Drug Evaluation For reprint orders, please contact: [email protected]
Alemtuzumab in multiple sclerosis: an update
Robert H Gross1 & Stephen Krieger*,1 Practice points ●●
Alemtuzumab is a humanized monoclonal antibody to CD52 that has demonstrated efficacy in the treatment of relapsing-remitting multiple sclerosis.
●●
Alemtuzumab is given as an initial infusion of 12 mg daily for 5 consecutive days, then as another course 1 year later for 3 days.
●●
In clinical trials, alemtuzumab was shown to be more effective at reducing relapse rates and MRI activity and
●●
Data suggest that alemtuzumab’s effects are long-lasting, with patients often not requiring subsequent retreatment
improving disability scores than IFN β-1a SC in patients with active multiple sclerosis. after the first 2 years.
●●
The potential for serious side effects, including infusion-associated reactions, autoimmune disorders and increased infections, will limit use of alemtuzumab to those whose disease warrants more aggressive treatment.
●●
Clinical experience with alemtuzumab in multiple sclerosis outside of trials is limited given its recent approval.
Summary Since the introduction of IFN-β, disease-modifying treatments, acting through various immune mechanisms, have been shown to reduce disease activity and severity in relapsing multiple sclerosis. Nevertheless, there remain patients for whom these treatments are incompletely effective, poorly tolerated or contraindicated. Alemtuzumab is a humanized monoclonal antibody that works by selectively depleting circulating lymphocytes. It is given as an intravenous infusion of 12 mg daily for 5 days, then a year later for 3 days. Effectiveness in patients with active relapsing-remitting multiple sclerosis has been demonstrated in two Phase III clinical trials, where it outperformed IFN-β-1a 44 mcg on clinical and radiographic efficacy measures. Its side effect profile, including infusionassociated reactions, infections and secondary autoimmunity, coupled with its long-lasting biological effect, requires patients to commit to close monitoring while on the drug and for 4 years after the final infusion. For select patients with active disease, alemtuzumab offers a powerful therapeutic option. Background Alemtuzumab (Lemtrada®, Genzyme, MA, USA) is the second monoclonal antibody, after natalizumab (Tysabri®, Biogen Idec, MA, USA) to be approved for the treatment of multiple sclerosis (MS), a field that has experienced an explosion of new therapeutic options in the 21st century. As of this writing, there are 12 disease-modifying agents (DMAs) approved by the US FDA to treat MS: three oral, six injectable and three intravenous infusions. With the evolving DMA landscape, 1 Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA *Author for correspondence: [email protected]
10.2217/NMT.15.14 © 2015 Future Medicine Ltd
part of
Neurodegener. Dis. Manag. (2015) 5(3), 225–232
ISSN 1758-2024
225
Drug Evaluation Gross & Krieger Keywords
• active MS • alemtuzumab • disease-modifying agent • monoclonal antibody • multiple sclerosis
226
caring for MS patients has become an increasingly complex undertaking. Treatment decisions are generally made on the basis of MS-related factors (disease activity, prior failed or poorly tolerated DMAs and JC virus antibody status), other health or lifestyle concerns (age, comorbidities, pregnancy plans, comfort and convenience), logistical issues (drug availability, cost and insurance) and provider approach (familiarity and preference). Disease activity in MS is characteristically unpredictable, and we are limited in our ability to predict a priori how a patient will respond to a given agent. Some patients might have no disease activity regardless of the DMA (or on no treatment at all); conversely, even the most aggressive therapies do not eliminate disease activity in all patients. A clinician trying to decide on the optimal DMA for a given patient may justifiably approach this sea of choices with uncertainty. There is no consensus as to whether a patient experiencing a severe first attack of MS should initiate treatment with a highly efficacious agent conferring a higher risk of serious side effects, or if safer, traditionally ‘first-line’ agents should first be employed. The treatment escalation paradigm, by which first-line treatment options are exhausted before switching to second-line, potentially more toxic medications, conforms to the Hippocratic dictum primum non nocere and has been traditionally favored over induction therapy for most patients [1,2] . A tension exists, however, between this incremental approach and the desire to stamp out inflammation early before the arrival of irreversible disability, as data suggest that early suboptimal response leads to poorer long-term outcomes [3–5] . Clearly with evidence of recurrent breakthrough disease, it becomes reasonable to consider therapies that confer higher risk but offer a greater likelihood of disease control. It should be noted that there is no class 1 evidence to inform decisions about switching MS therapies, so a certain amount of empiricism is necessary. Though beyond the scope of this review, the development of rational treatment algorithms is a significant topic of interest among MS clinicians, and this background is included here to provide context in which alemtuzumab can be considered. Alemtuzumab is a humanized monoclonal antibody that binds to CD52, a cell-surface protein found on lymphocytes. It is administered as an intravenous infusion and produces a
Neurodegener. Dis. Manag. (2015) 5(3)
rapid depletion of these cells in the circulation. Originally developed at the Waldmann laboratory in Cambridge, then-called CAMPATH-1H was the first humanized antibody used in the treatment of patients [6] . Under the brand name Campath® (Genzyme), alemtuzumab was produced by Genzyme for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Following Sanofi’s acquisition of Genzyme in 2011 and subsequent completion of a full clinical development program, alemtuzumab, at a lower dose and frequency, was rebranded as Lemtrada for exclusive use in MS. Indications & usage In September 2013, the European Commission licensed alemtuzumab to be used in the EU for MS patients with active disease defined by clinical or imaging characteristics, including as a first-line option. Approval followed in Australia, Brazil and Mexico. In Canada, it is authorized for patients with active disease by clinical and imaging features who have had an inadequate response to IFN-β or other DMAs. The US FDA, which approved alemtuzumab for relapsing forms of MS in November 2014, stipulated that it should ‘generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS’. How exactly one defines ‘active disease’ and ‘inadequate response’ in these instances is left to the clinician’s empirical judgment. Dosage & administration Alemtuzumab is available only as an infusion of 12 mg, administered once daily for 5 consecutive days in year 1, then again for 3 consecutive days in year 2. Its effect on the immune system is enduring: in the Phase III clinical trials CARE-MS I and CARE-MS II, 82 and 80% of patients, respectively, did not require retreatment in year 3 [7] . Among the 151 patients who received alemtuzumab in the Phase II trial, CAMMS223, and participated in the extension study, only nine patients were retreated with alemtuzumab between 36 and 60 months [8] . Clinical pharmacology Alemtuzumab is a 150-kDa protein that essentially remains confined to the plasma and interstitial space [9] . Following infusion, it disappears relatively quickly from the circulation,
future science group
Alemtuzumab in multiple sclerosis: an update with concentrations becoming undetectable by 1 month post-treatment in all patients, although its pharmacodynamic activity and clinical impact are long-lasting. The target of alemtuzumab is CD52, a cell surface marker of unclear function found on mature T and B lymphocytes, as well as natural killer cells, dendritic cells, most monocytes and macrophages, and some granulocytes (but not neutrophils) [10] . Alemtuzumab exerts its effects on the immune system primarily through the depletion and subsequent repopulation of T and B lymphocytes, which are thought to play a central role in MS pathogenesis and disease activity. Binding of the antibody induces cell-mediated and complement-mediated lysis of these cells [11,12] . Length of time for the immune cells to reconstitute depends on the cell type: in the CAMMS223 extension study, CD19 + B cells reemerged roughly 3–6 months after each treatment cycle, while CD8 + and CD4 + T cells returned in a more delayed fashion, attaining the lower limit of normal by 11 and 12 months, respectively (median time for total lymphocytes to reach this threshold was 9 months) [8] . In addition to the differential recovery of lymphocyte numbers by class, alemtuzumab alters the immunological milieu through the promotion of certain lymphocyte subpopulations. Beyond 3 months post-treatment, the newly reemerged B cells, driven by elevated levels of serum B-cell activating factor (BAFF), come to be dominated by CD19 + CD23 + CD27- ‘mature naive’ B cells, with a relative paucity of B memory cells [13] . Meanwhile, the residual T-cell pool becomes enriched for CD4 + CD25high regulatory T cells (Treg) expressing the transcription factor FoxP3 [14,15] . Impaired Treg function has been implicated in the pathogenesis of MS [16] , and Tregs have been shown to be increased in the peripheral blood of MS patients with stable disease compared with those with active disease [17] . Alemtuzumab’s durable effect likely owes as much to its distinct profile of lymphocytic recovery as to its powerful lymphocyte-depleting capability. Clinical evidence CAMMS223, a Phase II study of 334 treatment-naive patients with early, active RRMS, compared alemtuzumab with high-dose IFNβ-1a, 44 mcg three-times weekly (Rebif ®, EMD Serono, MA, USA) [18] . ‘Active RRMS’
future science group
Drug Evaluation
was defined as two relapses in the 2 years prior to study entry and one or more gadoliniumenhancing lesion on screening MRI. Subjects were randomized in a 1:1:1 ratio to alemtuzumab 12 mg, alemtuzumab 24 mg or IFN. In this study, which ran for 3 years, alemtuzumab was found to be more effective than IFN at reducing the annualized relapse rate (ARR): pooled alemtuzumab ARR was 0.10 versus 0.36 for IFN, a 74% relative reduction (p < 0.001). Disability in MS trials, as in this study and the subsequent studies to be discussed, is measured by the Expanded Disability Status Scale (EDSS) – a 0–10 scale of MS-related disability. From baseline to 36 months, average EDSS decreased slightly among alemtuzumab-treated patients, while IFN-treated patients had a mild increase in disability (-0.39 vs + 0.38; p < 0.001). Sustained accumulation of disability (SAD) occurs when there is an increase in the EDSS by 1 point (or 1.5 points if the baseline EDSS is 0) that is sustained over a 6-month period. By 36 months, alemtuzumab treatment resulted in fewer patients with SAD (9 vs 26%; p < 0.001) and more patients with sustained reduction of disability (SRD) than IFN (52 vs 27%; p = 0.0004) [19] . Data from the CAMMS223 extension study supported these earlier findings, demonstrating a sustained reduction in both the relapse rate and the number of patients who developed SAD by 60 months (69% ARR reduction, 72% fewer patients with SAD; p < 0.0001 for both) [8] . Based on the impressive Phase II results, alemtuzumab was studied in active RRMS again against Rebif in two successful multicenter Phase III trials – CARE-MS I [20] and CARE-MS II [21] . In CARE-MS I, treatmentnaive patients with EDSS less than or equal to 3.0 at baseline were enrolled. CARE-MS II included only patients who had relapsed on prior therapy and had EDSS less than or equal to 5.0 at baseline, but otherwise followed a very similar protocol as CARE-MS I. Inclusion criteria in both trials defined patients with ‘active RRMS’ as having had greater than or equal to 2 relapses in the prior 2 years and greater than or equal to 1 relapse in the prior year. CARE-MS II initially included both 12 and 24 mg alemtuzumab groups but the latter arm was eliminated to expedite recruitment. In both of these Phase III studies, alemtuzumab performed better than IFN on the primary outcome of reducing the ARR over
www.futuremedicine.com
227
Drug Evaluation Gross & Krieger 2 years. In CARE-MS I, the ARR was reduced by 55% in the alemtuzumab group versus the IFN group (0.18 vs 0.39; p < 0.0001). In CARE-MS II, the ARR in the alemtuzumab group was also decreased compared with the IFN group: 0.26 versus 0.52 (49% relative reduction; p < 0.0001). The other primary clinical end point in both Phase III trials was the time to SAD. In this measure, CARE-MS I did not show a statistically significant difference between the two groups, with only 8 versus 11% of patients attaining SAD during the 2 years the trial ran in the alemtuzumab and IFN groups, respectively. The investigators suggested that the trial might have been underpowered to detect the difference. CARE-MS II did show a statistically significant difference in disability between the two groups: fewer alemtuzumab-treated patients developed SAD and more had SRD than IFN-treated patients after 2 years (13 vs 20% for SAD; p = 0.008, and 29 vs 13% for SRD, p = 0.0002). Additionally, the mean EDSS was again mildly reduced from baseline in the alemtuzumab group, while the EDSS in the IFN group increased slightly on average (-0.17 vs +0.24; p < 0.0001). It has been post ulated that this improvement in disability is not just related to the anti-inflammatory effects of alemtuzumab, but also from increased delivery of neurotrophins like brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) to the CNS in response to lymphocyte depletion [22] . The Phase III clinical data were supported by reductions in MRI measures of disease activity. Through year 2 in CARE-MS I, there were fewer alemtuzumab-treated patients than IFN-treated patients with new gadoliniumenhancing lesions (7 vs 19%; p < 0.0001) and new or enlarging T2-hyperintense lesions (48 vs 58%, p = 0.04). The MRI metrics were similar in CARE-MS II: 9 versus 23% had gadolinium-enhancing lesions and 46 versus 68% had new or enlarging T2 lesions on alemtuzumab versus IFN, respectively (p < 0.0001 for both). Both trials reported changes in brain parenchymal fraction (BPF), which was relatively preserved in alemtuzumab compared with IFN. According to extension data from CARE-MS I, the majority of patients (72%) remained free of MRI activity following alemtuzumab treatment by 36 months, despite most (>80%) not receiving additional treatment in
228
Neurodegener. Dis. Manag. (2015) 5(3)
the third year [23] . The percentage of patients who are free of all disease activity (sometimes referred to as having ‘no evidence of disease activity’ or NEDA) is a composite outcome measure with greater sensitivity to detect treatment effects in an era of increasingly effective agents, and is typically defined as the absence of clinical relapses, progression and new T2/FLAIR and gadolinium-enhancing lesions on MRI [24] . In CARE-MS I, at the end of 2 years, 39% of alemtuzumab-treated patients had NEDA, compared with 27% of IFN-treated patients. CARE-MS II had a similar profile: 32% of alemtuzumab-treated patients were free of all clinical and radiographic disease activity, compared with 14% of IFN-treated patients. In post-hoc analyses of the subset of patients with highly active disease, defined as having greater than or equal to 2 relapses the year before randomization and greater than or equal to 1 gadolinium-enhancing lesion at baseline, 24% of alemtuzumab-treated patients in CARE-MS II achieved NEDA status, while no IFN-treated patients did [25] . Early, open-label, uncontrolled studies of alemtuzumab with secondary-progressive MS patients failed to show slowing of disability progression despite suppression of new lesion formation [26,27] . These results support the theory that axonal degeneration and brain atrophy in progressive MS, irrespective of their early relationship with inflammation, proceed despite the suppression of inflammatory disease activity. In an observational cohort of 87 active RRMS patients treated with alemtuzumab and followed for a median of 7 years – the largest group to date outside of clinical trials – mean ARR was reduced from 1.78 (SD: 0.26) to 0.16 (SD: 0.82), and more patients were found to have SRD (43.5%) than SAD (32.2%) following treatment [28] . Higher baseline relapse rate was associated with worse long-term disability in this cohort, and there was a trend for patients of older age and longer disease duration to fare worse, supporting the investigators’ hypothesis of an early ‘window of therapeutic opportunity’ in patients with active disease (Table 1) . Adverse reactions Adverse reactions recorded in the clinical trials were both immediate and delayed. Infusion reactions occurred in 90% of patients who received
future science group
Alemtuzumab in multiple sclerosis: an update
Drug Evaluation
Table 1. Summary of clinical trial efficacy data. Clinical trial
Phase
Subjects
Comparator ARR % with SAD % with SRD reduction (%) (Lemtrada® vs Rebif®) (Lemtrada® vs Rebif®)
CAMMS223
II
CARE-MS I
III
CARE-MS II
III
Tx-naive, 2 relapses in prior 2 years, Rebif® ≥1 enhancing lesion on MRI, EDSS ≤3 Tx-naive, 2 relapses in prior 2 years, Rebif® 1 relapse in last year, ≥1 enhancing lesion on MRI, EDSS ≤3 Relapse while on IFN or GA after Rebif® ≥6 months tx, 2 relapses in prior 2 years, 1 relapse in last year, ≥1 enhancing lesion on MRI, EDSS ≤5
74
9 vs 26
52 vs 27
55
8 vs 11†
23 vs 27†
49
13 vs 20
29 vs 13
Not statistically significant. ARR: Annualized relapse rate; EDSS: Expanded disability status scale; SAD: Sustained accumulation of disability; SRD: Sustained reduction of disability.
†
alemtuzumab 12 mg in the two Phase III clinical trials, although the overwhelming majority of these were mild-to-moderate [20,21] . Among the 3% of infusion-associated reactions considered serious were atrial fibrillation, hypotension, angioedema, rash, nausea, vomiting and pyrexia. In CARE-MS I, there was a suspected case of anaphylactic shock associated with the first infusion, though this was later reclassified as nonanaphylactoid hypotension, as well as one case of angioedema. Both received their second course of alemtuzumab without incident. Patients who received alemtuzumab were at increased risk of developing infections [20,21] . These tended to be of mild-to-moderate severity, for example, upper respiratory, urinary tract and herpetic infections. Three percent of alemtuzumab-treated patients versus 1% of IFN-treated patients developed severe infections, including pneumonia, gastroenteritis, appendicitis, herpes zoster and tooth infection [9] . Two patients from tuberculosisendemic regions were diagnosed with pulmonary tuberculosis. Both responded to antimycobacterial treatment. One patient who received alemtuzumab 24 mg developed listeria meningitis and responded to parenteral antibiotics [29] . No infections were life-threatening or fatal. Secondary autoimmune conditions were found to develop in patients who received alemtuzumab. Of these, thyroid disease was the most common, with 33.8% of RRMS patients in CAMMS223 developing autoimmune thyroid disorder, mostly Graves’ disease. The incidence peaked at year 3 at 16.1%, but events were reported up to 7 years after the initial dose [30] . Most responded to conventional medical therapy, but some needed further
future science group
intervention (three patients in the Phase III trials underwent thyroidectomy and two received radioiodine ablation [29]). Alemtuzumab-treated patients were at increased risk of autoimmune cytopenias, principally idiopathic thrombocytopenia purpura (ITP), which was seen in 2% of patients. One patient in CAMMS223 whose ITP went unrecognized died from intracerebral hemorrhage. In the clinical trials, there were two cases of anti-GBM disease (Goodpasture) and three cases of membranous glomerulonephritis among alemtuzumab-treated patients. There are also published cases of anti-GBM disease in MS patients treated with alemtuzumab outside of clinical trials, where patients developed end stage renal disease and required renal transplantation [31] . Several mechanisms have been proposed for this increased rate of secondary autoimmunity, including relative B-cell overactivity (particularly plausible considering the observed autoimmune conditions are antibodymediated) [32] , higher levels of IL-21 driving enhanced T-cell cycling [33] and repetitive T-cell receptor interactions increasing the opportunity for T cells to encounter self-antigen and break tolerance [29,32] . Further research is needed to identify early who is at risk for secondary autoimmune conditions and how to modulate the postalemtuzumab immune recovery to prevent these complications. Cancer occurred in seven patients treated with alemtuzumab versus two patients treated with IFN-β in the clinical trials – both less than 1%. Of these seven patients, three were diagnosed with thyroid cancer, though it should be noted that alemtuzumab-treated patients received more frequent thyroid screening due to the higher incidence of autoimmune thyroid disease in these patients. Of the remaining
www.futuremedicine.com
229
Drug Evaluation Gross & Krieger four malignancies, there were two basal cell carcinomas, one vulval cancer and one colon cancer. Melanoma was found in 0.3% of ale mtuzumab-treated patients in uncontrolled studies [9] . Because of the increased risk of potentially serious infections and autoimmune conditions, enhanced vigilance is paramount. In order to prescribe alemtuzumab, clinicians and healthcare centers must become certified through participation in a training program, and patients must be enrolled in the Lemtrada Risk Evaluation and Mitigation Strategy (REMS) program. Prior to initiating treatment, the following studies must be completed: complete blood count (CBC), serum creatinine level, urinalysis with urine cell counts and thyroid function tests (TFTs). All patients considering treatment with alemtuzumab should be evaluated for HIV. Skin exam should be performed at baseline, and women should be screened for human papilloma virus (HPV). Screening for hepatitis B virus, hepatitis C virus and tuberculosis (TB) infections should be performed at the discretion of the clinician and in accordance with local guidelines. Patients who screen positive for TB should be treated by standard medical practice prior to initiating alemtuzumab. Patients without a known history of varicella zoster virus (VZV) exposure (e.g., chicken pox) should be tested for VZV antibodies and vaccination considered. Alemtuzumab treatment should be postponed for 6 weeks after VZV vaccination. At the time of dosing, it is recommended that patients be pretreated with methylprednisolone 1000 mg daily for the first 3 days of each alemtuzumab course as prophylaxis against infusion reactions. Pretreatment with antihistamines and/or antipyretics may also be considered. Prophylaxis with an oral antiherpes agent should begin on the first day of alemtuzumab infusion and continue for at least 1 month after each course of treatment. Infusion is given over 4 h, and patients are to be observed for at least 2 h after completing the infusion. Beginning 1 month after the initial infusion, CBC, serum creatinine and urinalysis must be performed at monthly intervals until 48 months from the last infusion. TFTs must be checked every 3 months after treatment initiation until 48 months after the last infusion. Skin exams and, for women, HPV screening should be
230
Neurodegener. Dis. Manag. (2015) 5(3)
performed annually. Throughout this time, patients should be counseled on the importance of self-monitoring for symptoms of infection or autoimmune disease. Drug interactions There are no specific drug–drug interactions with alemtuzumab, but live vaccines should not be given to MS patients who have recently received it. Use in specific populations HIV infection is the only absolute contraindication to treatment with alemtuzumab. Clinical judgment should be exercised when considering patients who have previously taken or are currently on other immunosuppressants. Because these patients were not well represented in the clinical trials, little is known about the cumulative risk of such therapies. Similarly, one should exercise caution in patients with severe active infections or a history of progressive multifocal leukoencephalopathy (PML). PML, an opportunistic brain infection caused by the John Cunningham virus, has not been reported in the alemtuzumab-MS clinical trials. PML has been observed in patients with B-CLL both with and without alemtuzumab treatment; the frequency of PML was no greater among alemtuzumab-treated patients than the background frequency [34] . For certain low-incidence adverse effects like PML to become manifest, large numbers of patients need to be exposed to the medication in the postapproval period, as has been the case with other MS medications – natalizumab (Tysabri®), dimethyl fumarate (Tecfidera®, Biogen Idec) and fingolimod (Gilenya®, Novartis). Whether or not PML will be independently associated with alemtuzumab treatment in MS patients is not yet known. Alemtuzumab has not been studied in pediatric or geriatric populations. Alemtuzumab is rated as a Pregnancy Category C (it has not been adequately studied in pregnant women, but animal studies suggest it may have embryolethal effects) [9] . Women of child-bearing potential are encouraged to use effective contraception while on treatment and for 4 months after treatment is stopped. Breast feeding should be discontinued during each course of treatment and for 4 months following the last infusion of each course. Conclusion By selectively depleting subsets of immune cells, alemtuzumab has emerged as a powerful
future science group
Alemtuzumab in multiple sclerosis: an update new therapeutic option for treating MS. Its efficacy has been demonstrated in CAMMS223, CARE-MS I and CARE-MS II, where it performed favorably against SC IFN β-1a in terms of reducing relapse rates and measures of disability, and suppressing MRI activity in patients with active disease. Its long-lasting biological effect distinguishes it from other multiple sclerosis DMTs and could be advantageous given the chronic nature of the disease. The side effect profile, which includes increased risk of autoimmune conditions and infections, requires that patients and clinicians commit to close monitoring during treatment cycles
and for 4 years after the last infusion. Careful patient selection and education is paramount. Financial & competing interests disclosure S Krieger reports compensation for consulting activities with Acorda Therapeutics, Bayer Healthcare, Biogen Idec, EMD Serono, Genentech, Genzyme, Questcor and Teva Neuroscience. 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. No writing assistance was utilized in the production of this manuscript.
References
9
Papers of special note have been highlighted as: • of interest; •• of considerable interest
10 Ratzinger G, Reagan JL, Heller G et al.
1
2
3
4
5
6
Río J, Comabella M, Montalban X. Multiple sclerosis: current treatment algorithms. Curr. Opin. Neurol. 24, 230–237 (2011). Karussis D, Biermann LD, Bohlega S et al. The International Working Group for Treatment Optimization in MS. A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting. Eur. J. Neurol. 13, 61–71 (2006). Río J, Nos C, Tintoré M et al. Defining the response to interferon-β in relapsing-remitting multiple sclerosis patients. Ann. Neurol. 59, 344–352 (2006). Freedman MS, Forrestal FG, On behalf of the PRISMS study group. Canadian treatment optimization recommendations (TOR) as a predictor of disease breakthrough in patients with multiple sclerosis treated with interferon β-1a: analysis of the PRISMS study. Mult. Scler. 14, 1234–1241 (2008). Montalban X. Treatment algorithms in patients with ongoing disease activity. Poster presentation. Presented at: ACTRIMSECTRIMS, Boston, MA, USA, 10– 13 September 2014 (Abstract PS9.2). Hale G, Bright S, Chumbley G et al. Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood 62, 873–882 (1983).
7
Arnold DL, Barkhof F, Cohen JA et al. Alemtuzumab: MS disease activity in CARE-MS I and II studies. Presented at: ACTRIMS-ECTRIMS, Boston, MA, USA, 10–13 September 2014 (Abstract FC2.2).
8
Coles AJ, Fox E, Vladic A et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurol. 78, 1069–1078 (2012).
future science group
Drug Evaluation
Lemtrada® Package Insert. Genzyme Corporation, MA, USA (2014). Differential CD52 expression by distinct myeloid dendritic cell subsets: implications for alemtuzumab activity at the level of antigen presentation in allogeneic graft-host interactions in transplantation. Blood 101, 1422–1429 (2003).
11 Hu Y, Turner MJ, Shields J et al. Investigation
of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunol. 128, 260–270 (2009). 12 Freedman MS, Kaplan JM, Markovic-Plese S.
Insights into the mechanisms of the therapeutic efficacy of alemtuzumab in multiple sclerosis. J. Clin. Cell. Immunol. 4, 1–18 (2013). 13 Thompson SAJ, Jones JL, Cox AL et al. B-cell
reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J. Clin. Immunol. 30, 99–105 (2010). 14 Cox AL, Thompson SAJ, Jones JL et al.
Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur. J. Immunol. 35, 3332–3342 (2005). 15 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. Immunol. 141, 123–131 (2013). 16 Kumar M, Putzki N, Limmroth V et al.
CD4 + CD25 +FoxP3 + T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J. Neuroimmunol. 180, 178–184 (2006). 17 Sarasella M, Marventano I, Longhi R et al.
CD4 + CD25 +FoxP3 +PD1- regulatory T cells in acute and stable relapsing-remitting multiple sclerosis and their modulation by therapy. FASEB J. 22, 3500–3508 (2008).
18 CAMMS223 Trial Investigators.
Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801 (2008). •• The Phase II clinical trial is the first randomized clinical trial to systematically show alemtuzumab’s efficacy in the treatment of multiple sclerosis. 19 Coles AJ, Fox E, Vladic A et al. Alemtuzumab
versus interferon beta-1a in early relapsingremitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet 10, 338–348 (2011). 20 Cohen JA, Coles AJ, Arnold DL et al.
Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomized controlled Phase 3 trial. Lancet 380, 1819–1828 (2012). •• One of two successful Phase III clinical trials demonstrating superiority of alemtuzumab over SC interferon β-1a, in treatment-naive patients. 21 Coles AJ, Twyman CL, Arnold DL et al.
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled Phase 3 trial. Lancet 380, 1829–1839 (2012). •• One of two successful Phase III clinical trials demonstrating superiority of alemtuzumab over SC IFN β-1a, in patients who had failed prior disease-modifying therapy. 22 Jones JL, Anderson JM, Phuah CL et al.
Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 133, 2232–2247 (2010). 23 Arnold DL, Barkhof F, Cohen JA et al.
Alemtuzumab improves MRI outcomes in treatment-naïve active relapsing-remitting MS patients: 3-year follow-up from CARE-MS I.
www.futuremedicine.com
231
Drug Evaluation Gross & Krieger Presented at: ACTRIMS-ECTRIMS, MA, USA, 10–13 September 2014 (Abstract FC2.2). 24 Lublin FD. Disease activity free status in MS.
Mult. Scler. Relat. Dis. 1, 6–7 (2012). 25 Krieger SC, Arnold DL, Cohen JA et al. On
behalf of CARE-MS II Investigators. ‘Alemtuzumab is efficacious in highly-active RRMS patients in CARE-MS II’. Presented at: 27th CMSC Annual Meeting. Orlando, FL, USA (2013). 26 Coles AJ, Wing MG, Molyneux P et al.
Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann. Neurol. 46, 296–304 (1999). •
232
An early open-label trial of alemtuzumab, showing no benefit in patients with SPMS.
27 Coles AJ, Cox A, le Page E et al. The window
of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J. Neurol. 253(1), 98–108 (2006). 28 Tuohy O, Costelloe L, Hill-Cawthorne G
et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J. Neurol. Neurosurg. Psychiatry 86(2), 208–215 (2015). 29 Hartung HP, Aktas O, Boyko AN.
Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Mult. Scler. 21(1) 22–34 (2015). 30 Daniels GH, Vladic A, Brinar V et al.
Alemtuzumab-related thyroid dysfunction in a Phase 2 trial of patients with relapsingremitting multiple sclerosis. J. Clin. Endocrinol. Metab. 99, 80–89 (2013).
Neurodegener. Dis. Manag. (2015) 5(3)
31 Clatworthy MR, Wallin EF. Anti-
glomerular basement membrane disease after alemtuzumab [letter to the editor]. NEJM 359, 768–769 (2008). 32 Klotz L, Meuth SG, Wiendl H. Immune
mechanisms of new therapeutic strategies in multiple sclerosis: a focus on alemtuzumab. Clin. Immunol. 142, 25–30 (2012). 33 Jones JL, Phuah CL, Cox AL et al. IL-21
drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J. Clin. Invest. 119, 2052–2061 (2009). 34 Lemtrada® Summary of Product
Characteristics. Genzyme Therapeutics Ltd, Oxford, UK (2013).
future science group
Alemtuzumab in multiple sclerosis: an update
Robert H Gross1 & Stephen Krieger*,1 Practice points ●●
Alemtuzumab is a humanized monoclonal antibody to CD52 that has demonstrated efficacy in the treatment of relapsing-remitting multiple sclerosis.
●●
Alemtuzumab is given as an initial infusion of 12 mg daily for 5 consecutive days, then as another course 1 year later for 3 days.
●●
In clinical trials, alemtuzumab was shown to be more effective at reducing relapse rates and MRI activity and
●●
Data suggest that alemtuzumab’s effects are long-lasting, with patients often not requiring subsequent retreatment
improving disability scores than IFN β-1a SC in patients with active multiple sclerosis. after the first 2 years.
●●
The potential for serious side effects, including infusion-associated reactions, autoimmune disorders and increased infections, will limit use of alemtuzumab to those whose disease warrants more aggressive treatment.
●●
Clinical experience with alemtuzumab in multiple sclerosis outside of trials is limited given its recent approval.
Summary Since the introduction of IFN-β, disease-modifying treatments, acting through various immune mechanisms, have been shown to reduce disease activity and severity in relapsing multiple sclerosis. Nevertheless, there remain patients for whom these treatments are incompletely effective, poorly tolerated or contraindicated. Alemtuzumab is a humanized monoclonal antibody that works by selectively depleting circulating lymphocytes. It is given as an intravenous infusion of 12 mg daily for 5 days, then a year later for 3 days. Effectiveness in patients with active relapsing-remitting multiple sclerosis has been demonstrated in two Phase III clinical trials, where it outperformed IFN-β-1a 44 mcg on clinical and radiographic efficacy measures. Its side effect profile, including infusionassociated reactions, infections and secondary autoimmunity, coupled with its long-lasting biological effect, requires patients to commit to close monitoring while on the drug and for 4 years after the final infusion. For select patients with active disease, alemtuzumab offers a powerful therapeutic option. Background Alemtuzumab (Lemtrada®, Genzyme, MA, USA) is the second monoclonal antibody, after natalizumab (Tysabri®, Biogen Idec, MA, USA) to be approved for the treatment of multiple sclerosis (MS), a field that has experienced an explosion of new therapeutic options in the 21st century. As of this writing, there are 12 disease-modifying agents (DMAs) approved by the US FDA to treat MS: three oral, six injectable and three intravenous infusions. With the evolving DMA landscape, 1 Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA *Author for correspondence: [email protected]
10.2217/NMT.15.14 © 2015 Future Medicine Ltd
part of
Neurodegener. Dis. Manag. (2015) 5(3), 225–232
ISSN 1758-2024
225
Drug Evaluation Gross & Krieger Keywords
• active MS • alemtuzumab • disease-modifying agent • monoclonal antibody • multiple sclerosis
226
caring for MS patients has become an increasingly complex undertaking. Treatment decisions are generally made on the basis of MS-related factors (disease activity, prior failed or poorly tolerated DMAs and JC virus antibody status), other health or lifestyle concerns (age, comorbidities, pregnancy plans, comfort and convenience), logistical issues (drug availability, cost and insurance) and provider approach (familiarity and preference). Disease activity in MS is characteristically unpredictable, and we are limited in our ability to predict a priori how a patient will respond to a given agent. Some patients might have no disease activity regardless of the DMA (or on no treatment at all); conversely, even the most aggressive therapies do not eliminate disease activity in all patients. A clinician trying to decide on the optimal DMA for a given patient may justifiably approach this sea of choices with uncertainty. There is no consensus as to whether a patient experiencing a severe first attack of MS should initiate treatment with a highly efficacious agent conferring a higher risk of serious side effects, or if safer, traditionally ‘first-line’ agents should first be employed. The treatment escalation paradigm, by which first-line treatment options are exhausted before switching to second-line, potentially more toxic medications, conforms to the Hippocratic dictum primum non nocere and has been traditionally favored over induction therapy for most patients [1,2] . A tension exists, however, between this incremental approach and the desire to stamp out inflammation early before the arrival of irreversible disability, as data suggest that early suboptimal response leads to poorer long-term outcomes [3–5] . Clearly with evidence of recurrent breakthrough disease, it becomes reasonable to consider therapies that confer higher risk but offer a greater likelihood of disease control. It should be noted that there is no class 1 evidence to inform decisions about switching MS therapies, so a certain amount of empiricism is necessary. Though beyond the scope of this review, the development of rational treatment algorithms is a significant topic of interest among MS clinicians, and this background is included here to provide context in which alemtuzumab can be considered. Alemtuzumab is a humanized monoclonal antibody that binds to CD52, a cell-surface protein found on lymphocytes. It is administered as an intravenous infusion and produces a
Neurodegener. Dis. Manag. (2015) 5(3)
rapid depletion of these cells in the circulation. Originally developed at the Waldmann laboratory in Cambridge, then-called CAMPATH-1H was the first humanized antibody used in the treatment of patients [6] . Under the brand name Campath® (Genzyme), alemtuzumab was produced by Genzyme for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Following Sanofi’s acquisition of Genzyme in 2011 and subsequent completion of a full clinical development program, alemtuzumab, at a lower dose and frequency, was rebranded as Lemtrada for exclusive use in MS. Indications & usage In September 2013, the European Commission licensed alemtuzumab to be used in the EU for MS patients with active disease defined by clinical or imaging characteristics, including as a first-line option. Approval followed in Australia, Brazil and Mexico. In Canada, it is authorized for patients with active disease by clinical and imaging features who have had an inadequate response to IFN-β or other DMAs. The US FDA, which approved alemtuzumab for relapsing forms of MS in November 2014, stipulated that it should ‘generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS’. How exactly one defines ‘active disease’ and ‘inadequate response’ in these instances is left to the clinician’s empirical judgment. Dosage & administration Alemtuzumab is available only as an infusion of 12 mg, administered once daily for 5 consecutive days in year 1, then again for 3 consecutive days in year 2. Its effect on the immune system is enduring: in the Phase III clinical trials CARE-MS I and CARE-MS II, 82 and 80% of patients, respectively, did not require retreatment in year 3 [7] . Among the 151 patients who received alemtuzumab in the Phase II trial, CAMMS223, and participated in the extension study, only nine patients were retreated with alemtuzumab between 36 and 60 months [8] . Clinical pharmacology Alemtuzumab is a 150-kDa protein that essentially remains confined to the plasma and interstitial space [9] . Following infusion, it disappears relatively quickly from the circulation,
future science group
Alemtuzumab in multiple sclerosis: an update with concentrations becoming undetectable by 1 month post-treatment in all patients, although its pharmacodynamic activity and clinical impact are long-lasting. The target of alemtuzumab is CD52, a cell surface marker of unclear function found on mature T and B lymphocytes, as well as natural killer cells, dendritic cells, most monocytes and macrophages, and some granulocytes (but not neutrophils) [10] . Alemtuzumab exerts its effects on the immune system primarily through the depletion and subsequent repopulation of T and B lymphocytes, which are thought to play a central role in MS pathogenesis and disease activity. Binding of the antibody induces cell-mediated and complement-mediated lysis of these cells [11,12] . Length of time for the immune cells to reconstitute depends on the cell type: in the CAMMS223 extension study, CD19 + B cells reemerged roughly 3–6 months after each treatment cycle, while CD8 + and CD4 + T cells returned in a more delayed fashion, attaining the lower limit of normal by 11 and 12 months, respectively (median time for total lymphocytes to reach this threshold was 9 months) [8] . In addition to the differential recovery of lymphocyte numbers by class, alemtuzumab alters the immunological milieu through the promotion of certain lymphocyte subpopulations. Beyond 3 months post-treatment, the newly reemerged B cells, driven by elevated levels of serum B-cell activating factor (BAFF), come to be dominated by CD19 + CD23 + CD27- ‘mature naive’ B cells, with a relative paucity of B memory cells [13] . Meanwhile, the residual T-cell pool becomes enriched for CD4 + CD25high regulatory T cells (Treg) expressing the transcription factor FoxP3 [14,15] . Impaired Treg function has been implicated in the pathogenesis of MS [16] , and Tregs have been shown to be increased in the peripheral blood of MS patients with stable disease compared with those with active disease [17] . Alemtuzumab’s durable effect likely owes as much to its distinct profile of lymphocytic recovery as to its powerful lymphocyte-depleting capability. Clinical evidence CAMMS223, a Phase II study of 334 treatment-naive patients with early, active RRMS, compared alemtuzumab with high-dose IFNβ-1a, 44 mcg three-times weekly (Rebif ®, EMD Serono, MA, USA) [18] . ‘Active RRMS’
future science group
Drug Evaluation
was defined as two relapses in the 2 years prior to study entry and one or more gadoliniumenhancing lesion on screening MRI. Subjects were randomized in a 1:1:1 ratio to alemtuzumab 12 mg, alemtuzumab 24 mg or IFN. In this study, which ran for 3 years, alemtuzumab was found to be more effective than IFN at reducing the annualized relapse rate (ARR): pooled alemtuzumab ARR was 0.10 versus 0.36 for IFN, a 74% relative reduction (p < 0.001). Disability in MS trials, as in this study and the subsequent studies to be discussed, is measured by the Expanded Disability Status Scale (EDSS) – a 0–10 scale of MS-related disability. From baseline to 36 months, average EDSS decreased slightly among alemtuzumab-treated patients, while IFN-treated patients had a mild increase in disability (-0.39 vs + 0.38; p < 0.001). Sustained accumulation of disability (SAD) occurs when there is an increase in the EDSS by 1 point (or 1.5 points if the baseline EDSS is 0) that is sustained over a 6-month period. By 36 months, alemtuzumab treatment resulted in fewer patients with SAD (9 vs 26%; p < 0.001) and more patients with sustained reduction of disability (SRD) than IFN (52 vs 27%; p = 0.0004) [19] . Data from the CAMMS223 extension study supported these earlier findings, demonstrating a sustained reduction in both the relapse rate and the number of patients who developed SAD by 60 months (69% ARR reduction, 72% fewer patients with SAD; p < 0.0001 for both) [8] . Based on the impressive Phase II results, alemtuzumab was studied in active RRMS again against Rebif in two successful multicenter Phase III trials – CARE-MS I [20] and CARE-MS II [21] . In CARE-MS I, treatmentnaive patients with EDSS less than or equal to 3.0 at baseline were enrolled. CARE-MS II included only patients who had relapsed on prior therapy and had EDSS less than or equal to 5.0 at baseline, but otherwise followed a very similar protocol as CARE-MS I. Inclusion criteria in both trials defined patients with ‘active RRMS’ as having had greater than or equal to 2 relapses in the prior 2 years and greater than or equal to 1 relapse in the prior year. CARE-MS II initially included both 12 and 24 mg alemtuzumab groups but the latter arm was eliminated to expedite recruitment. In both of these Phase III studies, alemtuzumab performed better than IFN on the primary outcome of reducing the ARR over
www.futuremedicine.com
227
Drug Evaluation Gross & Krieger 2 years. In CARE-MS I, the ARR was reduced by 55% in the alemtuzumab group versus the IFN group (0.18 vs 0.39; p < 0.0001). In CARE-MS II, the ARR in the alemtuzumab group was also decreased compared with the IFN group: 0.26 versus 0.52 (49% relative reduction; p < 0.0001). The other primary clinical end point in both Phase III trials was the time to SAD. In this measure, CARE-MS I did not show a statistically significant difference between the two groups, with only 8 versus 11% of patients attaining SAD during the 2 years the trial ran in the alemtuzumab and IFN groups, respectively. The investigators suggested that the trial might have been underpowered to detect the difference. CARE-MS II did show a statistically significant difference in disability between the two groups: fewer alemtuzumab-treated patients developed SAD and more had SRD than IFN-treated patients after 2 years (13 vs 20% for SAD; p = 0.008, and 29 vs 13% for SRD, p = 0.0002). Additionally, the mean EDSS was again mildly reduced from baseline in the alemtuzumab group, while the EDSS in the IFN group increased slightly on average (-0.17 vs +0.24; p < 0.0001). It has been post ulated that this improvement in disability is not just related to the anti-inflammatory effects of alemtuzumab, but also from increased delivery of neurotrophins like brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) to the CNS in response to lymphocyte depletion [22] . The Phase III clinical data were supported by reductions in MRI measures of disease activity. Through year 2 in CARE-MS I, there were fewer alemtuzumab-treated patients than IFN-treated patients with new gadoliniumenhancing lesions (7 vs 19%; p < 0.0001) and new or enlarging T2-hyperintense lesions (48 vs 58%, p = 0.04). The MRI metrics were similar in CARE-MS II: 9 versus 23% had gadolinium-enhancing lesions and 46 versus 68% had new or enlarging T2 lesions on alemtuzumab versus IFN, respectively (p < 0.0001 for both). Both trials reported changes in brain parenchymal fraction (BPF), which was relatively preserved in alemtuzumab compared with IFN. According to extension data from CARE-MS I, the majority of patients (72%) remained free of MRI activity following alemtuzumab treatment by 36 months, despite most (>80%) not receiving additional treatment in
228
Neurodegener. Dis. Manag. (2015) 5(3)
the third year [23] . The percentage of patients who are free of all disease activity (sometimes referred to as having ‘no evidence of disease activity’ or NEDA) is a composite outcome measure with greater sensitivity to detect treatment effects in an era of increasingly effective agents, and is typically defined as the absence of clinical relapses, progression and new T2/FLAIR and gadolinium-enhancing lesions on MRI [24] . In CARE-MS I, at the end of 2 years, 39% of alemtuzumab-treated patients had NEDA, compared with 27% of IFN-treated patients. CARE-MS II had a similar profile: 32% of alemtuzumab-treated patients were free of all clinical and radiographic disease activity, compared with 14% of IFN-treated patients. In post-hoc analyses of the subset of patients with highly active disease, defined as having greater than or equal to 2 relapses the year before randomization and greater than or equal to 1 gadolinium-enhancing lesion at baseline, 24% of alemtuzumab-treated patients in CARE-MS II achieved NEDA status, while no IFN-treated patients did [25] . Early, open-label, uncontrolled studies of alemtuzumab with secondary-progressive MS patients failed to show slowing of disability progression despite suppression of new lesion formation [26,27] . These results support the theory that axonal degeneration and brain atrophy in progressive MS, irrespective of their early relationship with inflammation, proceed despite the suppression of inflammatory disease activity. In an observational cohort of 87 active RRMS patients treated with alemtuzumab and followed for a median of 7 years – the largest group to date outside of clinical trials – mean ARR was reduced from 1.78 (SD: 0.26) to 0.16 (SD: 0.82), and more patients were found to have SRD (43.5%) than SAD (32.2%) following treatment [28] . Higher baseline relapse rate was associated with worse long-term disability in this cohort, and there was a trend for patients of older age and longer disease duration to fare worse, supporting the investigators’ hypothesis of an early ‘window of therapeutic opportunity’ in patients with active disease (Table 1) . Adverse reactions Adverse reactions recorded in the clinical trials were both immediate and delayed. Infusion reactions occurred in 90% of patients who received
future science group
Alemtuzumab in multiple sclerosis: an update
Drug Evaluation
Table 1. Summary of clinical trial efficacy data. Clinical trial
Phase
Subjects
Comparator ARR % with SAD % with SRD reduction (%) (Lemtrada® vs Rebif®) (Lemtrada® vs Rebif®)
CAMMS223
II
CARE-MS I
III
CARE-MS II
III
Tx-naive, 2 relapses in prior 2 years, Rebif® ≥1 enhancing lesion on MRI, EDSS ≤3 Tx-naive, 2 relapses in prior 2 years, Rebif® 1 relapse in last year, ≥1 enhancing lesion on MRI, EDSS ≤3 Relapse while on IFN or GA after Rebif® ≥6 months tx, 2 relapses in prior 2 years, 1 relapse in last year, ≥1 enhancing lesion on MRI, EDSS ≤5
74
9 vs 26
52 vs 27
55
8 vs 11†
23 vs 27†
49
13 vs 20
29 vs 13
Not statistically significant. ARR: Annualized relapse rate; EDSS: Expanded disability status scale; SAD: Sustained accumulation of disability; SRD: Sustained reduction of disability.
†
alemtuzumab 12 mg in the two Phase III clinical trials, although the overwhelming majority of these were mild-to-moderate [20,21] . Among the 3% of infusion-associated reactions considered serious were atrial fibrillation, hypotension, angioedema, rash, nausea, vomiting and pyrexia. In CARE-MS I, there was a suspected case of anaphylactic shock associated with the first infusion, though this was later reclassified as nonanaphylactoid hypotension, as well as one case of angioedema. Both received their second course of alemtuzumab without incident. Patients who received alemtuzumab were at increased risk of developing infections [20,21] . These tended to be of mild-to-moderate severity, for example, upper respiratory, urinary tract and herpetic infections. Three percent of alemtuzumab-treated patients versus 1% of IFN-treated patients developed severe infections, including pneumonia, gastroenteritis, appendicitis, herpes zoster and tooth infection [9] . Two patients from tuberculosisendemic regions were diagnosed with pulmonary tuberculosis. Both responded to antimycobacterial treatment. One patient who received alemtuzumab 24 mg developed listeria meningitis and responded to parenteral antibiotics [29] . No infections were life-threatening or fatal. Secondary autoimmune conditions were found to develop in patients who received alemtuzumab. Of these, thyroid disease was the most common, with 33.8% of RRMS patients in CAMMS223 developing autoimmune thyroid disorder, mostly Graves’ disease. The incidence peaked at year 3 at 16.1%, but events were reported up to 7 years after the initial dose [30] . Most responded to conventional medical therapy, but some needed further
future science group
intervention (three patients in the Phase III trials underwent thyroidectomy and two received radioiodine ablation [29]). Alemtuzumab-treated patients were at increased risk of autoimmune cytopenias, principally idiopathic thrombocytopenia purpura (ITP), which was seen in 2% of patients. One patient in CAMMS223 whose ITP went unrecognized died from intracerebral hemorrhage. In the clinical trials, there were two cases of anti-GBM disease (Goodpasture) and three cases of membranous glomerulonephritis among alemtuzumab-treated patients. There are also published cases of anti-GBM disease in MS patients treated with alemtuzumab outside of clinical trials, where patients developed end stage renal disease and required renal transplantation [31] . Several mechanisms have been proposed for this increased rate of secondary autoimmunity, including relative B-cell overactivity (particularly plausible considering the observed autoimmune conditions are antibodymediated) [32] , higher levels of IL-21 driving enhanced T-cell cycling [33] and repetitive T-cell receptor interactions increasing the opportunity for T cells to encounter self-antigen and break tolerance [29,32] . Further research is needed to identify early who is at risk for secondary autoimmune conditions and how to modulate the postalemtuzumab immune recovery to prevent these complications. Cancer occurred in seven patients treated with alemtuzumab versus two patients treated with IFN-β in the clinical trials – both less than 1%. Of these seven patients, three were diagnosed with thyroid cancer, though it should be noted that alemtuzumab-treated patients received more frequent thyroid screening due to the higher incidence of autoimmune thyroid disease in these patients. Of the remaining
www.futuremedicine.com
229
Drug Evaluation Gross & Krieger four malignancies, there were two basal cell carcinomas, one vulval cancer and one colon cancer. Melanoma was found in 0.3% of ale mtuzumab-treated patients in uncontrolled studies [9] . Because of the increased risk of potentially serious infections and autoimmune conditions, enhanced vigilance is paramount. In order to prescribe alemtuzumab, clinicians and healthcare centers must become certified through participation in a training program, and patients must be enrolled in the Lemtrada Risk Evaluation and Mitigation Strategy (REMS) program. Prior to initiating treatment, the following studies must be completed: complete blood count (CBC), serum creatinine level, urinalysis with urine cell counts and thyroid function tests (TFTs). All patients considering treatment with alemtuzumab should be evaluated for HIV. Skin exam should be performed at baseline, and women should be screened for human papilloma virus (HPV). Screening for hepatitis B virus, hepatitis C virus and tuberculosis (TB) infections should be performed at the discretion of the clinician and in accordance with local guidelines. Patients who screen positive for TB should be treated by standard medical practice prior to initiating alemtuzumab. Patients without a known history of varicella zoster virus (VZV) exposure (e.g., chicken pox) should be tested for VZV antibodies and vaccination considered. Alemtuzumab treatment should be postponed for 6 weeks after VZV vaccination. At the time of dosing, it is recommended that patients be pretreated with methylprednisolone 1000 mg daily for the first 3 days of each alemtuzumab course as prophylaxis against infusion reactions. Pretreatment with antihistamines and/or antipyretics may also be considered. Prophylaxis with an oral antiherpes agent should begin on the first day of alemtuzumab infusion and continue for at least 1 month after each course of treatment. Infusion is given over 4 h, and patients are to be observed for at least 2 h after completing the infusion. Beginning 1 month after the initial infusion, CBC, serum creatinine and urinalysis must be performed at monthly intervals until 48 months from the last infusion. TFTs must be checked every 3 months after treatment initiation until 48 months after the last infusion. Skin exams and, for women, HPV screening should be
230
Neurodegener. Dis. Manag. (2015) 5(3)
performed annually. Throughout this time, patients should be counseled on the importance of self-monitoring for symptoms of infection or autoimmune disease. Drug interactions There are no specific drug–drug interactions with alemtuzumab, but live vaccines should not be given to MS patients who have recently received it. Use in specific populations HIV infection is the only absolute contraindication to treatment with alemtuzumab. Clinical judgment should be exercised when considering patients who have previously taken or are currently on other immunosuppressants. Because these patients were not well represented in the clinical trials, little is known about the cumulative risk of such therapies. Similarly, one should exercise caution in patients with severe active infections or a history of progressive multifocal leukoencephalopathy (PML). PML, an opportunistic brain infection caused by the John Cunningham virus, has not been reported in the alemtuzumab-MS clinical trials. PML has been observed in patients with B-CLL both with and without alemtuzumab treatment; the frequency of PML was no greater among alemtuzumab-treated patients than the background frequency [34] . For certain low-incidence adverse effects like PML to become manifest, large numbers of patients need to be exposed to the medication in the postapproval period, as has been the case with other MS medications – natalizumab (Tysabri®), dimethyl fumarate (Tecfidera®, Biogen Idec) and fingolimod (Gilenya®, Novartis). Whether or not PML will be independently associated with alemtuzumab treatment in MS patients is not yet known. Alemtuzumab has not been studied in pediatric or geriatric populations. Alemtuzumab is rated as a Pregnancy Category C (it has not been adequately studied in pregnant women, but animal studies suggest it may have embryolethal effects) [9] . Women of child-bearing potential are encouraged to use effective contraception while on treatment and for 4 months after treatment is stopped. Breast feeding should be discontinued during each course of treatment and for 4 months following the last infusion of each course. Conclusion By selectively depleting subsets of immune cells, alemtuzumab has emerged as a powerful
future science group
Alemtuzumab in multiple sclerosis: an update new therapeutic option for treating MS. Its efficacy has been demonstrated in CAMMS223, CARE-MS I and CARE-MS II, where it performed favorably against SC IFN β-1a in terms of reducing relapse rates and measures of disability, and suppressing MRI activity in patients with active disease. Its long-lasting biological effect distinguishes it from other multiple sclerosis DMTs and could be advantageous given the chronic nature of the disease. The side effect profile, which includes increased risk of autoimmune conditions and infections, requires that patients and clinicians commit to close monitoring during treatment cycles
and for 4 years after the last infusion. Careful patient selection and education is paramount. Financial & competing interests disclosure S Krieger reports compensation for consulting activities with Acorda Therapeutics, Bayer Healthcare, Biogen Idec, EMD Serono, Genentech, Genzyme, Questcor and Teva Neuroscience. 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. No writing assistance was utilized in the production of this manuscript.
References
9
Papers of special note have been highlighted as: • of interest; •• of considerable interest
10 Ratzinger G, Reagan JL, Heller G et al.
1
2
3
4
5
6
Río J, Comabella M, Montalban X. Multiple sclerosis: current treatment algorithms. Curr. Opin. Neurol. 24, 230–237 (2011). Karussis D, Biermann LD, Bohlega S et al. The International Working Group for Treatment Optimization in MS. A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting. Eur. J. Neurol. 13, 61–71 (2006). Río J, Nos C, Tintoré M et al. Defining the response to interferon-β in relapsing-remitting multiple sclerosis patients. Ann. Neurol. 59, 344–352 (2006). Freedman MS, Forrestal FG, On behalf of the PRISMS study group. Canadian treatment optimization recommendations (TOR) as a predictor of disease breakthrough in patients with multiple sclerosis treated with interferon β-1a: analysis of the PRISMS study. Mult. Scler. 14, 1234–1241 (2008). Montalban X. Treatment algorithms in patients with ongoing disease activity. Poster presentation. Presented at: ACTRIMSECTRIMS, Boston, MA, USA, 10– 13 September 2014 (Abstract PS9.2). Hale G, Bright S, Chumbley G et al. Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood 62, 873–882 (1983).
7
Arnold DL, Barkhof F, Cohen JA et al. Alemtuzumab: MS disease activity in CARE-MS I and II studies. Presented at: ACTRIMS-ECTRIMS, Boston, MA, USA, 10–13 September 2014 (Abstract FC2.2).
8
Coles AJ, Fox E, Vladic A et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurol. 78, 1069–1078 (2012).
future science group
Drug Evaluation
Lemtrada® Package Insert. Genzyme Corporation, MA, USA (2014). Differential CD52 expression by distinct myeloid dendritic cell subsets: implications for alemtuzumab activity at the level of antigen presentation in allogeneic graft-host interactions in transplantation. Blood 101, 1422–1429 (2003).
11 Hu Y, Turner MJ, Shields J et al. Investigation
of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunol. 128, 260–270 (2009). 12 Freedman MS, Kaplan JM, Markovic-Plese S.
Insights into the mechanisms of the therapeutic efficacy of alemtuzumab in multiple sclerosis. J. Clin. Cell. Immunol. 4, 1–18 (2013). 13 Thompson SAJ, Jones JL, Cox AL et al. B-cell
reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J. Clin. Immunol. 30, 99–105 (2010). 14 Cox AL, Thompson SAJ, Jones JL et al.
Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur. J. Immunol. 35, 3332–3342 (2005). 15 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. Immunol. 141, 123–131 (2013). 16 Kumar M, Putzki N, Limmroth V et al.
CD4 + CD25 +FoxP3 + T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J. Neuroimmunol. 180, 178–184 (2006). 17 Sarasella M, Marventano I, Longhi R et al.
CD4 + CD25 +FoxP3 +PD1- regulatory T cells in acute and stable relapsing-remitting multiple sclerosis and their modulation by therapy. FASEB J. 22, 3500–3508 (2008).
18 CAMMS223 Trial Investigators.
Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801 (2008). •• The Phase II clinical trial is the first randomized clinical trial to systematically show alemtuzumab’s efficacy in the treatment of multiple sclerosis. 19 Coles AJ, Fox E, Vladic A et al. Alemtuzumab
versus interferon beta-1a in early relapsingremitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet 10, 338–348 (2011). 20 Cohen JA, Coles AJ, Arnold DL et al.
Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomized controlled Phase 3 trial. Lancet 380, 1819–1828 (2012). •• One of two successful Phase III clinical trials demonstrating superiority of alemtuzumab over SC interferon β-1a, in treatment-naive patients. 21 Coles AJ, Twyman CL, Arnold DL et al.
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled Phase 3 trial. Lancet 380, 1829–1839 (2012). •• One of two successful Phase III clinical trials demonstrating superiority of alemtuzumab over SC IFN β-1a, in patients who had failed prior disease-modifying therapy. 22 Jones JL, Anderson JM, Phuah CL et al.
Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 133, 2232–2247 (2010). 23 Arnold DL, Barkhof F, Cohen JA et al.
Alemtuzumab improves MRI outcomes in treatment-naïve active relapsing-remitting MS patients: 3-year follow-up from CARE-MS I.
www.futuremedicine.com
231
Drug Evaluation Gross & Krieger Presented at: ACTRIMS-ECTRIMS, MA, USA, 10–13 September 2014 (Abstract FC2.2). 24 Lublin FD. Disease activity free status in MS.
Mult. Scler. Relat. Dis. 1, 6–7 (2012). 25 Krieger SC, Arnold DL, Cohen JA et al. On
behalf of CARE-MS II Investigators. ‘Alemtuzumab is efficacious in highly-active RRMS patients in CARE-MS II’. Presented at: 27th CMSC Annual Meeting. Orlando, FL, USA (2013). 26 Coles AJ, Wing MG, Molyneux P et al.
Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann. Neurol. 46, 296–304 (1999). •
232
An early open-label trial of alemtuzumab, showing no benefit in patients with SPMS.
27 Coles AJ, Cox A, le Page E et al. The window
of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J. Neurol. 253(1), 98–108 (2006). 28 Tuohy O, Costelloe L, Hill-Cawthorne G
et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J. Neurol. Neurosurg. Psychiatry 86(2), 208–215 (2015). 29 Hartung HP, Aktas O, Boyko AN.
Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Mult. Scler. 21(1) 22–34 (2015). 30 Daniels GH, Vladic A, Brinar V et al.
Alemtuzumab-related thyroid dysfunction in a Phase 2 trial of patients with relapsingremitting multiple sclerosis. J. Clin. Endocrinol. Metab. 99, 80–89 (2013).
Neurodegener. Dis. Manag. (2015) 5(3)
31 Clatworthy MR, Wallin EF. Anti-
glomerular basement membrane disease after alemtuzumab [letter to the editor]. NEJM 359, 768–769 (2008). 32 Klotz L, Meuth SG, Wiendl H. Immune
mechanisms of new therapeutic strategies in multiple sclerosis: a focus on alemtuzumab. Clin. Immunol. 142, 25–30 (2012). 33 Jones JL, Phuah CL, Cox AL et al. IL-21
drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J. Clin. Invest. 119, 2052–2061 (2009). 34 Lemtrada® Summary of Product
Characteristics. Genzyme Therapeutics Ltd, Oxford, UK (2013).
future science group
