Drug Safety Evaluation
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Drug safety evaluation of alemtuzumab for multiple sclerosis 1.
Introduction
2.
Mechanism of action and pharmacokinetics
3.
Clinical applications
4.
Safety evaluation
5.
Conclusion
6.
Expert opinion
Mark Willis & Neil P Robertson† Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University School of Medicine, Cardiff, UK
Introduction: Alemtuzumab is a humanised anti-CD52 mAb which has recently been licensed for the treatment of relapsing multiple sclerosis in Europe. Areas covered: The efficacy and safety of alemtuzumab from open label, Phase II and Phase III trials is reported. Expert opinion: Alemtuzumab causes rapid and profound complement mediated lysis of circulating lymphocytes and allows beneficial modulation of the immune system during a subsequent reconstitution phase. Clinical trials have demonstrated superior efficacy against an active comparator, with reduction in annualised relapse rates and sustained accumulation of disability at 3 years and sustained efficacy at 5 years. The main adverse effects are mild to moderate infusion reactions, an increased incidence of mild to moderate infections and autoimmune adverse events. Thyroid disorders are the most common form of autoimmune adverse events, occurring in approximately one third of patients. Overt Graves’ hyperthyroidism represents approximately half of these cases. Careful patient selection and structured monitoring programs allow for effective patient management resulting in a favourable risk benefit profile. Keywords: alemtuzumab, autoimmune disease, multiple sclerosis, novel therapeutics Expert Opin. Drug Saf. [Early Online]
1.
Introduction
Multiple sclerosis (MS) is a complex, inflammatory disorder of the CNS and represents a major cause of chronic neurological disability in western societies. The aetiology of MS remains poorly understood but is generally considered to be related to an interaction of genetic and environmental factors. Recent genome wide association studies have identified > 100 disease associated genetic variants with a common theme being proximity to genes with immunological function and in particular T cell function and signalling [1]. Current treatment strategies are predominantly aimed at reducing inflammatory activity in the CNS in relapsing MS by modulating lymphocyte function [2,3], affecting lymphocyte trafficking [4] or depleting lymphocyte numbers, in the hope that early intervention may lead to the delay or prevention of progressive disease and avoidance of fixed long-term disability. MS has recently been an active and expanding area of research that has seen an evolution from an improved understanding of pathogenesis to bedside therapeutics and, as a result, there are an increasing number of new drugs in development. Although currently available medications have been shown to be effective at reducing relapse rates and radiological disease activity in the form of T2 lesion load or gadolinium enhancement, the evidence for impact on long-term disability remains elusive. The range of disease-modifying drugs licensed for relapsing MS has expanded considerably over recent years and an 10.1517/14740338.2014.928691 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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M. Willis & N. P. Robertson
Box 1. Drug summary Drug name Phase Indication Pharmacology description/mechanism of action Route of administration Chemical structure
Alemtuzumab Licenced in EU, Canada, Mexico, Canada and Brazil Relapsing multiple sclerosis Anti-CD52 mAb. Depletes lymphocyte pool Intravenous V L’
L70
VL
VH
D S
L18
L9
R
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3.1Å 2.9Å
S
L10
2.6Å L11 L
2-fold S
L12 L13 A S
L14
CAMPATH-1H
Pivotal trial(s)
Mechanism of action and pharmacokinetics
CD52 is a 12 amino acid glycosylated glycosylphosphatidylinositol-linked protein present on ~ 5% of the cell surface of lymphocytes. It is also expressed, at lower levels, on monocytes, macrophages, eosinophils and NK cells [13,14] as well as on epithelial cells lining the epididymis, vas deferens and seminal vesicle [13,15]. Importantly, it is not expressed on haematopoietic precursors allowing lymphocyte reconstitution [16]. The function of CD52 is largely unknown but has been shown to act as a co-stimulatory T cell activating molecule [17], to contribute to the induction of regulatory T cells and in blocking T cell transmigration [18]. Alemtuzumab is a humanised anti-CD52 mAb of the IgG1 subclass [19], which was first developed to treat fludarabine2
2-fold
CL
[19] [10-12]
understanding of their mechanism of action, efficacy and adverse event profile has become increasingly important to inform appropriate patient management. Alemtuzumab (Box 1) is an anti-CD52 mAb approved in the European Union [5], Australia [6], Canada [7], Mexico [8] and Brazil [9] for the treatment of relapsing MS. It has been shown to be highly efficacious at reducing relapse rates and in some studies has been shown to improve disability [10-12]. In this review, we will discuss the mechanism of action of alemtuzumab as well as its clinical efficacy and safety profile. 2.
CH1
resistant chronic lymphocytic leukaemia and has also been used in transplantation and other selected autoimmune disorders [20]. When used in MS it has a unique dosing regimen and is infused intravenously at a dose of 12 mg/day for 5 days, with a further 3-day course 12 months later [10-12]. Patients should be treated with corticosteroids for the first 3 days of each treatment course; in clinical trials, patients received 1 g/day methylprednisolone [10-12]. The benefits and risks of subsequent treatment courses with alemtuzumab have not been fully elucidated; however, limited observations from patients who received additional ‘as-needed’ alemtuzumab treatment during the open-label extension of the comparison of alemtuzumab and rebif efficacy in multiple sclerosis (CARE-MS) trials suggest the safety profile does not change with additional courses [21,22]. Re-treatment criteria in the clinical trials included ‡ 1 protocol-defined relapse or ‡ 2 new or enlarging brain or spinal cord lesions [23]. The pharmacokinetics of the drug are complex and follow non-linear elimination [24].There is rapid initial clearance which is dependent on peripheral lymphocyte load, with a terminal t1/2 between 7 and 21 days [25]. Soluble CD52 levels, which are likely to be lower in MS than leukaemia patients, do seem to influence serum levels [26]. Clearance of the drug reduces with repeated administration due to loss of receptormediated clearance [27]. Humanised antibodies against alemtuzumab can also develop, as its binding sites are murine;
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Alemtuzumab
among patients treated with alemtuzumab 12 mg, antibodies were reported in 30% of patients 1 month after the first course and 78% after the second course [25]. This does not usually cause problems for initial treatment courses but may become more problematic after multiple doses [27]. However, a strategy for the reduction of immunogenicity with alemtuzumab treatment is being developed with the use of SM3, a non-cell binding variant reducing the proportion of patients developing neutralising antibodies when administered before alemtuzumab [25]. The anti-CD52 effect of alemtuzumab results in rapid and profound depletion of circulating lymphocytes after initial infusion as a result of antibody-dependent cell-mediated cytotoxicity [28]. Subsequent immune reconstitution is thought to ‘reset’ the immune system in a manner which remains unclear, but appears to be beneficial for treatment [29] and also exhibits a degree of individual variability, which has recently been the focus of investigation as a biomarker of treatment response [30]. Long-term data in patients with progressive MS showed that the geometric mean recovery time of B cells to the lower limit of normal (LLN) was 7.1 months after a single course of alemtuzumab treatment, whereas CD8+ and CD4+ cells took a median of 20 and 35 months, respectively, to recover to LLN. However, CD8+ and CD4+ counts were not restored to baseline values in most patients (30 and 21% of patients, respectively) [31]. In other studies, B cell reconstitution has been shown to be even more rapid with levels returning to baseline by 3 months and rising to 165% of baseline by 12 months after treatment, driven by B-cell activating factor [32]. For a few months following treatment, regulatory CD4+ T cells dominate the T cell repertoire [33,34] which is thought to play a role in the long-term efficacy of alemtuzumab [34,35]. Although the exact mechanism of action of alemtuzumab in MS remains unclear, it is thought to be related to remodelling of the immune system [29], rather than immunodeficiency, a hypothesis supported first by the lack of disease activity in most patients despite normalizing levels of lymphocytes and by the relative lack of opportunistic infections seen in treated patients [11]. 3.
Clinical applications
Early experience and open-label studies Alemtuzumab has recently been licensed in the European Union, Australia, Mexico Canada and Brazil (but not in the USA) for the treatment of patients with RMS who have clinical evidence of active disease confirmed by clinical relapse profile or by imaging features [5-9] and has been the result of a prolonged phase of drug development and clinical trials [10-12]. Early experience with alemtuzumab had demonstrated a reduction in MRI lesions in patients with progressive disease [36,37]. However, when observed 7 years after initial treatment, these patients had experienced sustained accumulation of disability with continuing cerebral atrophy noted on 3.1
MRI [20,38]. However, most patients with secondary progressive MS were only administered a single treatment course. Conversely, patients with a relapsing disease course, observed over 29 months, had a reduction in annualised relapse rate and improved disability [20,38]. The results of these early open label studies also helped to inform the modern understanding of disease pathogenesis in MS, which is now thought to comprise a dominant role for inflammation and demyelination in early disease correlating with the relapsing clinical phase of MS and a later progressive phase characterised pathologically by axonal degeneration and provoked by previous inflammation [37,38]. As a result, subsequent clinical studies of the effect of alemtuzumab were directed at early relapsing phase disease when inflammatory pathology was dominant. Improvement in relapse rates and widely accepted disability outcomes in treatment-naive patients and those with early relapsing remitting Multiple sclerosis (RRMS) who had previously failed to respond to b-IFN were then demonstrated in two further open-label studies in different centres [39,40]. Phase II trial: CAMMS223 Following the promising results of these early, open-label studies, a Phase II trial comparing low and high dose alemtuzumab (and for the first time in MS clinical trials) against an active comparator (high-dose IFN-b la) in patients with early, active relapsing-remitting multiple sclerosis (CAMMS223) was undertaken [10]. From December 2002 to July 2004, 334 patients were randomised across sites in Europe and the USA [10]. Inclusion criteria were: diagnosis of RRMS according to the 2001 McDonald criteria [41], disease onset < 36 months before screening, at least two clinical episodes during the previous 2 years, an expanded disability status scale (EDSS) disability score [42] of 3.0 or less and one or more enhancing lesions, as seen on at least one of up to four monthly MRI scans [10]. Patients were randomised to alemtuzumab 12mg/day, alemtuzumab 24mg/day, or high dose (44 micrograms) subcutaneous (SC) IFNb-1a three times weekly [10]. Compared with IFNb-1a, alemtuzumab reduced the risk of sustained disability by 71% (pooled 12-mg and 24-mg doses) with no significant difference in efficacy between the 12-mg and 24-mg doses. When both alemtuzumab treatment groups were considered together, the mean EDSS score improved by 0.39 points at 36 months, in contrast to those patients randomised to the SC IFNb-1a arm in which mean EDSS worsened by 0.38 points. In addition to these encouraging disability outcomes, alemtuzumab also reduced annualised relapse rates by 74% (pooled 12-mg and 24-mg doses). These clinical outcomes were further supported by MRI data showing a reduction in the volume of lesions on T2-weighted MRI across all patient groups; however, this reduction was more marked in the alemtuzumab groups, with significant differences from SC IFNb-1a at months 12 and 24, but not 36. Reduction in brain volume was also significantly less in the alemtuzumab group (pooled 12-mg and 24-mg doses) [10]. 3.2
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M. Willis & N. P. Robertson
This cohort of patients was followed up over 5 years and although overall improvement in EDSS had persisted, it was apparent that improvement had only occurred in the first 36 months, with a slight worsening in each group from months 36 -- 60 [43]. An additional post-hoc analysis introducing a new outcome measure of sustained reduction in disability demonstrated significantly greater numbers of alemtuzumab-treated patients met this outcome compared with patients treated with IFNb-1a [44]. Phase III trials Two Phase III randomised controlled trials then followed. CARE-MSI investigated the use of alemtuzumab with relapsing MS in treatment-naı¨ve patients [12], and CARE-MSII in patients who had previously been treated with alternative disease-modifying therapies [11]. In CARE-MSI, previously untreated RRMS patients aged 18 -- 50 were randomly assigned in a 2:1 ratio to either alemtuzumab 12 mg or high-dose SC IFNb-1a. Alemtuzumab was given at a dose of 12 mg for 5 days in the first course and then for 3 days 12 months later. IFNb-1a was given at a dose of 44 µg 3 times weekly. Primary end points were relapse rate and time to 6 month sustained accumulation of disability (‡ 1-point increase in EDSS from baseline if baseline EDSS > 0, or ‡ 1.5-point increase if baseline EDSS = 0) over a study period of 2 years. Those patients in the alemtuzumab arm experienced a similar but somewhat less striking reduction in relapse rate of 54.9%. However, in contrast to previous studies, although there was a numerical reduction in disability outcomes, this did not achieve statistical significance [12]. In the parallel CARE-MSII study in patients who were clinically active on traditional disease-modifying therapy, there was a similar 49.4% improvement in relapse rate in the alemtuzumab arm compared with the SC IFNb-1a arm. In contrast to CARE-MSI but commensurate with the Phase II trial, alemtuzumab-treated patients showed some improvement in the EDSS score compared with SC IFNb1a [11]. It has been postulated that this improvement in disability may relate from neuroprotection associated with increased lymphocytic delivery of neurotrophins to the CNS [45]. Table 1 shows a comparison of the clinical outcomes in the Phase II and III trials.
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3.3
4.
Safety evaluation
Infusion reactions From an early stage in the clinical evaluation of alemtuzumab, it became apparent that infusion related side effects were common (Table 2) [10-12]. In addition, one intriguing manifestation was a transient worsening of existing symptoms or a recurrence of previous clinical events coinciding with alemtuzumab infusion, as well as the more predictable adverse events associated with mAb infusion including headaches, rigors, pyrexia and a rather characteristic rash [46]. It was noted that these transient neurological symptoms coincided with a 4.1
4
reduction in circulating lymphocytes and an elevation of cytokines TNF-a, IL-6 and IFN-g. This rise in cytokines was not observed in patients pre-medicated with methylprednisolone (in whom this clinical phenomena was not observed) and therefore cytokine release was postulated to be the mechanism of action by directly affecting conduction in partially demyelinated pathways [46]. As a result, all patients now receive concomitant corticosteroids for the first 3 days of each alemtuzumab treatment course together with ‘as required’ use of anti-histamines and anti-pyretics to ameliorate this cytokine release effect [21,22]. Autoimmune disease The most significant adverse event identified to date has been autoimmune adverse events. The thyroid gland is the most common target, possibly due to exposure of an inherited susceptibility in patients with MS [27]. Other more serious forms of autoimmune adverse events have also been observed and include autoimmune thrombocytopaenic purpura (ITP) haemolytic anaemia, autoimmune neutropaenia and glomerulonephritis (Goodpasture’s syndrome) (Table 3) [10-12,27]. Initial studies reported a frequency of 27 -- 33% for Graves’ disease with alemtuzumab treatment, with events occurring between 5 and 31 months of the first infusion [20,47]. These results were mirrored in the CAMMS223 trial, with thyroid autoimmune disease (AID) seen in 23% of alemtuzumabtreated patients within 2 years compared with only 3% in the IFNb-1a group. Of these patients, 96% had thyroid antibodies and 32 (14.8%) developed hyperthyroidism disease [10]. In a multicentre UK cohort of 248 patients, 42 (17%) patients developed autoimmune thyroid disease with Graves’ disease occurring in 31 (12.5%). 50% of AID had emerged within 24 months of initial treatment with the peak rate seen between 12 and 18 months after the first treatment [48]. In this study, the proportion of patients developing autoimmune adverse events was unaffected by the cumulative dose, dosage interval or dosage frequency suggesting that total risk was acquired at the time of first dose. In the Phase III trials, thyroid AID occurred in 16 -- 18% of patients over a 2-year period [11,12]. Interestingly, Graves’ disease is not seen in patients with B-cell chronic lymphocytic leukaemia treated with alemtuzumab so appears to be a disease-specific adverse event and therefore offers a unique insight into the mechanisms of human autoimmunity [49] and is thought to be caused by homeostatic T cell proliferation after lymphocyte depletion [50]. However, the risk of AID is not confined to the thyroid and other AID, in particular ITP, represents a small but significant safety concern. In the Phase II trial, suspension of the study occurred between September 2005 and April 2008 after identification of three cases of ITP, including one case in which death resulted from a brain haemorrhage before diagnosis could be established [10,43]. Three further cases were diagnosed during the period of study suspension [10]. Remission of ITP occurred without treatment in one patient, after corticosteroid therapy 4.2
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Alemtuzumab
Table 1. Comparison of alemtuzumab-treated patients (receiving 12-mg alemtuzumab) in Phase II (CAMMS223) and Phase III (CARE-MSI and II) clinical trials.
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CAMMS223 [10]
Number of participants % female Mean EDSS score Mean no. of relapses in previous year =[ Relapse rate reduction (alemtuzumab vs IFNb-1a) Annualised relapse rate [alemtuzumab vs IFNb-1a] % patients with 6-month sustained accumulation of disability Change in mean EDSS from baseline
CARE-MSI (treatment naı¨ve) [12]
12-mg
24-mg
112 64.3 1.9 Data not given
110 64.5 2.0 Data not given
CARE-MSII (failed previous treatment) [11] 12-mg
24-mg
376 65 2.0 1.8
426 66 2.7 1.7
170 71 2.7 1.6
All patients 74% (p < 0.001)
55% (p < 0.0001)
12-mg group only 49.4% (p < 0.0001)
0.10 versus 0.36
0.18 versus 0.39
0.26 versus 0.52
9 versus 26% (p < 0.01)
8 versus 11% (not significant)
13 versus 21% (p < 0.01)
Improvement of 0.39 compared with deterioration of 0.38 on IFNb-1a (p < 0.01)
No significant change
Improvement of 0.17 compared with deterioration of 0.24 on IFNb-1a (p < 0.0001)
Adapted from Coles [27]. CARE-MS: Comparison of alemtuzumab and rebif efficacy in multiple sclerosis; EDSS: Expanded disability status scale.
Table 2. Comparison of safety outcomes from Phase II and III trials (of patients receiving 12-mg alemtuzumab).
Number of participants Deaths
Infusion-associated symptoms Infections Autoimmunity Thyroid ITP Goodpasture’s syndrome Neoplasia (alemtuzumab vs IFNb-1a) For details see text
CAMMS223
CARE-MSI (treatment naı¨ve)
CARE-MSII (failed previous treatment)
333 One due to ITP One due to myocardial infarction 98% 66% mild to moderate
581 One due to motor accident
90% 67% mild to moderate
637 One due to motor accident One due to aspiration pneumonia 92% 79% mild to moderate
26% 0.9% 0 2.8 versus 0.9%
18% 0.8% 1 0.5% versus 0
17% 1% 0 0.6 versus 1.5%
Adapted from Coles [27]. CARE-MS: Comparison of alemtuzumab and rebif efficacy in multiple sclerosis; ITP: thrombocytopaenic purpura.
in two patients, and after rituxumab therapy in two patients. In the large open-label cohort reported from five centres in the UK, five patients (2%) developed ITP during a mean follow up period of 41.2 months with one patient also having co morbidity with autoimmune neutropaenia [48]. All these patients required treatment with steroids and responded well. Refinement of this risk in the Phase III trials suggests that the risk of developing ITP is ~ 1% within 2 years of treatment [11,12]. In CARE-MSI, three patients developed ITP. One patient required rituxumab after failure to respond to steroids and
intravenous gammaglobulin. One patient required a platelet transfusion, corticosteroids, and intravenous gammaglobulin with subsequent recovery and the third patient recovered after prednisolone treatment [12]. In CARE-MSII, seven patients developed ITP -- one patient did not require treatment, six patients received corticosteroids and two patients had intravenous immunoglobulin. One of these patients subsequently required a splenectomy [11]. The risk of ITP has therefore led to a safety monitoring programme which includes monthly full blood counts
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M. Willis & N. P. Robertson
Table 3. Autoimmune conditions following alemtuzumab therapy. For CARE-MS Phase III trials, data for 12-mg alemtuzumab dose shown. Study [year]
Autoimmune disease
No. of patients [%]
Coles et al. (1999) [37] Coles et al. (2006) [38]
Graves’ disease Graves’ disease Hypothyroidism Goodpasture’s disease Graves’ disease Hypothyroidism ITP Thyroid disease ITP Goodpasture’s disease Thyroid ITP Goodpasture’s Thyroid ITP Goodpasture’s
9 (33%) 15 (27%) 1 (1.7%) 1 (1.7%) 32 (14.8%) 15 (6.9%) 6 (2.8%) 29 (12%) 5 (2%) 1 (0.4%) 68 (18%) 3 (0.9%) 1 (0.27%) 69 (16%) 3 (0.69%) 0
CAMMS223 (2008) [10]
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Cossburn et al. (2011) [48]
CARE-MSI [12]
CARE-MSII [11]
Adapted from Costelloe et al. [61]. CARE-MS: Comparison of alemtuzumab and rebif efficacy in multiple sclerosis; ITP: thrombocytopaenic purpura.
although patient and treating physician awareness of clinical features of ITP remain essential [10]. However, it is anticipated that with appropriate monitoring, more slowly evolving subclinical thrombocytopaenia can be picked up quickly and appropriate treatment promptly instigated. Other forms of autoimmune adverse events are rare but include antiglomerular basement membrane disease which has been observed in four patients [12,38,51] and should also be screened for with regular urinalysis and blood tests for renal function [21,22,52]. In the four patients with Goodpasture’s syndrome, one was treated with plasma exchange, pulsed cyclophosphamide and corticosteroids but became dialysis dependent [38], two became dialysis dependent (one with MS and one with ANCA-associated vasculitis without renal involvement) and subsequently required renal transplantation [51] and one patient in CARE-MS1 was treated with plasmapharesis, cyclophosphamide and intravenous steroids and continued to receive low-dose oral steroids and cyclophosphamide after the study [12]. It is not currently possible to predict which patients are at risk of AID, but the development of AID post-alemtuzumab in one study was associated with increased T cell apoptosis and cell cycling driven by IL-21 levels. The cycle of T cell expansion and apoptosis is thought to allow autoreactive T cells to escape tolerance mechanisms and thus cause disease. Currently, IL-21 levels are being investigated for utility as a predictive biomarker for risk of developing AID, therefore aiding patient counselling and clinical management [53]. Infections Despite profound and prolonged lymphopaenia serious infections are rarely seen. The reasons for this are unclear but the relative preservation of more general immune 4.3
6
competence is thought to be possible as a result of relative sparing of the innate immune system, haemopoetic stem cells and the nature of subsequent immune reconstitution [16]. Furthermore, as a result of the year-long interval between treatments, lymphocyte repopulation is permitted as opposed to chronic suppression with other therapies. Following alemtuzumab treatment of humanised CD52 transgenic mouse, few serious infections are noted [54]. The loss of circulating immune cells post treatment representing only a small percentage of the total lymphocyte pool and minimal depletion is observed in the bone marrow and thymus [54]. Function of the remaining lymphocytes appears unimpaired and as the innate immune system has only low levels of CD52 on NK cells, macrophages and polymorphonuclear cells, these components of the immune system are also relatively spared [54]. Central memory, effector memory and regulatory T cells were depleted to a lesser extent than naı¨ve T cells [54] suggesting that memory responses may be unaffected post treatment. Remaining B cells were also sufficient to mount an immune response [54]. Perhaps as a result of these factors, most infections seen after alemtuzumab are mild to moderate and respond to conventional antimicrobial therapies. The most common infections noted in clinical trials to date were nasopharyngitis, upper respiratory tract infections, urinary tract infections, herpes viral infections, sinusitis and influenza [11,12]. No infections that might have been expected to occur in immune deficient patients -- such as progressive multifocal leuko-encephalopathy, cytomegalovirus or pneumocystis pneumonia -were reported. In the Phase III trials infections were observed in 67 -- 77% of patients treated with alemtuzumab 12 mg [11,12]. Due to the increased risk of herpes virus infection, oral acyclovir 200 mg BD is now given during treatment
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Alemtuzumab
and for one month afterwards [11,12,21,22,52]. Infections seen in the open-label studies which may have been attributable to immunosuppression include one case each of spirochaetal gingivitis, pyogenic granuloma and listeria meningitis; The listeria infection was contracted after eating unpasteurised cheese and as a result all patients are given dietary advice regarding this [27]. Precaution is also advised against live vaccinations and immunisation early after alemtuzumab therapy may not be effective [55]. Progressive multifocal leucoencephalopathy (PML), a chronic CNS infection caused by the polyomavirus, JC virus has been observed in a patient with chronic lymphocytic leukaemia treated with alemtuzumab [56], although these patients have an increased underlying risk of developing this condition [57]. PML has not so far been observed in patients receiving alemtuzumab for MS. Malignancy Malignancy was rarely observed and statistically did not occur more frequently in the treated arms compared with those patients in the IFNb-1a arm [10-12]. However, the studies were not powered in such a way as to detect small changes. In the Phase II trial, malignancy was observed in 2.8% of patients taking the 24-mg dose versus 0.9% of patients on the IFNb-1a arm. One each of cervical cancer, breast cancer and non-EBV-associated Burkitt’s lymphoma were seen [10]. Two cases of papillary thyroid cancer were seen in CAREMS I (12-mg dose) (0.5%) versus none taking IFNb-1a [12]. In CARE-MS II one basal cell carcinoma and one thyroid cancer were seen in patients taking the 12-mg dose and one vulval and one colon cancer in patients taking the 24-mg dose. Overall, 0.6% of patients taking alemtuzumab versus 1.5% on the IFNb-1a arm developed malignancy [11]. Outside of the trials one case of malignant melanoma has been reported [58] and a further patient developed Castleman’s disease (a prelymphomatous condition) and is now in remission following R-CHOP chemotherapy [27]. The patient who developed non-EBV-associated Burkitt’s lymphoma in the Phase II trial subsequently died off study [43]. 4.4
5.
Conclusion
Alemtuzumab is an effective treatment in early RRMS. Compared to an active comparator, IFNb-1a, it significantly reduces the annualised relapse rate with some suggestion of improved disability. Aside from these positive outcomes, alemtuzumab does carry a small but significant risk of serious, but manageable, side effects. The principal concern relates to AID, with Graves’ disease being most common. Vigilance is required to ensure that regular blood monitoring leads to early diagnosis and treatment before more serious sequelae occur. Infections associated with alemtuzumab are usually mild and infections more commonly associated with immunosuppression are very rare, and there is no evidence for any increased risk of malignancy. Long-term follow-up of patients treated with alemtuzumab is now required to assess long-term
clinical efficacy, indications for retreatment and safety concerns. When available these data will allow a better understanding of the risk/benefit profile of this treatment and enhanced patient counselling. 6.
Expert opinion
Alemtuzumab is one of a range of repurposed treatments undergoing clinical trials in MS and therefore has the unusual feature of having longer-term practical experience for this indication, as it has been used in a few select centres, particularly in the UK for more than a decade for patients with aggressive MS. In our centre, we have treated 96 highly selected patients with poor prognostic features within 5 years of disease onset as well as some patients who have failed alternative conventional therapeutic interventions, the outcomes for whom have been published [39,48]. Our experience in using this drug has been largely positive for patients and clinicians alike, but requires commitment to a dedicated long-term surveillance programme. In line with published clinical trials, we have noted a marked improvement in annualised relapse rates post-treatment but to date have not been able to confirm previous reports of improved disability outcomes (unpublished data). Thyroid AID has been the most commonly observed adverse effect of treatment, which we have largely been able to detect and treat effectively at an early stage as the result of effective surveillance mechanisms. This currently includes a monthly full blood count, urea and electrolytes and urine dipstick and 6-monthly thyroid function tests, to monitor for ITP for thyroid and renal AID respectively. With a growing therapeutic armament for MS now available to clinicians, treatment choices in this disease have become more complex. Drug efficacy has to be weighed carefully against possible side effects and patient counselling has become an increasingly important component of patient management. For those patients with poor prognostic features and recent onset disease as well as those patients failing conventional treatments, the risks of AID may be offset by the high levels of efficacy offered by alemtuzumab. However, in a disease which has a mean disease duration of over 20 years, and mindful of the late emergence of significant adverse events in previous treatments for MS, it is clear that further long-term outcome data is required. A post-marketing surveillance phase will clearly be important, and data collected, possibly through the use of national registries, may be informative in this regard. Given alemtuzumab’s advantage of efficacy, longevity and ease of administration over other disease-modifying therapies, clinicians are likely to be encouraged to use the drug, but there is current concern over the proposed cost of £56,360 for a full 2-year treatment course [59]. It is yet to be determined how regulatory bodies will instruct on the timing of treatment with alemtuzumab. Its effects are likely to be greatest early in the disease -- the so-called ‘window of therapeutic opportunity’ [38] but the price of treatment may prove
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prohibitive for some national health services and push treatment towards patients who have failed more conventional therapies. Despite being approved for use in the European Union, Australia, Canada, Mexico and Brazil, the US FDA Advisory Committee recently decided not to approve it for licence for use in the USA. This has caused disquiet amongst advocates for the drug [60] with American patients set to miss out on the benefits that this drug may offer. It should also be noted that the majority of patients who may be treated with alemtuzumab are likely to be female and of childbearing age. There is currently no data regarding the safety of alemtuzumab in pregnancy and therefore patients are currently advised against conceiving, although it remains unclear for how long after the last dose this advice is appropriate for. The data available to date support the use of alemtuzumab as an effective treatment for both treatment naı¨ve and treatment experienced patients and suggests that potential adverse effects can be effectively managed with adequate clinical surveillance programmes. However, there are complexities involved in the administration and subsequent management Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Hafler D, Compston A, Sawcer S, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007;357(9):851-62 Zafranskaya M, Oschmann P, Engel R, et al. Interferon-beta therapy reduces CD4+ and CD8+ T-cell reactivity in multiple sclerosis. Immunology 2007;121(1):29-39 Neuhaus O, Farina C, Yassouridis A, et al. Multiple sclerosis: comparison of copolymer-1- reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. Proc Natl Acad Sci USA 2000;97(13):7452-7 Johnson TA, Lapierre Y, Bar-Or A, Antel JP. Distinct properties of circulating CD8+ T cells in FTY720treated patients with multiple sclerosis. Arch Neurol 2010;67(12):1449-55
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Available from: http://news.genzyme. com/press-release/genzymes-lemtrada-
8
Declaration of interest N Robertson and his institution, Cardiff University, have received funding from a neuroimmunology fellow programme supported by Genzyme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
approved-canada-treatment-multiplesclerosis 8.
..
a randomised controlled phase 3 trial. Lancet 2012;380(9856):1819-28 Phase III trial of alemtuzumab versus IFNb-1a in treatment-naive patients (CARE-MS1).
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Hale G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy 2001;3(3):137-43
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Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab versus interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359(17):1786-801 Phase II trial demonstrating superior efficacy of alemtuzumab versus IFNb1a.
Rao SP, Sancho J, Campos-Rivera J, et al. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS One 2012;7(6):e39416
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Hale G, Rye PD, Warford A, et al. The glycosylphosphatidylinositol-anchored lymphocyte antigen CDw52 is associated with the epididymal maturation of human spermatozoa. J Reprod Immunol 1993;23(2):189-205
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Klotz L, Meuth SG, Wiendl H. Immune mechanisms of new therapeutic strategies in multiple sclerosis-a focus on alemtuzumab. Clin Immunol 2012;142(1):25-30
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Rowan WC, Hale G, Tite JP, Brett SJ. Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes. Int immunol 1995;7(1):69-77
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6.
of patients treated with this medication which may restrict its use to larger specialised centres with established resources and prompt access to relevant specialist medical services such as haematology and renal medicine. Greater confidence in the use of alemtuzumab by treating neurologists will no doubt come over time as it has with other disease modifying therapies, particularly if longer-term follow-up reveals no additional unexpected adverse events, and is like to offer a novel and effective treatment option for specific patient subgroups.
12.
Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after diseasemodifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380(9856):1829-39 Phase III trial of alemtuzumab versus IFNb-1a in treatment experienced patients (comparison of alemtuzumab and rebif efficacy in multiple sclerosis [CARE-MS]II). Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis:
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molecule for induction of CD4+ regulatory T cells. Clin Immunol 2006;120(3):247-59 19.
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Cheetham G, Hale G. Crystal structures of a rat anti-CD52 (CAMPATH-1) therapeutic antibody Fab fragment and its humanized counterpart. J Mol Biol 1998;284(1):85-99 Coles A, Deans J, Compston A. Campath-1H treatment of multiple sclerosis: lessons from the bedside for the bench. Clin neurol neurosurg 2004;106(3):270-4 Lemtrada (alemtuzumab). Summary of Product Characteristics. Genzyme Therapeutics Ltd; 2013
Fox E, Arnold DL, Cohen J, et al. Durable efficacy of alemtuzumab in relapsing-remitting multiple sclerosis patients who participated in the CAREMS studies: three-year follow-up. Neurology 2013;80(Meeting Abstracts 1):S41.001 Rebello P, Cwynarski K, Varughese M, et al. Pharmacokinetics of CAMPATH1H in BMT patients. Cytotherapy 2001;3(4):261-7 Somerfield J, Hill-Cawthorne GA, Lin A, et al. A novel strategy to reduce the immunogenicity of biological therapies. J Immunol 2010;185(1):763-81
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Cox AL, Thompson SAJ, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005;35(11):3332-42 Zhang X, Tao Y, Chopra M, et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (antiCD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol 2013;191(12):5867-74 Havari E, Turner MJ, Campos-Rivera J, et al. Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro. Immunology 2014;141(1):123-31
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Moreau T, Thorpe J, Miller D, et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994;344(8918):298-301 First experience of treating multiple sclerosis (MS) patients with alemtuzumab.
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Fox EJ. Alemtuzumab in the treatment of relapsing-remitting multiple sclerosis. Expert Rev Neurother 2010;10(12):1789-97 Cossburn MD, Harding K, Ingram G, et al. Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis. Neurology 2013;80(1):55-61
Thompson SAJ, Jones JL, Cox AL, et al. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J clin Immunol 2010;30(1):99-105
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Coles AJ. Alemtuzumab treatment of multiple sclerosis. Semin Neurol 2013;33(1):66-73 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(2):260-70
Hill-Cawthorne GA, Button T, Tuohy O, et al. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J neurol neurosurg psychiatry 2012;83(3):298-304
Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46(3):296-304 Further open-label trial reporting outlining potential pathogenic mechanisms of MS based on results of alemtuzumab therapy. 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(1):98-108
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Hirst CL, Pace A, Pickersgill TP, et al. Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis. J Neurol 2008;255(2):231-8
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patients with multiple sclerosis. Eur J Neurol 2012;19(2):307-11 41.
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann neurol 2001;50(1):121-7
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Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444-52
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Coles AJ, Fox E, Vladic A, et al. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet neurol 2011;10(4):338-48
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Jones JL, Anderson JM, Phuah C-L, et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 2010;133(Pt 8):2232-47
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Coles a J, Wing M, Smith S, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999;354(9191):1691-5
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Daniels GH, Vladic A, Brinar V, et al. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin endocrinol metab 2014;99(1):80
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Isidoro L, Pires P, Rito L, et al. Progressive multifocal leukoencephalopathy in a patient with chronic lymphocytic leukaemia treated with alemtuzumab. BMJ Case Rep 2014;2014:2013-15 Keene DL, Legare C, Taylor E, et al. Monoclonal antibodies and progressive multifocal leukoencephalopathy. Can J Neurol Sci 2011;38(4):565-71
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Affiliation
Mark Willis BSc MB BCh & Neil P Robertson† † Author for correspondence Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University School of Medicine, Cardiff, UK E-mail: [email protected]
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Drug safety evaluation of alemtuzumab for multiple sclerosis 1.
Introduction
2.
Mechanism of action and pharmacokinetics
3.
Clinical applications
4.
Safety evaluation
5.
Conclusion
6.
Expert opinion
Mark Willis & Neil P Robertson† Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University School of Medicine, Cardiff, UK
Introduction: Alemtuzumab is a humanised anti-CD52 mAb which has recently been licensed for the treatment of relapsing multiple sclerosis in Europe. Areas covered: The efficacy and safety of alemtuzumab from open label, Phase II and Phase III trials is reported. Expert opinion: Alemtuzumab causes rapid and profound complement mediated lysis of circulating lymphocytes and allows beneficial modulation of the immune system during a subsequent reconstitution phase. Clinical trials have demonstrated superior efficacy against an active comparator, with reduction in annualised relapse rates and sustained accumulation of disability at 3 years and sustained efficacy at 5 years. The main adverse effects are mild to moderate infusion reactions, an increased incidence of mild to moderate infections and autoimmune adverse events. Thyroid disorders are the most common form of autoimmune adverse events, occurring in approximately one third of patients. Overt Graves’ hyperthyroidism represents approximately half of these cases. Careful patient selection and structured monitoring programs allow for effective patient management resulting in a favourable risk benefit profile. Keywords: alemtuzumab, autoimmune disease, multiple sclerosis, novel therapeutics Expert Opin. Drug Saf. [Early Online]
1.
Introduction
Multiple sclerosis (MS) is a complex, inflammatory disorder of the CNS and represents a major cause of chronic neurological disability in western societies. The aetiology of MS remains poorly understood but is generally considered to be related to an interaction of genetic and environmental factors. Recent genome wide association studies have identified > 100 disease associated genetic variants with a common theme being proximity to genes with immunological function and in particular T cell function and signalling [1]. Current treatment strategies are predominantly aimed at reducing inflammatory activity in the CNS in relapsing MS by modulating lymphocyte function [2,3], affecting lymphocyte trafficking [4] or depleting lymphocyte numbers, in the hope that early intervention may lead to the delay or prevention of progressive disease and avoidance of fixed long-term disability. MS has recently been an active and expanding area of research that has seen an evolution from an improved understanding of pathogenesis to bedside therapeutics and, as a result, there are an increasing number of new drugs in development. Although currently available medications have been shown to be effective at reducing relapse rates and radiological disease activity in the form of T2 lesion load or gadolinium enhancement, the evidence for impact on long-term disability remains elusive. The range of disease-modifying drugs licensed for relapsing MS has expanded considerably over recent years and an 10.1517/14740338.2014.928691 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
1
M. Willis & N. P. Robertson
Box 1. Drug summary Drug name Phase Indication Pharmacology description/mechanism of action Route of administration Chemical structure
Alemtuzumab Licenced in EU, Canada, Mexico, Canada and Brazil Relapsing multiple sclerosis Anti-CD52 mAb. Depletes lymphocyte pool Intravenous V L’
L70
VL
VH
D S
L18
L9
R
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3.1Å 2.9Å
S
L10
2.6Å L11 L
2-fold S
L12 L13 A S
L14
CAMPATH-1H
Pivotal trial(s)
Mechanism of action and pharmacokinetics
CD52 is a 12 amino acid glycosylated glycosylphosphatidylinositol-linked protein present on ~ 5% of the cell surface of lymphocytes. It is also expressed, at lower levels, on monocytes, macrophages, eosinophils and NK cells [13,14] as well as on epithelial cells lining the epididymis, vas deferens and seminal vesicle [13,15]. Importantly, it is not expressed on haematopoietic precursors allowing lymphocyte reconstitution [16]. The function of CD52 is largely unknown but has been shown to act as a co-stimulatory T cell activating molecule [17], to contribute to the induction of regulatory T cells and in blocking T cell transmigration [18]. Alemtuzumab is a humanised anti-CD52 mAb of the IgG1 subclass [19], which was first developed to treat fludarabine2
2-fold
CL
[19] [10-12]
understanding of their mechanism of action, efficacy and adverse event profile has become increasingly important to inform appropriate patient management. Alemtuzumab (Box 1) is an anti-CD52 mAb approved in the European Union [5], Australia [6], Canada [7], Mexico [8] and Brazil [9] for the treatment of relapsing MS. It has been shown to be highly efficacious at reducing relapse rates and in some studies has been shown to improve disability [10-12]. In this review, we will discuss the mechanism of action of alemtuzumab as well as its clinical efficacy and safety profile. 2.
CH1
resistant chronic lymphocytic leukaemia and has also been used in transplantation and other selected autoimmune disorders [20]. When used in MS it has a unique dosing regimen and is infused intravenously at a dose of 12 mg/day for 5 days, with a further 3-day course 12 months later [10-12]. Patients should be treated with corticosteroids for the first 3 days of each treatment course; in clinical trials, patients received 1 g/day methylprednisolone [10-12]. The benefits and risks of subsequent treatment courses with alemtuzumab have not been fully elucidated; however, limited observations from patients who received additional ‘as-needed’ alemtuzumab treatment during the open-label extension of the comparison of alemtuzumab and rebif efficacy in multiple sclerosis (CARE-MS) trials suggest the safety profile does not change with additional courses [21,22]. Re-treatment criteria in the clinical trials included ‡ 1 protocol-defined relapse or ‡ 2 new or enlarging brain or spinal cord lesions [23]. The pharmacokinetics of the drug are complex and follow non-linear elimination [24].There is rapid initial clearance which is dependent on peripheral lymphocyte load, with a terminal t1/2 between 7 and 21 days [25]. Soluble CD52 levels, which are likely to be lower in MS than leukaemia patients, do seem to influence serum levels [26]. Clearance of the drug reduces with repeated administration due to loss of receptormediated clearance [27]. Humanised antibodies against alemtuzumab can also develop, as its binding sites are murine;
Expert Opin. Drug Saf. (2014) 13(8)
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Alemtuzumab
among patients treated with alemtuzumab 12 mg, antibodies were reported in 30% of patients 1 month after the first course and 78% after the second course [25]. This does not usually cause problems for initial treatment courses but may become more problematic after multiple doses [27]. However, a strategy for the reduction of immunogenicity with alemtuzumab treatment is being developed with the use of SM3, a non-cell binding variant reducing the proportion of patients developing neutralising antibodies when administered before alemtuzumab [25]. The anti-CD52 effect of alemtuzumab results in rapid and profound depletion of circulating lymphocytes after initial infusion as a result of antibody-dependent cell-mediated cytotoxicity [28]. Subsequent immune reconstitution is thought to ‘reset’ the immune system in a manner which remains unclear, but appears to be beneficial for treatment [29] and also exhibits a degree of individual variability, which has recently been the focus of investigation as a biomarker of treatment response [30]. Long-term data in patients with progressive MS showed that the geometric mean recovery time of B cells to the lower limit of normal (LLN) was 7.1 months after a single course of alemtuzumab treatment, whereas CD8+ and CD4+ cells took a median of 20 and 35 months, respectively, to recover to LLN. However, CD8+ and CD4+ counts were not restored to baseline values in most patients (30 and 21% of patients, respectively) [31]. In other studies, B cell reconstitution has been shown to be even more rapid with levels returning to baseline by 3 months and rising to 165% of baseline by 12 months after treatment, driven by B-cell activating factor [32]. For a few months following treatment, regulatory CD4+ T cells dominate the T cell repertoire [33,34] which is thought to play a role in the long-term efficacy of alemtuzumab [34,35]. Although the exact mechanism of action of alemtuzumab in MS remains unclear, it is thought to be related to remodelling of the immune system [29], rather than immunodeficiency, a hypothesis supported first by the lack of disease activity in most patients despite normalizing levels of lymphocytes and by the relative lack of opportunistic infections seen in treated patients [11]. 3.
Clinical applications
Early experience and open-label studies Alemtuzumab has recently been licensed in the European Union, Australia, Mexico Canada and Brazil (but not in the USA) for the treatment of patients with RMS who have clinical evidence of active disease confirmed by clinical relapse profile or by imaging features [5-9] and has been the result of a prolonged phase of drug development and clinical trials [10-12]. Early experience with alemtuzumab had demonstrated a reduction in MRI lesions in patients with progressive disease [36,37]. However, when observed 7 years after initial treatment, these patients had experienced sustained accumulation of disability with continuing cerebral atrophy noted on 3.1
MRI [20,38]. However, most patients with secondary progressive MS were only administered a single treatment course. Conversely, patients with a relapsing disease course, observed over 29 months, had a reduction in annualised relapse rate and improved disability [20,38]. The results of these early open label studies also helped to inform the modern understanding of disease pathogenesis in MS, which is now thought to comprise a dominant role for inflammation and demyelination in early disease correlating with the relapsing clinical phase of MS and a later progressive phase characterised pathologically by axonal degeneration and provoked by previous inflammation [37,38]. As a result, subsequent clinical studies of the effect of alemtuzumab were directed at early relapsing phase disease when inflammatory pathology was dominant. Improvement in relapse rates and widely accepted disability outcomes in treatment-naive patients and those with early relapsing remitting Multiple sclerosis (RRMS) who had previously failed to respond to b-IFN were then demonstrated in two further open-label studies in different centres [39,40]. Phase II trial: CAMMS223 Following the promising results of these early, open-label studies, a Phase II trial comparing low and high dose alemtuzumab (and for the first time in MS clinical trials) against an active comparator (high-dose IFN-b la) in patients with early, active relapsing-remitting multiple sclerosis (CAMMS223) was undertaken [10]. From December 2002 to July 2004, 334 patients were randomised across sites in Europe and the USA [10]. Inclusion criteria were: diagnosis of RRMS according to the 2001 McDonald criteria [41], disease onset < 36 months before screening, at least two clinical episodes during the previous 2 years, an expanded disability status scale (EDSS) disability score [42] of 3.0 or less and one or more enhancing lesions, as seen on at least one of up to four monthly MRI scans [10]. Patients were randomised to alemtuzumab 12mg/day, alemtuzumab 24mg/day, or high dose (44 micrograms) subcutaneous (SC) IFNb-1a three times weekly [10]. Compared with IFNb-1a, alemtuzumab reduced the risk of sustained disability by 71% (pooled 12-mg and 24-mg doses) with no significant difference in efficacy between the 12-mg and 24-mg doses. When both alemtuzumab treatment groups were considered together, the mean EDSS score improved by 0.39 points at 36 months, in contrast to those patients randomised to the SC IFNb-1a arm in which mean EDSS worsened by 0.38 points. In addition to these encouraging disability outcomes, alemtuzumab also reduced annualised relapse rates by 74% (pooled 12-mg and 24-mg doses). These clinical outcomes were further supported by MRI data showing a reduction in the volume of lesions on T2-weighted MRI across all patient groups; however, this reduction was more marked in the alemtuzumab groups, with significant differences from SC IFNb-1a at months 12 and 24, but not 36. Reduction in brain volume was also significantly less in the alemtuzumab group (pooled 12-mg and 24-mg doses) [10]. 3.2
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M. Willis & N. P. Robertson
This cohort of patients was followed up over 5 years and although overall improvement in EDSS had persisted, it was apparent that improvement had only occurred in the first 36 months, with a slight worsening in each group from months 36 -- 60 [43]. An additional post-hoc analysis introducing a new outcome measure of sustained reduction in disability demonstrated significantly greater numbers of alemtuzumab-treated patients met this outcome compared with patients treated with IFNb-1a [44]. Phase III trials Two Phase III randomised controlled trials then followed. CARE-MSI investigated the use of alemtuzumab with relapsing MS in treatment-naı¨ve patients [12], and CARE-MSII in patients who had previously been treated with alternative disease-modifying therapies [11]. In CARE-MSI, previously untreated RRMS patients aged 18 -- 50 were randomly assigned in a 2:1 ratio to either alemtuzumab 12 mg or high-dose SC IFNb-1a. Alemtuzumab was given at a dose of 12 mg for 5 days in the first course and then for 3 days 12 months later. IFNb-1a was given at a dose of 44 µg 3 times weekly. Primary end points were relapse rate and time to 6 month sustained accumulation of disability (‡ 1-point increase in EDSS from baseline if baseline EDSS > 0, or ‡ 1.5-point increase if baseline EDSS = 0) over a study period of 2 years. Those patients in the alemtuzumab arm experienced a similar but somewhat less striking reduction in relapse rate of 54.9%. However, in contrast to previous studies, although there was a numerical reduction in disability outcomes, this did not achieve statistical significance [12]. In the parallel CARE-MSII study in patients who were clinically active on traditional disease-modifying therapy, there was a similar 49.4% improvement in relapse rate in the alemtuzumab arm compared with the SC IFNb-1a arm. In contrast to CARE-MSI but commensurate with the Phase II trial, alemtuzumab-treated patients showed some improvement in the EDSS score compared with SC IFNb1a [11]. It has been postulated that this improvement in disability may relate from neuroprotection associated with increased lymphocytic delivery of neurotrophins to the CNS [45]. Table 1 shows a comparison of the clinical outcomes in the Phase II and III trials.
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3.3
4.
Safety evaluation
Infusion reactions From an early stage in the clinical evaluation of alemtuzumab, it became apparent that infusion related side effects were common (Table 2) [10-12]. In addition, one intriguing manifestation was a transient worsening of existing symptoms or a recurrence of previous clinical events coinciding with alemtuzumab infusion, as well as the more predictable adverse events associated with mAb infusion including headaches, rigors, pyrexia and a rather characteristic rash [46]. It was noted that these transient neurological symptoms coincided with a 4.1
4
reduction in circulating lymphocytes and an elevation of cytokines TNF-a, IL-6 and IFN-g. This rise in cytokines was not observed in patients pre-medicated with methylprednisolone (in whom this clinical phenomena was not observed) and therefore cytokine release was postulated to be the mechanism of action by directly affecting conduction in partially demyelinated pathways [46]. As a result, all patients now receive concomitant corticosteroids for the first 3 days of each alemtuzumab treatment course together with ‘as required’ use of anti-histamines and anti-pyretics to ameliorate this cytokine release effect [21,22]. Autoimmune disease The most significant adverse event identified to date has been autoimmune adverse events. The thyroid gland is the most common target, possibly due to exposure of an inherited susceptibility in patients with MS [27]. Other more serious forms of autoimmune adverse events have also been observed and include autoimmune thrombocytopaenic purpura (ITP) haemolytic anaemia, autoimmune neutropaenia and glomerulonephritis (Goodpasture’s syndrome) (Table 3) [10-12,27]. Initial studies reported a frequency of 27 -- 33% for Graves’ disease with alemtuzumab treatment, with events occurring between 5 and 31 months of the first infusion [20,47]. These results were mirrored in the CAMMS223 trial, with thyroid autoimmune disease (AID) seen in 23% of alemtuzumabtreated patients within 2 years compared with only 3% in the IFNb-1a group. Of these patients, 96% had thyroid antibodies and 32 (14.8%) developed hyperthyroidism disease [10]. In a multicentre UK cohort of 248 patients, 42 (17%) patients developed autoimmune thyroid disease with Graves’ disease occurring in 31 (12.5%). 50% of AID had emerged within 24 months of initial treatment with the peak rate seen between 12 and 18 months after the first treatment [48]. In this study, the proportion of patients developing autoimmune adverse events was unaffected by the cumulative dose, dosage interval or dosage frequency suggesting that total risk was acquired at the time of first dose. In the Phase III trials, thyroid AID occurred in 16 -- 18% of patients over a 2-year period [11,12]. Interestingly, Graves’ disease is not seen in patients with B-cell chronic lymphocytic leukaemia treated with alemtuzumab so appears to be a disease-specific adverse event and therefore offers a unique insight into the mechanisms of human autoimmunity [49] and is thought to be caused by homeostatic T cell proliferation after lymphocyte depletion [50]. However, the risk of AID is not confined to the thyroid and other AID, in particular ITP, represents a small but significant safety concern. In the Phase II trial, suspension of the study occurred between September 2005 and April 2008 after identification of three cases of ITP, including one case in which death resulted from a brain haemorrhage before diagnosis could be established [10,43]. Three further cases were diagnosed during the period of study suspension [10]. Remission of ITP occurred without treatment in one patient, after corticosteroid therapy 4.2
Expert Opin. Drug Saf. (2014) 13(8)
Alemtuzumab
Table 1. Comparison of alemtuzumab-treated patients (receiving 12-mg alemtuzumab) in Phase II (CAMMS223) and Phase III (CARE-MSI and II) clinical trials.
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CAMMS223 [10]
Number of participants % female Mean EDSS score Mean no. of relapses in previous year =[ Relapse rate reduction (alemtuzumab vs IFNb-1a) Annualised relapse rate [alemtuzumab vs IFNb-1a] % patients with 6-month sustained accumulation of disability Change in mean EDSS from baseline
CARE-MSI (treatment naı¨ve) [12]
12-mg
24-mg
112 64.3 1.9 Data not given
110 64.5 2.0 Data not given
CARE-MSII (failed previous treatment) [11] 12-mg
24-mg
376 65 2.0 1.8
426 66 2.7 1.7
170 71 2.7 1.6
All patients 74% (p < 0.001)
55% (p < 0.0001)
12-mg group only 49.4% (p < 0.0001)
0.10 versus 0.36
0.18 versus 0.39
0.26 versus 0.52
9 versus 26% (p < 0.01)
8 versus 11% (not significant)
13 versus 21% (p < 0.01)
Improvement of 0.39 compared with deterioration of 0.38 on IFNb-1a (p < 0.01)
No significant change
Improvement of 0.17 compared with deterioration of 0.24 on IFNb-1a (p < 0.0001)
Adapted from Coles [27]. CARE-MS: Comparison of alemtuzumab and rebif efficacy in multiple sclerosis; EDSS: Expanded disability status scale.
Table 2. Comparison of safety outcomes from Phase II and III trials (of patients receiving 12-mg alemtuzumab).
Number of participants Deaths
Infusion-associated symptoms Infections Autoimmunity Thyroid ITP Goodpasture’s syndrome Neoplasia (alemtuzumab vs IFNb-1a) For details see text
CAMMS223
CARE-MSI (treatment naı¨ve)
CARE-MSII (failed previous treatment)
333 One due to ITP One due to myocardial infarction 98% 66% mild to moderate
581 One due to motor accident
90% 67% mild to moderate
637 One due to motor accident One due to aspiration pneumonia 92% 79% mild to moderate
26% 0.9% 0 2.8 versus 0.9%
18% 0.8% 1 0.5% versus 0
17% 1% 0 0.6 versus 1.5%
Adapted from Coles [27]. CARE-MS: Comparison of alemtuzumab and rebif efficacy in multiple sclerosis; ITP: thrombocytopaenic purpura.
in two patients, and after rituxumab therapy in two patients. In the large open-label cohort reported from five centres in the UK, five patients (2%) developed ITP during a mean follow up period of 41.2 months with one patient also having co morbidity with autoimmune neutropaenia [48]. All these patients required treatment with steroids and responded well. Refinement of this risk in the Phase III trials suggests that the risk of developing ITP is ~ 1% within 2 years of treatment [11,12]. In CARE-MSI, three patients developed ITP. One patient required rituxumab after failure to respond to steroids and
intravenous gammaglobulin. One patient required a platelet transfusion, corticosteroids, and intravenous gammaglobulin with subsequent recovery and the third patient recovered after prednisolone treatment [12]. In CARE-MSII, seven patients developed ITP -- one patient did not require treatment, six patients received corticosteroids and two patients had intravenous immunoglobulin. One of these patients subsequently required a splenectomy [11]. The risk of ITP has therefore led to a safety monitoring programme which includes monthly full blood counts
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M. Willis & N. P. Robertson
Table 3. Autoimmune conditions following alemtuzumab therapy. For CARE-MS Phase III trials, data for 12-mg alemtuzumab dose shown. Study [year]
Autoimmune disease
No. of patients [%]
Coles et al. (1999) [37] Coles et al. (2006) [38]
Graves’ disease Graves’ disease Hypothyroidism Goodpasture’s disease Graves’ disease Hypothyroidism ITP Thyroid disease ITP Goodpasture’s disease Thyroid ITP Goodpasture’s Thyroid ITP Goodpasture’s
9 (33%) 15 (27%) 1 (1.7%) 1 (1.7%) 32 (14.8%) 15 (6.9%) 6 (2.8%) 29 (12%) 5 (2%) 1 (0.4%) 68 (18%) 3 (0.9%) 1 (0.27%) 69 (16%) 3 (0.69%) 0
CAMMS223 (2008) [10]
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Cossburn et al. (2011) [48]
CARE-MSI [12]
CARE-MSII [11]
Adapted from Costelloe et al. [61]. CARE-MS: Comparison of alemtuzumab and rebif efficacy in multiple sclerosis; ITP: thrombocytopaenic purpura.
although patient and treating physician awareness of clinical features of ITP remain essential [10]. However, it is anticipated that with appropriate monitoring, more slowly evolving subclinical thrombocytopaenia can be picked up quickly and appropriate treatment promptly instigated. Other forms of autoimmune adverse events are rare but include antiglomerular basement membrane disease which has been observed in four patients [12,38,51] and should also be screened for with regular urinalysis and blood tests for renal function [21,22,52]. In the four patients with Goodpasture’s syndrome, one was treated with plasma exchange, pulsed cyclophosphamide and corticosteroids but became dialysis dependent [38], two became dialysis dependent (one with MS and one with ANCA-associated vasculitis without renal involvement) and subsequently required renal transplantation [51] and one patient in CARE-MS1 was treated with plasmapharesis, cyclophosphamide and intravenous steroids and continued to receive low-dose oral steroids and cyclophosphamide after the study [12]. It is not currently possible to predict which patients are at risk of AID, but the development of AID post-alemtuzumab in one study was associated with increased T cell apoptosis and cell cycling driven by IL-21 levels. The cycle of T cell expansion and apoptosis is thought to allow autoreactive T cells to escape tolerance mechanisms and thus cause disease. Currently, IL-21 levels are being investigated for utility as a predictive biomarker for risk of developing AID, therefore aiding patient counselling and clinical management [53]. Infections Despite profound and prolonged lymphopaenia serious infections are rarely seen. The reasons for this are unclear but the relative preservation of more general immune 4.3
6
competence is thought to be possible as a result of relative sparing of the innate immune system, haemopoetic stem cells and the nature of subsequent immune reconstitution [16]. Furthermore, as a result of the year-long interval between treatments, lymphocyte repopulation is permitted as opposed to chronic suppression with other therapies. Following alemtuzumab treatment of humanised CD52 transgenic mouse, few serious infections are noted [54]. The loss of circulating immune cells post treatment representing only a small percentage of the total lymphocyte pool and minimal depletion is observed in the bone marrow and thymus [54]. Function of the remaining lymphocytes appears unimpaired and as the innate immune system has only low levels of CD52 on NK cells, macrophages and polymorphonuclear cells, these components of the immune system are also relatively spared [54]. Central memory, effector memory and regulatory T cells were depleted to a lesser extent than naı¨ve T cells [54] suggesting that memory responses may be unaffected post treatment. Remaining B cells were also sufficient to mount an immune response [54]. Perhaps as a result of these factors, most infections seen after alemtuzumab are mild to moderate and respond to conventional antimicrobial therapies. The most common infections noted in clinical trials to date were nasopharyngitis, upper respiratory tract infections, urinary tract infections, herpes viral infections, sinusitis and influenza [11,12]. No infections that might have been expected to occur in immune deficient patients -- such as progressive multifocal leuko-encephalopathy, cytomegalovirus or pneumocystis pneumonia -were reported. In the Phase III trials infections were observed in 67 -- 77% of patients treated with alemtuzumab 12 mg [11,12]. Due to the increased risk of herpes virus infection, oral acyclovir 200 mg BD is now given during treatment
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Alemtuzumab
and for one month afterwards [11,12,21,22,52]. Infections seen in the open-label studies which may have been attributable to immunosuppression include one case each of spirochaetal gingivitis, pyogenic granuloma and listeria meningitis; The listeria infection was contracted after eating unpasteurised cheese and as a result all patients are given dietary advice regarding this [27]. Precaution is also advised against live vaccinations and immunisation early after alemtuzumab therapy may not be effective [55]. Progressive multifocal leucoencephalopathy (PML), a chronic CNS infection caused by the polyomavirus, JC virus has been observed in a patient with chronic lymphocytic leukaemia treated with alemtuzumab [56], although these patients have an increased underlying risk of developing this condition [57]. PML has not so far been observed in patients receiving alemtuzumab for MS. Malignancy Malignancy was rarely observed and statistically did not occur more frequently in the treated arms compared with those patients in the IFNb-1a arm [10-12]. However, the studies were not powered in such a way as to detect small changes. In the Phase II trial, malignancy was observed in 2.8% of patients taking the 24-mg dose versus 0.9% of patients on the IFNb-1a arm. One each of cervical cancer, breast cancer and non-EBV-associated Burkitt’s lymphoma were seen [10]. Two cases of papillary thyroid cancer were seen in CAREMS I (12-mg dose) (0.5%) versus none taking IFNb-1a [12]. In CARE-MS II one basal cell carcinoma and one thyroid cancer were seen in patients taking the 12-mg dose and one vulval and one colon cancer in patients taking the 24-mg dose. Overall, 0.6% of patients taking alemtuzumab versus 1.5% on the IFNb-1a arm developed malignancy [11]. Outside of the trials one case of malignant melanoma has been reported [58] and a further patient developed Castleman’s disease (a prelymphomatous condition) and is now in remission following R-CHOP chemotherapy [27]. The patient who developed non-EBV-associated Burkitt’s lymphoma in the Phase II trial subsequently died off study [43]. 4.4
5.
Conclusion
Alemtuzumab is an effective treatment in early RRMS. Compared to an active comparator, IFNb-1a, it significantly reduces the annualised relapse rate with some suggestion of improved disability. Aside from these positive outcomes, alemtuzumab does carry a small but significant risk of serious, but manageable, side effects. The principal concern relates to AID, with Graves’ disease being most common. Vigilance is required to ensure that regular blood monitoring leads to early diagnosis and treatment before more serious sequelae occur. Infections associated with alemtuzumab are usually mild and infections more commonly associated with immunosuppression are very rare, and there is no evidence for any increased risk of malignancy. Long-term follow-up of patients treated with alemtuzumab is now required to assess long-term
clinical efficacy, indications for retreatment and safety concerns. When available these data will allow a better understanding of the risk/benefit profile of this treatment and enhanced patient counselling. 6.
Expert opinion
Alemtuzumab is one of a range of repurposed treatments undergoing clinical trials in MS and therefore has the unusual feature of having longer-term practical experience for this indication, as it has been used in a few select centres, particularly in the UK for more than a decade for patients with aggressive MS. In our centre, we have treated 96 highly selected patients with poor prognostic features within 5 years of disease onset as well as some patients who have failed alternative conventional therapeutic interventions, the outcomes for whom have been published [39,48]. Our experience in using this drug has been largely positive for patients and clinicians alike, but requires commitment to a dedicated long-term surveillance programme. In line with published clinical trials, we have noted a marked improvement in annualised relapse rates post-treatment but to date have not been able to confirm previous reports of improved disability outcomes (unpublished data). Thyroid AID has been the most commonly observed adverse effect of treatment, which we have largely been able to detect and treat effectively at an early stage as the result of effective surveillance mechanisms. This currently includes a monthly full blood count, urea and electrolytes and urine dipstick and 6-monthly thyroid function tests, to monitor for ITP for thyroid and renal AID respectively. With a growing therapeutic armament for MS now available to clinicians, treatment choices in this disease have become more complex. Drug efficacy has to be weighed carefully against possible side effects and patient counselling has become an increasingly important component of patient management. For those patients with poor prognostic features and recent onset disease as well as those patients failing conventional treatments, the risks of AID may be offset by the high levels of efficacy offered by alemtuzumab. However, in a disease which has a mean disease duration of over 20 years, and mindful of the late emergence of significant adverse events in previous treatments for MS, it is clear that further long-term outcome data is required. A post-marketing surveillance phase will clearly be important, and data collected, possibly through the use of national registries, may be informative in this regard. Given alemtuzumab’s advantage of efficacy, longevity and ease of administration over other disease-modifying therapies, clinicians are likely to be encouraged to use the drug, but there is current concern over the proposed cost of £56,360 for a full 2-year treatment course [59]. It is yet to be determined how regulatory bodies will instruct on the timing of treatment with alemtuzumab. Its effects are likely to be greatest early in the disease -- the so-called ‘window of therapeutic opportunity’ [38] but the price of treatment may prove
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M. Willis & N. P. Robertson
prohibitive for some national health services and push treatment towards patients who have failed more conventional therapies. Despite being approved for use in the European Union, Australia, Canada, Mexico and Brazil, the US FDA Advisory Committee recently decided not to approve it for licence for use in the USA. This has caused disquiet amongst advocates for the drug [60] with American patients set to miss out on the benefits that this drug may offer. It should also be noted that the majority of patients who may be treated with alemtuzumab are likely to be female and of childbearing age. There is currently no data regarding the safety of alemtuzumab in pregnancy and therefore patients are currently advised against conceiving, although it remains unclear for how long after the last dose this advice is appropriate for. The data available to date support the use of alemtuzumab as an effective treatment for both treatment naı¨ve and treatment experienced patients and suggests that potential adverse effects can be effectively managed with adequate clinical surveillance programmes. However, there are complexities involved in the administration and subsequent management Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Affiliation
Mark Willis BSc MB BCh & Neil P Robertson† † Author for correspondence Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University School of Medicine, Cardiff, UK E-mail: [email protected]
