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.
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.