Goodin D, Francis G, et al., Benefits of high-dose, high-frequency interferon beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial, J Neurol Sci, 2005;239:67–74.
  26. Durelli L, Verdun E, Barbero P, et al., Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomized multicentre study (INCOMIN), Lancet, 2002;359:1453–60.
  27. Deisenhammer F, Neutralizing antibodies to interferon-beta and other immunological treatments for multiple sclerosis: prevalence and impact on outcomes, CNS Drugs, 2009;23: 379–96.
  28. Goodin DS, Frohman EM, Hurwitz B, et al., Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, Neurology, 2007;68: 977–84.
  29. Hartung HP, Munschauer F III, Schellekens H, Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: expert opinions based on the Proceedings of an International Consensus Conference, Eur J Neurol, 2005;12:588–601.
  30. Koch-Henriksen N, Sorensen PS, Bendtzen K, et al., The clinical effect of neutralizing antibodies against interferonbeta is independent of the type of interferon-beta used for patients with relapsing-remitting multiple sclerosis, Mult Scler, 2009;15:601–5.
  31. Pachner AR, Warth JD, Pace A, et al., Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study, Neurology, 2009;73:1493–1500.
  32. van der Voort LF, Gilli F, Bertolotto A, et al., Clinical effect of neutralizing antibodies to interferon beta that persist long after cessation of therapy for multiple sclerosis, Arch Neurol, 2010;67:402–7.
  33. Wiendl H, Toyka KV, Rieckmann P, et al., Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations, J Neurol, 2008;255:1449–63.
  34. Belachew S, Phan-Ba R, Bartholome E, et al., Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing–remitting multiple sclerosis, Eur J Neurol, 2010 [Epub ahead of print].
  35. Coyle PK, The role of natalizumab in the treatment of multiple sclerosis, Am J Manag Care, 2010;16:S164–70.
  36. Kleinschmidt-DeMasters BK, Tyler KL, Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis, N Engl J Med, 2005;353:369–74.
  37. Langer-Gould A, Atlas SW, Green AJ, et al., Progressive multifocal leukoencephalopathy in a patient treated with natalizumab, N Engl J Med, 2005;353:375–81.
  38. Yousry TA, Major EO, Ryschkewitsch C, et al., Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy, N Engl J Med, 2006;354:924–33.
  39. Subramanyam M, Plavina T, Simon K, et al., Factors associated with anti-JCV antibody prevalence in a large cohort of natalizumab-treated MS patients. 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. P138, Gothenberg, Sweden, 13–16 October 2010.
  40. Ghalie RG, Edan G, Laurent M, et al., Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS, Neurology, 2002;59:909–13.
  41. Martinelli V, Incidence of Acute Leukemia in Multiple Sclerosis Patients Treated with Mitoxandrone: A Multicentre Retrospective Italian Study. Abstract from the 61st Annual Meeting of the American Academy of Neurology (AAN), Seattle, WA, 2009.
  42. Rammohan KW, Shoemaker J, Emerging multiple sclerosis oral therapies, Neurology, 2010;74(Suppl. 1):S47–53.
  43. Patti F, Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence, Patient Prefer Adherence, 2010;4:1–9.
  44. Turner AP, Williams RM, Sloan AP, et al., Injection anxiety remains a long-term barrier to medication adherence in multiple sclerosis, Rehabil Psychol, 2009;54:116–21.
  45. Comi G, Pulizzi A, Rovaris M, et al., Effect of laquinimod on MRI-monitored disease activity in patients with relapsing–remitting multiple sclerosis, Lancet, 2008;371:2085–92.
  46. Conway D, Cohen JA, Emerging Oral Therapies in Multiple Sclerosis, Curr Neurol Neurosci Rep, 2010;10(5):381–8.
  47. Giovannoni G, Comi G, Cook S, et al., A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis, N Engl J Med, 2010;362:416–26.
  48. Kappos L, Gold R, Miller DH, et al., Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomized, double-blind, placebocontrolled phase IIb study, Lancet, 2008;372:1463–72.
  49. Marriott JJ, O'Connor PW, Emerging Therapies in Relapsing- Remitting Multiple Sclerosis, Rev Recent Clin Trials, 2010;5(3):179–88.
  50. O'Connor P, Wolinsky J, Confavreux C, et al., A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: clinical efficacy and safety outcomes. 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Gothenberg, Sweden, 13–16 October 2010.
  51. Buttmann M, Treating multiple sclerosis with monoclonal antibodies: a 2010 update, Expert Rev Neurother, 2010;10: 791–809.
  52. Demko S, Summers J, Keegan P, et al., FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia, Oncologist, 2008;13: 167–74.
  53. Jones JL, Coles AJ, Spotlight on alemtuzumab, Int MS J, 2009;16:77–81.
  54. Jones JL, Anderson JM, Phuah CL, et al., Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity, Brain, 2010;133(Pt 8):2232–47.
  55. Xia MQ, Tone M, Packman L, et al., Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone, Eur J Immunol, 1991;21:1677–84.
  56. Simpson BS, Coles AJ, Rationale for cytotoxic monoclonal antibodies in MS, Int MS J, 2007;14:48–56.
  57. Gilleece MH, Dexter TM, Effect of Campath-1H antibody on human hematopoietic progenitors in vitro, Blood, 1993;82:807–12.
  58. Hu Y, Turner MJ, Shields J, et al., Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model, Immunology, 2009;128:260–70.
  59. Cox AL, Thompson SA, Jones JL, et al., Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis, Eur J Immunol, 2005;35:3332–42.
  60. Thompson SA, Jones JL, Cox AL, et al., B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis, J Clin Immunol, 2010;30:99–105.
  61. Coles AJ, Cox A, Le Page E, et al., The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy, J Neurol, 2006;253:98–108.
  62. The CAMMS223 Trial Investigators, Alemtuzumab versus interferon beta-1a in early multiple sclerosis, N Engl J Med, 2008;359:1786–801.
  63. Coles A on behalf of the CAMMS223 Study Group, Alemtuzumab treatment benefit is durable: primary efficacy outcomes of CAMMS223 at 4 years Presented at the 25TH Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Dusseldorf, Germany, 9–12 September 2009, Poster P 890.
  64. Khan O on Behalf of the CAMMS223 Study Group, Alemtuzumab Reduces Disease Progression in RRMS: Long- Term Results of the CAMMS223 Trial, presented at the 62nd Annual meeting of the American Society of Neurology, Toronto, Canada, 12–17 April 2010, Poster P04.213.
  65. Fox E on Behalf of the CAMMS223 Study Group, Long-Term Follow-Up of Immune Thrombocytopenia after Treatment of Multiple Sclerosis Patients with Alemtuzumab in CAMMS223, Presented at the 62nd Annual meeting of the American Society of Neurology, Toronto, Canada, 12–17 April 2010, P05.036.
  66. Brinar V on Behalf of the CAMMS223 Study Group, Benefits of Alemtuzumab Are Evident Even in Relapsing-Remitting Multiple Sclerosis Patients Who Experience Autoimmune Adverse Events, Presented at the 62nd Annual meeting of the American Society of Neurology, Toronto, Canada, 12–17 April 2010, P03.114.
  67. Meyer D, Coles A on behalf of the CAMMS223 Study Group, Case report of anti-glomerular basement membrane disease following alemtuzumab treatment, 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 13–16 September 2010 Gothenberg, Sweden 2010.
  68. Jones JL, Phuah CL, Cox AL, et al., IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H), J Clin Invest, 2009;119:2052–61.
  69. Clatworthy MR, Wallin EF, Jayne DR, Anti-glomerular basement membrane disease after alemtuzumab, N Engl J Med, 2008;359:768–9.
  70. Havrdova E for the Care-MS Steering Committee. The CAREMS I trial (Comparison of Alemtuzumab and Rebif Efficacy in multiple sclerosis): design of a Phase 3, open-label, rater-blinded study of alemtuzumab in treatment-naive patients with relapsing MS. 60th Annual meeting of the American academy of Neurology, Chicago, USA, 2008.
  71. Fox E for the CARE-MS Steering Committee. The CARE-MS II trial (Comparison of Alemtuzumab and rebif Efficacy in multiple sclerosis): design of a Phase 3, open-label, rater-blinded study of alemtuzumab in treatment-naive patients who have relapsed on therapy. 60th Annual meeting of the American academy of Neurology, Chicago, USA, 2008.
  72. LaGanke C on behalf of the the CAMMS Study Groups. CARE-MS extension study: as needed RRMS treatment paradigm with alemtuzumab. 24th Annual meeting of the Consortium of Multiple Sclerosis Centers, San Antonio, USA, 2–5 June 2010.
  73. Boster A, Edan G, Frohman E, et al., Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician, Lancet Neurol, 2008;7:173–83.
  74. Harris VK, Sadiq SA, Disease biomarkers in multiple sclerosis: potential for use in therapeutic decision making, Mol Diagn Ther, 2009;13:225–44.
  75. Hauser SL, Waubant E, Arnold DL, et al., B-cell depletion with rituximab in relapsing-remitting multiple sclerosis, N Engl J Med, 2008;358:676–88.
  76. Wynn D, Kaufman M, Montalban X, et al., Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomized, double-blind, placebo-controlled, add-on trial with interferon beta, Lancet Neurol, 2010;9:381–90.

Further Resources

Share this Article
Related Content In Multiple Sclerosis
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72