Abstract
Monoclonal antibody (mAb) therapies for relapsing-remitting multiple sclerosis (MS) target immune cells or other molecules involved in pathogenic pathways with extraordinary specificity. Natalizumab and alemtuzumab are the only two currently approved mAbs for the treatment of MS, having demonstrated significant reduction in clinical and magnetic resonance imaging disease activity and disability in clinical studies. Ocrelizumab and daclizumab are in the late stages of phase III trials, and several other mAbs are in the early stages of clinical evaluation. mAbs have distinct structural characteristics (e.g. chimeric, humanized, fully human) and unique targets (e.g. blocking interactions, induction of signal transduction by receptor binding, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity) conferring different mechanisms of action in MS. Because of these differences, mAbs for MS do not constitute a single treatment class; each must be considered individually when selecting appropriate therapy. Furthermore, in reviewing the data from clinical studies of mAbs, attention should be drawn to use of different comparators (e.g. placebo or interferon β-1a) and study designs. Each mAb treatment has a unique administration schedule. In the decision to select the appropriate treatment for each individual MS patient, careful review of the benefits relative to risks of mAbs is balanced against the risk of development of MS-associated disability.
Introduction
Multiple sclerosis (MS) is an immune-mediated, inflammatory, demyelinating disease of the central nervous system (CNS) [Gensicke et al. 2012; National Multiple Sclerosis Society, 2014]. In recent years, increasing numbers of monoclonal antibodies (mAbs) have been investigated for MS, as unmet needs remain in finding a treatment that markedly reduces or stops disease progression and reverses the CNS damage in MS. Unlike small molecule and other biologic therapies used in the treatment of MS, mAbs target immune cells or other molecules involved in pathogenic pathways of MS with far greater specificity [Gensicke et al. 2012] and they are associated with unique pharmacologic properties. However, because mAb therapies for MS vary in their structures (e.g. isotype, chimeric, humanized, fully human), mechanisms of action and unique toxicities, they cannot be considered a single treatment class and each must be assessed individually for efficacy and safety to optimize therapy for patients [Gensicke et al. 2012].
The aim of this review is to compare and contrast the mechanisms of action and the pharmacokinetic, pharmacodynamic, efficacy, safety and immunogenicity profiles of approved mAb therapies or those in late-stage development for relapsing-remitting MS. A brief summary of these agents is provided in Table 1 [Bielekova et al. 2011; Biogen Idec, 2013; European Medicines Agency, 2013a, 2013b, 2013d; Hoffmann-La Roche, 2005; Kappos et al. 2011b]. Here, we predominantly focus on natalizumab and alemtuzumab, which are the only two currently approved mAbs for MS [Biogen Idec, 2013; European Medicines Agency, 2013b, 2013d; Genzyme, 2014].
Summary of monoclonal antibody therapies approved or in late-stage development for MS.
Note: Natalizumab is approved in over 65 countries as of April 2015 (indications vary by country), and
Alemtuzumab is approved in over 45 countries as of September 2015 (indications vary by country).
Biogen Idec, 2013; European Medicines Agency, 2013d.
European Medicines Agency, 2013b; Genzyme, 2014.
Bielekova et al. 2011.
Kappos et al. 2011b.
CNS, central nervous system; IFNβ, interferon β; IgG, immunoglobulin G; IL, interleukin; MS, multiple sclerosis; NK, natural killer; RRMS, relapsing-remitting multiple sclerosis.
Natalizumab
Natalizumab is a recombinant, humanized immunoglobulin (Ig) G4κ mAb targeted to the α4 subunit of the α4β1 and α4β7 integrins on the surface of leukocytes [Biogen Idec, 2013] (α4β1 integrins are not well characterized but have been demonstrated on neutrophils [Futosi et al. 2013; Neumann et al. 2015]). In 2004, natalizumab became the first mAb to be approved by the US Food and Drug Administration (FDA) for the treatment of MS [Biogen Idec, 2013]. It was approved in 2006 in the European Union (EU), where it is used as a disease-modifying monotherapy in patients with relapsing forms of MS who show inadequate responses to treatments considered less efficacious [e.g. interferon beta (IFNβ) and glatiramer acetate] or in treatment-naïve patients who have rapidly evolving, severe relapsing MS [European Medicines Agency, 2013d]. In clinical practice, natalizumab may also be considered for patients with poor response to other therapies, including teriflunomide, dimethyl fumarate and fingolimod. However, in patients who are John Cunningham virus (JCV) antibody positive, and particularly in those who have received natalizumab treatment for >24 months, physicians should consider whether the expected benefit is sufficient to offset the increased risk of progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment [Biogen Idec, 2013]. Higher JCV antibody index level has also been correlated with higher risk of PML in patients who are JCV-positive with no prior immunosuppressant use [Plavina et al. 2014].
The mechanism of action of natalizumab is to bind to the α4 subunit of the α4β1 and α4β7 integrins; this inhibits the ability of lymphocytes to bind to endothelial receptors and prevents their migration into the CNS, thereby reducing inflammation [Yednock et al. 1992]. α4β1 Integrin blockade also prevents recruitment of additional immune cells, including immature dendritic [Jain et al. 2010] and natural killer cells [Gan et al. 2012] to the CNS. The migration of T-helper (Th1) but not Th17 lymphocytes [Glatigny et al. 2011; Rothhammer et al. 2011] to the CNS is dependent on α4 integrins, underlining the crucial role of Th1 in MS. As a result of apparent demargination, natalizumab increases the number of circulating lymphocytes in the periphery [Biogen Idec, 2013; Stuve et al. 2006]. Natalizumab is administered by intravenous (IV) infusion over 1 hour (300 mg every 4 weeks) [Biogen Idec, 2013]. The mean time to steady-state plasma concentrations is approximately 36 weeks after every 4 weeks of dosing, and the mean (SD) halflife is 16 (4) days [European Medicines Agency, 2013c]. Natalizumab is thought to be cleared from the circulation approximately 2 months after discontinuation [O’Connor et al. 2011], although it may be detected in plasma for up to 200 days [Rispens et al. 2012]. A washout period of less than 3 months has been suggested between natalizumab withdrawal and initiation of other immunosuppressive therapies [Cohen et al. 2014; Fox et al. 2014]. In fact, owing to the risk of reappearance of disease activity after discontinuation of natalizumab, most MS centers limit the washout period to 1–2 months or less.
Clinical efficacy and safety
The efficacy of natalizumab in relapsing-remitting MS (RRMS) was established in three phase II trials and two pivotal phase III trials (Table 2) [Cohen et al. 2012; Coles et al. 2008, 2012a, 2012b; Goodman et al. 2009; Miller et al. 2003, 2007; Polman et al. 2006; Rudick et al. 2006; Tubridy et al. 1999]. The phase III trial examining the safety and efficacy of natalizumab as monotherapy (AFFIRM) [ClinicalTrials.gov identifier: NCT00027300] [Polman et al. 2006] or as addon to IFNβ-1a (SENTINEL [ClinicalTrials.gov identifier: NCT00030966]) in patients with RRMS showed that the benefits of natalizumab, compared with placebo, were sustained over 2 years (Table 2) [Miller et al. 2007; Rudick et al. 2006]. A further analysis of the AFFIRM study after an additional year of open-label dosing demonstrated a sustained effect on relapses and disability progression [O’Connor et al. 2007].
Clinical trial efficacy and safety of available monoclonal antibody therapies for MS: results from clinical development studies.
AE, adverse event; ARR, annualized relapse rate; Gd, gadolinium; IFN, interferon; ITP, immune thrombocytopenia; LFT, liver function test; MRI, magnetic resonance imaging; MS, multiple sclerosis; NS, not significant; OR, odds ratio; PML, progressive multifocal leukoencephalopathy; SAD, sustained accumulation of disability; SC, subcutaneous; UTI, urinary tract infection.
In AFFIRM and SENTINEL, discontinuation rates with natalizumab were comparable with those with placebo, with 6% and 8% of patients, respectively, discontinuing treatment owing to adverse events (AEs) [Polman et al. 2006; Rudick et al. 2006]. The development of PML in one patient in SENTINEL and a second patient in the corresponding extension study prompted discontinuation of the trial approximately 1 month early [Rudick et al. 2006]. No increased risk of lymphoma, malignant melanoma or hypereosinophilia was reported in these studies [Abbas et al. 2011; Bujold et al. 2014; Mullen et al. 2008]. No increase in infection among patients receiving natalizumab, compared with placebo, was found [Polman et al. 2006; Rudick et al. 2006], but postmarketing studies identified a slight excess of herpes virus infections [Fine et al. 2013; Holmen et al. 2011] with rare cases of fatal herpes encephalitis [Biogen Idec, 2013; Kwiatkowski et al. 2012] and meningitis [Biogen Idec, 2013; Shenoy et al. 2011; Valenzuela et al. 2014].
Latent, wildtype JCV can undergo neurovirulent transformation during natalizumab therapy [Reid et al. 2011] in combination with a number of ill-defined host factors including prior immune suppression [Biogen Idec, 2013; Bozic et al. 2011]. In a large multinational cohort, the overall incidence of anti-JCV antibodies was approximately 58% [Olsson et al. 2013]. As of 3 June 2015, 563 cases of PML have been reported in natalizumab-treated patients with MS [Bartsch et al. 2015]. Diagnosis of PML is usually confirmed by detection of JCV DNA in cerebrospinal fluid [Kappos et al. 2011a]. Based on the results of a quantitative analysis of risk factors for PML associated with natalizumab therapy, patients can now be stratified into five risk categories based on the presence or absence of anti-JCV antibodies, prior or no prior use of immunosuppressants, and treatment duration of 1–24 months or 25–48 months [Bloomgren et al. 2012]. Patients with anti-JCV antibodies, immunosuppressant therapy use and a natalizumab treatment duration of 25–48 months had the highest risk of PML (11.1 cases per 1000 patients) [Bloomgren et al. 2012]; a JCV index >1.5 also increases risk of PML [Plavina et al. 2013]. A recent preliminary analysis [Foley, 2013] suggests that low body mass (⩽75 kg), which is associated with higher natalizumab concentrations and potential saturation of α4 integrin, is a risk factor; however, this has not been determined to be an independent risk factor for PML. In 2012, the FDA confirmed that risk factors for PML in natalizumab-treated patients include the presence of anti-JCV antibodies, longer duration of natalizumab therapy (i.e. >2 years) and prior treatment with immunosuppressants, and this information was added to the prescribing information [Biogen Idec, 2013; European Medicines Agency, 2013d; US Food and Drug Administration, 2012].
Initial management of PML as a complication of natalizumab therapy includes plasma exchange or immunoadsorption to remove remaining natalizumab from the system after discontinuation. However, these measures are associated with the development of immune reconstitution inflammatory syndrome (IRIS), which is characterized by worsening neurologic deficits and the appearance of contrast-enhancing lesions on magnetic resonance imaging (MRI) [Tan et al. 2011]. IRIS develops in most patients when natalizumab is actively pheresed, facilitating restoration of normal lymphocyte trafficking into the CNS and resulting in an inflammatory reaction at PML lesion sites, enabling restoration of the immune response, potentiating a rebound of proinflammatory cytokines, and thus leading to highly morbid expansile lesions [Tan et al. 2011]. If IRIS occurs, it should be treated with cortico-steroid therapy [Antoniol et al. 2012].
Planned dosage interruption has been investigated as a strategy for mitigation of PML risk; however, this strategy has been associated with return of disease activity. Findings from the phase IV, randomized, partially placebo-controlled RESTORE study [ClinicalTrials.gov identifier: NCT01071083] showed that patients who interrupted natalizumab for up to 24 weeks had increased rates of MS recurrence compared with patients who remained on therapy [Fox et al. 2014]. Similar trends were observed in the TY-STOP study [Clerico et al. 2014]. Thus, proper patient selection and education regarding the potential risks and benefits of natalizumab therapy are necessary to optimize therapy.
Immunogenicity
Anti-natalizumab antibodies were shown to develop in 9% of natalizumab-treated patients in AFFIRM and in 12% in SENTINEL, with antibodies persisting (detected on at least two occasions at least 42 days apart) in 6% of these patients in each trial [Polman et al. 2006; Rudick et al. 2006]. However, in postmarketing reports, the frequency of anti-natalizumab antibodies has been lower (4.5%) [Holmen et al. 2011]. Anti-natalizumab antibodies tend to develop early in the treatment course, typically within the first 4 months [Oliver-Martos et al. 2013]. Persistence of anti-natalizumab antibodies was associated with a decrease in efficacy and an increased incidence of infusion-related AEs [Polman et al. 2006; Rudick et al. 2006]. In AFFIRM and SENTINEL, persistent anti-natalizumab antibodies were associated with sustained disability progression and/or declines in MS function composite Z-scores [Calabresi et al. 2007].
Pregnancy outcomes
In a global, observational registry, 314 live births (87%) and 34 spontaneous abortions (9%) occurred among 362 pregnancies with known outcomes in women with MS who were exposed to natalizumab during pregnancy. Birth defects were noted in 28 infants (8%) [Cristiano et al. 2013]. In a national German pregnancy registry of MS patients followed prospectively, outcomes were available for 98 pregnancies in women exposed to natalizumab; 17 (17%) resulted in spontaneous abortion, which was similar to the rate reported for disease-matched patients. The rate of birth defects was not different between groups [Ebrahimi et al. 2015]. In a study of 35 natalizumab-treated patients with RRMS who terminated treatment after notification of accidental pregnancy, there was no difference in relapse rate during pregnancy or postpartum between natalizumab-exposed patients and those with RRMS who were never exposed to a disease-modifying therapy (DMT) [Hellwig et al. 2011].
Alemtuzumab
Alemtuzumab is a humanized immunoglobulin G1κ (IgG1κ) mAb that selectively targets CD52 on the cell surface of lymphocytes and monocytes [Coles et al. 2008; European Medicines Agency, 2013b]. It is approved in more than 45 countries, including in the EU, for patients with RRMS [European Medicines Agency, 2013b]. In the US, alemtuzumab is approved for treatment of relapsing forms of MS and should generally be reserved for patients with an inadequate response to at least two drugs indicated for the treatment of MS [Genzyme, 2014]. Prior to its approval for RRMS, alemtuzumab was initially approved for B-cell chronic lymphocytic leukemia; however, it is no longer marketed for this indication [Genzyme, 2009].
Alemtuzumab binds to CD52 and depletes B and T lymphocytes; this is followed by a distinctive pattern of T- and B-cell repopulation that begins within weeks of treatment and leads to a rebalanced immune system [Cox et al. 2005; Jones et al. 2009; Thompson et al. 2010]. Although in vitro data suggest that complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity (ADCC) are both operant in the activity of alemtuzumab [Lowenstein et al. 2006], data from transgenic mice expressing human CD52 suggest that ADCC is the predominant mechanism [Hu et al. 2009]. Alemtuzumab rapidly and selectively depleted T and B lymphocytes, and repopulation led to shifts in relative proportions of lymphocyte subsets, including an increased percentage of regulatory and memory T cells [Hartung et al. 2012; Kasper et al.2013]. Absolute B- and T-lymphocyte counts were typically lowest approximately 1 month after treatment [Kovarova et al. 2012]. The immature compared with mature B-cell repertoire may be preserved with alemtuzumab treatment [Kasper et al. 2013]. Timing of B- and T-lymphocyte recovery varies among studies but typically occurs at 3–8 months and 1 to several years of follow up, respectively [Cox et al. 2005; Hill-Cawthorne et al. 2012; Kovarova et al. 2012]. The effects of alemtuzumab persisted after it was cleared from circulation [Hill-Cawthorne et al. 2012; Kovarova et al. 2012].
Alemtuzumab is administered by IV infusion (12 mg/day) over 4 hours in two annual treatment courses: once daily on 5 consecutive days and, after 12 months, once daily on 3 consecutive days [European Medicines Agency, 2013b]. Its alpha halflife is 4–5 days [European Medicines Agency, 2013b] and serum concentrations decrease to low or undetectable within approximately 1 month after each treatment course [Kasper et al. 2013].
Clinical efficacy and safety
The efficacy of alemtuzumab in MS was demonstrated against that of an active comparator, subcutaneous (SC) IFNβ-1a 44 µg, in one phase II and two phase III studies in treatment-naïve patients with active disease and in patients with an inadequate efficacy response on prior therapy (Table 2). The phase III CARE-MS I trial [ClinicalTrials.gov identifier: NCT00530348] compared alemtuzumab with SC IFNβ-1a in treatment-naïve RRMS patients for 2 years and found significant improvements with alemtuzumab on multiple endpoints (Table 2), including a 55% reduction in annualized relapse rate (ARR) (coprimary endpoint; p < 0.0001) and a 42% decrease in median change in brain parenchymal fraction (BPF) (p < 0.0001) compared with SC IFNβ-1a [Cohen et al. 2012]. Rates of 6-month sustained accumulation of disability (coprimary endpoint; 8% with alemtuzumab and 11% with SC IFNβ-1a) and changes in T2 hyperintense lesion volume were similar between groups (p = NS) [Cohen et al. 2012]; at year 2, lesion volumes were significantly lower than baseline levels with alemtuzumab (p < 0.001) [Arnold et al. 2014]. Interim data from the CARE-MS I extension [ClinicalTrials.gov identifier: NCT00930553] through year 4 indicated that alemtuzumab had a durable effect on both relapse rate [Coles et al. 2014] and on MRI outcomes [Arnold et al. 2015]. Mean Expanded Disability Status Scale (EDSS) scores remained below baseline values at year 4. In the extension study, 74% of patients did not receive retreatment with alemtuzumab [criteria were ⩾1 relapse and ⩾2 new or enlarging gadolinium (Gd) enhancing or T2 lesions] and <2% received another DMT [Arnold et al. 2015; Coles et al. 2014].
The phase III CARE-MS II trial [ClinicalTrials.gov identifier: NCT00548405] compared the effects of 2 years of SC IFNβ-1a with those of alemtuzumab in patients with an inadequate efficacy response while receiving IFNβ-1a or glatiramer acetate after at least 6 months of treatment. Results showed alemtuzumab was superior on multiple endpoints compared with SC IFNβ-1a, including the coprimary endpoints of relapse rate (49% risk reduction; p < 0.0001) and 6-month sustained accumulation of disability (42% risk reduction; p = 0.0084), as well as median change in BPF (24% reduction; p < 0.01) (Table 2) [Coles et al. 2012b]. Median T2 hyperintense lesion volumes decreased minimally (approximately 1%) from baseline levels in both treatment groups [Coles et al. 2012b]. Interim data from the CARE-MS II extension through year 4 indicated that improvement in relapse, disability and MRI outcomes were maintained, although most patients had not received alemtuzumab since year 1 [Hartung et al. 2014; Traboulsee et al. 2015]. A total of 68% of patients did not receive retreatment in the extension study and less than 5% of patients received another DMT [Hartung et al. 2014; Traboulsee et al. 2015].
In a long-term study (7-year follow up) of 87 RRMS patients, including 34 (39%) who had failed prior DMT [Tuohy et al. 2015], patients received 2 courses of alemtuzumab 12 months apart with additional courses offered for relapse. A total of 31 patients (36%) received 3 courses, 7 (8%) received 4 courses, and 1 (1%) received 5 courses, with a greater proportion of patients achieving sustained reduction in disability at 12 months (37.7%) than sustained accumulation of disability (21.8%). In summary, the efficacy of alemtuzumab in reducing both clinical and MRI disease activity persists for months and years after the last exposure. Long-term benefits remain even as lymphocyte repopulation is permitted and the immune system rebalances.
The principal AEs associated with alemtuzumab therapy are infusion-associated reactions, infection and autoimmunity. The safety profile of alemtuzumab was similar between the CAMMS-223, CARE-MS I and CARE-MS II populations. Patients treated with alemtuzumab had a discontinuation rate comparable to that with SC IFNβ-1a, with 1% of alemtuzumab patients in both CARE-MS I and II discontinuing owing to AEs [Cohen et al. 2012; Coles et al. 2012b]. Overall, the incidence of AEs with alemtuzumab was highest in the first month of each treatment course. Most AEs were mild to moderate infusion-associated reactions [LaGanke et al. 2013; Lycke et al. 2013a], which occurred in more than 90% of patients in active-controlled trials [Cohen et al. 2012; Coles et al. 2012b], were reduced with steroid pretreatment, and were less common with the second treatment course [Boyko et al. 2012; Caon et al. 2012]. Pretreatment with corticosteroids is recommended on the first 3 days of any treatment course, and pretreatment with antihistamines and/or antipyretics should be considered [European Medicines Agency, 2013b].
Infections were more frequent in the alemtuzumab treatment group than the SC IFNβ-1a treatment group in the active-controlled clinical trials. Infections were predominantly mild to moderate and were most commonly upper respiratory tract or urinary tract infections and herpetic infections [Cohen et al. 2012; Coles et al. 2012b]. The incidence of infection was highest in the first month after the first treatment course, with no additional peak observed at year 2 [LaGanke et al. 2013; Lycke et al. 2013a] or year 3 [Lycke et al. 2013b]. Risk of infection did not correlate with changes in lymphocyte counts after alemtuzumab therapy [Havrdova et al. 2013]. Rates of serious infections were low (<2%) in years 1, 2 and 3 [Lycke et al. 2013b]. Herpetic infections were observed more frequently with alemtuzumab than SC IFNβ-1a, with the highest risk in the first month of each treatment course; prophylactic acyclovir reduced the incidence of such infections [Wray et al. 2013]. The following are recommended to mitigate the risk of infection in alemtuzumab-treated patients [European Medicines Agency, 2013b]: consider delaying initiation of treatment in patients with active infection until the infection is fully controlled, perform annual human papillomavirus screening for female patients, evaluate patients for active and latent tuberculosis infection before treatment, and initiate prophylaxis with an oral anti-herpes agent from the first day of alemtuzumab treatment through at least 1 month after each course of treatment [European Medicines Agency, 2013b].
To date, no MS patient treated with alemtuzumab has developed PML, although rare cases have occurred during treatment for chronic lymphocytic leukemia [Martin et al. 2006] and non-Hodgkin’s lymphoma [Uppenkamp et al. 2002]; in both circumstances, patients had received prior and/or concomitant chemotherapy. PML is associated with some hematologic malignancies and lymphoproliferative disorders [D’Souza et al. 2010].
Alemtuzumab has been associated with the development of autoimmune AEs, which most frequently involve the thyroid and typically are responsive to standard management strategies [Tuohy et al. 2015]. A safety monitoring program that includes patient and physician education can facilitate early detection and improve outcomes in patients with these AEs [Coles et al. 2012a; US Food and Drug Administration, 2006].
Immune thrombocytopenia (ITP) was reported in approximately 1% of patients in the overall clinical trial program in patients receiving alemtuzumab 12 mg [Cuker et al. 2014; European Medicines Agency, 2013b]. With the exception of a single fatal index case before specific education and monitoring strategies were implemented [Coles et al. 2008], all ITP events occurring in the phase II and III trials were detected early through the safety monitoring program [Cuker et al. 2014; European Medicines Agency, 2013b]. An analysis of six cases of ITP in the CAMMS223 study found that onset occurred 19–39 months after the first treatment course and 1–15 months after last exposure; all five surviving patients achieved a complete response to therapy for ITP in a median of 4 months [Cuker et al. 2011]. The natural history of alemtuzumab-associated ITP was distinct from both typical drug-induced and primary ITP; features included delayed presentation (median of 24.5 months after initial administration and 10.5 months after last exposure), high responsiveness to conventional ITP therapies, and complete remission within 8 months of onset that was sustained (median follow up, 34 months) [Cuker et al. 2011]. In the CARE-MS I and II studies, incidence of ITP was similar in the core studies and in the first year of the ongoing extension study; all patients responded to therapy and most cases resolved with first-line treatment [Cuker et al. 2014]. Complete blood counts with differential are recommended prior to treatment initiation and monthly until 48 months after the last infusion. Most cases of ITP respond to first-line therapy with monitoring, early detection, and prompt initiation of treatment [European Medicines Agency, 2013b].
Anti-glomerular basement membrane (anti-GBM) disease and other nephropathies (glomerulonephritis with positive anti-GBM antibody and membranous glomerulonephritis) occurred in 0.3% (4/1486) of patients in MS clinical trials and may occur months or years after alemtuzumab treatment; these cases were identified early with monitoring, and all patients responded to treatment with no permanent renal failure [European Medicines Agency, 2013b; Wynne et al. 2013]. Assessments of serum creatinine levels are recommended before treatment initiation and monthly, together with urine samples, until 48 months after the last infusion [European Medicines Agency, 2013b].
Thyroid events were common in the alemtuzumab active-controlled trials, although few were serious [Fox et al. 2012]. The incidence of any thyroid event was 16.9% at 0–2 years in the CARE-MS I and II studies and 20.9% and 12.4% at 3 and 4 years in the extension study, respectively; the overall rate of thyroid events was 36% over 4 years [Lycke et al. 2013b; Twyman et al. 2014]. In the long-term follow up from the phase II CAMMS223 study, incidence of thyroid events also peaked after 3 years of treatment [Coles et al. 2012a]. Thyroid events in the overall alemtuzumab clinical development program included hyperthyroidism, hypothyroidism, thyroiditis and Graves’ disease [Cohen et al. 2012; Coles et al. 2008, 2012b; Daniels et al. 2014; Miller et al. 2013]. These events were managed with conventional treatment; three patients in the CARE-MS trials underwent thyroidectomy and two received radioablation [Miller et al. 2013]. In a post hoc analysis of CAMMS223 data, alemtuzumab efficacy did not differ between patients who developed thyroid events and the total cohort treated with alemtuzumab [Daniels et al. 2014]. In clinical trials, patients who developed thyroid events with alemtuzumab could receive retreatment and generally did not experience worsening of thyroid disorders [European Medicines Agency, 2013b]. Thyroid function tests are recommended before treatment initiation and every 3 months until 48 months after the last dose [European Medicines Agency, 2013b].
Analysis of the alemtuzumab clinical trial program demonstrated that risk of developing malignancies in alemtuzumab-treated patients with RRMS was not greater than in a reference population [Miller et al. 2014].
Immunogenicity
Anti-alemtuzumab antibodies developed in 26.3% of patients at 24 months in CAMMS223 [Coles et al. 2008], in 86% of patients after the second treatment in CARE-MS I [Cohen et al. 2012], and in 81% of patients after the second treatment in CARE-MS II [Coles et al. 2012b]. In CARE-MS I and II, the prevalence and mean peak anti-alemtuzumab antibody titers were higher after treatment course 2 than after treatment course 1 [Soelberg Sorensen et al. 2013; Ziemssen et al. 2013]. Anti-alemtuzumab antibodies did not appear to influence efficacy, safety, or lymphocyte depletion and repopulation in any of the trials [Soelberg Sorensen et al. 2013; Ziemssen et al. 2013].
Pregnancy outcomes
As of 17 October 2013, 139 pregnancies occurred in 104 patients treated with alemtuzumab. Of these, 133 pregnancies began more than 4 months after the last dose of alemtuzumab. Of the 106 completed pregnancies with known outcomes, 67 (63%) resulted in live births. Of the 139 pregnancies, the rate of spontaneous abortion was 17% and was comparable with rates observed in MS patients receiving other DMTs (4–18%) [Giannini et al. 2012; Hellwig et al. 2011; Jung Henson et al. 2014; Karlsson et al. 2014] and with the general population (17–22%) [Garcia-Enguidanos et al. 2002]. To date, there is no evidence of teratogenicity with alemtuzumab and the limited number of events reported in fetuses/infants were not suggestive of any emerging pattern [McCombe et al. 2014].
Other mAb therapies evaluated for the treatment of MS
Rituximab
Rituximab is a chimeric, IgG1, CD20-directed mAb approved for the treatment of patients with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (in combination with methotrexate) and granulomatosis with polyangiitis and microscopic polyangiitis (in combination with glucocorticoids) [Genentech, 2013]. In a randomized, double-blind, placebo-controlled phase II trial of patients with RRMS [Hauser et al. 2008], rituximab significantly reduced total and new Gd-enhancing lesions and the proportion of patients with relapse compared with placebo after 24 and 48 weeks; however, rituximab is not approved for the treatment of MS and is no longer in clinical development for this indication. However, offlabel use of rituximab for MS occurs in clinical practice in several countries.
Rituximab targets CD20 expressed on pre-B and mature B cells, depleting these cells in the circulation and CNS [Naismith et al. 2010]. Although MS was traditionally considered a T-cell mediated disease, accumulating evidence suggests that B cells play a role. As addon therapy, rituximab decreased the number of Gd-enhancing lesions in a phase II trial of patients with an inadequate response to standard injectable DMTs [Naismith et al. 2010]. In study patients with primary progressive MS, rituximab slowed increases in T2 hyperintense lesion volume but did not prolong time to confirmed disease progression compared with placebo [Hawker et al. 2009]; however, a subgroup analysis found that disease progression was slowed in patients younger than 51 years of age with ⩾1 Gd-enhancing lesion [Hawker et al. 2009].
Although not reported in MS trials of rituximab to date, PML has occurred in patients receiving rituximab for other indications; the majority of these patients with hematologic malignancies who were diagnosed with PML were treated with rituximab given in combination with chemotherapy or as part of a hematopoietic stem cell transplantation [Genentech, 2013]. In a Swedish population-based study, the incidence rate of PML in patients with rheumatoid arthritis who were exposed to a biologic treatment, which included rituximab, was 2.3 per 100,000 person-years [95% confidence interval (CI), 0.1–71; not statistically significantly different from that in unexposed patients]. Of four patients with rheumatoid arthritis and PML, one was exposed to rituximab and also received radiation for a previous malignancy but had no other known risk factor [Arkema et al. 2012].
Ocrelizumab
Ocrelizumab is a recombinant anti-CD20 humanized mAb. Like rituximab, ocrelizumab depletes CD20+ B cells, but it increases ADCC and reduces complement-dependent cytotoxicity effects compared with rituximab [Kappos et al. 2011b]. In a phase II, randomized, double-blind, placebo-controlled study, ocrelizumab reduced the total number of Gd-enhancing T1 hypointense lesions and reduced ARRs and clinical disease activity compared with placebo [Kappos et al. 2011b]. Development of ocrelizumab for rheumatoid arthritis was suspended in 2010 owing to reports of serious opportunistic infections that were fatal in some patients [Emery et al. 2014; Roche, 2014]; however, in the MS trial, no opportunistic infections were reported [Kappos et al. 2011b]. For MS, ocrelizumab is administered as an IV infusion every 24 weeks. The most frequent treatment-related AEs in the phase II trial of ocrelizumab in MS were upper respiratory tract infection, urinary tract infection and headache [Kappos et al. 2011b]. Three phase III trials of ocrelizumab in MS are ongoing [ClinicalTrials.gov identifier: NCT01194570, NCT01247324, NCT01412333], including one in primary progressive MS, and preliminary results are expected in 2015.
Daclizumab
Daclizumab is a humanized IgG1 mAb against the CD25 molecule on activated T lymphocytes. It blocks interleukin (IL) 2 binding, and its effect of increasing the number of CD56bright natural killer cells [Bielekova et al. 2011] leads to the reduction of activated and resting regulatory T cells and decreased production of proinflammatory cytokines [Huss et al. 2014]. Daclizumab was approved for prophylaxis of acute rejection of renal transplants [Hoffmann-La Roche, 2005], but was discontinued in 2011 because of a decreased demand [Roche, 2009]. This agent showed activity in phase II studies in patients with MS that included reduced number of contrast-enhancing lesions and formation of new contrast-enhancing lesions [Bielekova et al. 2004; Wynn et al. 2010]. In other studies, daclizumab administered as monotherapy or as addon to IFNβ reduced relapse rates and improved clinical scores [Bielekova et al. 2009]; in addition, relapse rates were reduced with daclizumab addon to IFN therapy with subsequent daclizumab monotherapy [Rose et al. 2007].
In a recent study, high-dose daclizumab monotherapy produced 50–54% reductions in the ARR compared with placebo after 52 weeks of treatment [Gold et al. 2013]. In the follow-up study, patients randomized to receive placebo received daclizumab and those who received daclizumab in the initial study were re-randomized (1:1) to continue therapy for 1 year or receive 20 weeks of placebo followed by 32 weeks of daclizumab [Giovannoni et al. 2014]. Reductions in clinical and radiologic activity were maintained in patients treated for 2 years, and the magnitude of clinical and radiologic benefit in patients treated for 1 year was similar to that in patients treated for 2 years.
Three phase III trials of daclizumab are in progress in patients with MS [ClinicalTrials.gov identifier: NCT01064401, NCT01462318, NCT01797965]. In the randomized, double-blind, double-dummy, phase III DECIDE study [ClinicalTrials.gov identifier: NCT01064401], 1841 patients were randomized to weekly administration of intramuscular IFNβ-1a 30 µg (n = 922) or SC daclizumab 150 mg high-yield process every 4 weeks (n = 919). After 96 weeks of treatment, daclizumab was associated with a 45% decrease in ARR, a 41% reduction in the proportion of patients who relapsed, and a 54% reduction in the number of new/enlarging T2 hyperintense lesions (p < 0.0001 for all endpoints) and a nonsignificant 16% reduction in risk of 3-month disability progression (p = 0.158) [Kappos et al. 2015]. No treatment-related deaths or increased risk of malignancies were observed. AEs of interest that occurred more frequently with daclizumab versus IFNβ-1a included infections (65% versus 57%), cutaneous (37% versus 19%) and hepatic events (approximately 18% versus 12%) [Selmaj et al. 2014]. Unlike natalizumab and alemtuzumab, which are administered intravenously, daclizumab is administered subcutaneously. In 2015, Biologics License Applications were accepted by the European Medicines Agency and the FDA for daclizumab in the treatment of relapsing forms of MS [Biogen, 2015].
Several other mAbs are in development for MS; data describing experience with some have been published, others are in ongoing trials or failed to demonstrate effect in RRMS. These agents include ofatumumab [GlaxoSmithKline, 2013; Sorensen et al. 2014], ustekinumab [Janssen Biotech, 2013; Segal et al. 2008], LY2127399 or tabalumab [ClinicalTrials.gov identifier: NCT00882999], secukinumab [ClinicalTrials.gov identifier: NCT01051817, NCT01433250], MEDI-551 [ClinicalTrials.gov identifier: NCT01585766], rHIgM22 [Pirko et al. 2004] [ClinicalTrials.gov identifier: NCT01803867], GNbAC1 [Curtin et al. 2012] [ClinicalTrials.gov identifier: NCT01639300], VX15/2503 [ClinicalTrials.gov identifier: NCT01764737], BIIB033 or anti-LINGO-1 [Tran et al. 2014] and vatelizumab [ClinicalTrials.gov identifier: NCT02222948, NCT02306811]. The characteristics and developmental status of each are summarized in Table 3 [Curtin et al. 2012; Pirko et al. 2004; Segal et al. 2008; Sorensen et al. 2014]. Treatment with mAbs against tumor necrosis factor α resulted in increased disease activity in MS patients [van Oosten et al. 1996] and may also lead to induction of demyelinating disease in other patients [Seror et al. 2013].
Monoclonal antibody therapies in development for MS.
BAFF, B-cell activating factor; IL, interleukin; MOA, mechanism of action; MRI, magnetic resonance imaging; MS, multiple sclerosis; PK, pharmacokinetic; SEMA4D, semaphorin 4D.
Discussion
The approved mAbs (natalizumab and alemtuzumab) and those in late-stage development for the treatment of RRMS (ocrelizumab and daclizumab) differ greatly with respect to target, mechanism of action, pharmacokinetic/pharmacodynamic properties, and clinical efficacy and safety. Selecting an appropriate mAb treatment for RRMS patients requires careful consideration of the known benefit-risk profile, mechanism of action in MS and patients’ risk of MS-related morbidity.
Target and mechanism of action
mAb effector functions vary with antibody type and include blocking interactions, induction of signal transduction by binding receptors, complement-dependent cytotoxicity and ADCC. Briefly, the role of T lymphocytes in the pathogenesis of MS is well defined. Th17 cells have been shown to be upregulated and the activity of regulatory T cells has been shown to be deficient in MS [Constantinescu and Gran, 2014; Fletcher et al. 2010]. B cells, as precursors of antibody-secreting plasma cells and as antigen-presenting cells for the activation of T cells, are integral in the pathogenesis of MS [Lehmann-Horn et al. 2013]. Natalizumab targets α4 integrin on leukocytes, which prevents leukocyte entry into the CNS [Biogen Idec, 2013]. Alemtuzumab targets CD52 on lymphocytes and monocytes, which results in selective depletion of circulating T and B lymphocytes and subsequent repopulation. Innate immune cells appear to be minimally or transiently affected [Coles et al. 1999; Hu et al. 2009; Kovarova et al. 2012]. The number and proportions of some lymphocyte subsets are altered with annual courses of alemtuzumab therapy, resulting in a rebalancing of the immune system [European Medicines Agency, 2013a]. Ocrelizumab selectively targets CD20 on B cells and depletes circulating CD20+ B cells via ADCC [Kappos et al. 2011b]. Daclizumab targets CD25 on the IL-2 receptor expressed on activated T cells to block IL-2 dependent activation and expansion of activated T cells [Milo, 2014].
Pharmacokinetics, pharmacodynamics, and dosing
The pharmacokinetics and dosing of the mAbs approved or in late-stage development for MS also vary greatly. For example, IV natalizumab is administered every 4 weeks and has a mean half-life of 16 days [European Medicines Agency, 2013c]. After discontinuation, it is cleared from the circulation within approximately 2 months and MS disease typically returns within 4–7 months [O’Connor et al. 2011]. Alemtuzumab is administered in two annual treatment courses and its effects persist long after it is cleared from the circulation [European Medicines Agency, 2013b]; lymphocyte repopulation after alemtuzumab treatment may reduce the potential for relapse and delay disease progression [European Medicines Agency, 2013b]. In ongoing phase III trials [ClinicalTrials.gov identifier: NCT01247324, NCT01412333, NCT01194570], ocrelizumab was administered as an IV infusion every 24 weeks and, in phase IIb and III trials, daclizumab was administered as a SC injection every 4 weeks [Gold et al. 2013; Milo, 2014]. Of these mAbs, alemtuzumab is distinct in that its pharmacokinetic/pharmacodynamic profile allows for two annual courses of treatment, with retreatment based on re-emergence of disease activity.
Clinical trial design
In clinical trials of natalizumab, alemtuzumab, ocrelizumab and daclizumab, efficacy has been evaluated using different methods and comparators. Phase III natalizumab trials were placebo-controlled investigations of monotherapy or addon therapy to IFNβ-1a, with key endpoints of rate of clinical relapse, 3 month sustained progression of disability, and MRI outcomes [Miller et al. 2007; Polman et al. 2006; Rudick et al. 2006]. Phase III alemtuzumab trials were rater-blinded, active-controlled investigations of alemtuzumab monotherapy compared with SC IFNβ-1a, and key endpoints included relapse rate, time to 6-month sustained accumulation of disability, and MRI outcomes [Cohen et al. 2012; Coles et al. 2012b]. Ocrelizumab has been evaluated as monotherapy in a phase II, placebo- and active-controlled (IFNβ-1a), 24-week study with a focus on MRI outcomes [Kappos et al. 2011b]. Daclizumab has been studied in a placebo-controlled 24-week trial as addon therapy to IFNβ with an endpoint of MRI outcomes [Wynn et al. 2010] and in a 52-week phase II trial as monotherapy with a key endpoint of ARR [Gold et al. 2013]. Interpretation of these results can be confounded by the differing patient populations, comparators and endpoints. Careful review of clinical efficacy results is necessary to guide optimal treatment decisions.
Clinical safety
Natalizumab, alemtuzumab, ocrelizumab and daclizumab have unique safety profiles and their rare serious AEs require specific management. Screening prior to therapy is essential for selecting appropriate patients for specific agents and monitoring during therapy is crucial for early detection and management of AEs. Natalizumab is associated with the development of PML, caused by neurovirulent transformation of wildtype JCV [Berger et al. 2013]. Management involves risk stratification prior to therapy (with increased risk for PML based on presence of anti-JCV antibodies, duration of natalizumab therapy greater than 2 years and prior treatment with immunosuppressants) and careful monitoring during therapy [Biogen Idec, 2013; US Food and Drug Administration, 2012]. Alemtuzumab is associated with infusion-associated reactions, infections and autoimmune AEs, including ITP, nephropathies and thyroid gland disorders. Safety monitoring includes complete blood counts, infection prophylaxis, serum creatinine assessments, urinalysis and thyroid function tests [Casady et al. 2014; Cuker et al. 2014; Twyman et al. 2014; Wynne et al. 2013]. In a phase II evaluation, ocrelizumab was associated with infusion-related reactions with the first dose, which led to the suggestion for preinfusion treatment with an oral analgesic or antipyretic and an oral antihistamine. One patient died during treatment due to brain edema following systematic inflammatory response syndrome; relationship to ocrelizumab was uncertain [Kappos et al. 2011b]. Although long-term safety with ocrelizumab in MS is not available, it is important to note that serious and sometimes fatal infections were observed in ocrelizumab patients with rheumatoid arthritis [Emery et al. 2014] and systemic lupus erythematosus [Mysler et al. 2013]. In phase II evaluations of daclizumab, the most frequent AEs were allergic skin reactions, infections (primarily upper respiratory and urinary tract infections), elevated liver function test results and autoimmune AEs [Kappos et al. 2011b]. Familiarity with the key AEs and their management is critical to successful treatment with mAbs available for the treatment of RRMS.
Immunogenicity
The development of antidrug antibodies and their potential for neutralizing effects vary among the mAbs for RRMS. Immunogenicity has occurred with natalizumab therapy and anti-natalizumab antibody persistence has been associated with compromised efficacy and increased frequency of infusion-related reactions in AFFIRM [Calabresi et al. 2007]. Anti-alemtuzumab antibodies have been detected in patients in clinical trials but did not appear to compromise efficacy, safety or lymphocyte depletion [Cohen et al. 2012; Coles et al. 2008, 2012b]. Similarly, in a phase II trial of rituximab, development of antichimeric antibodies in 24.6% of patients did not influence the rate of AEs or efficacy of rituximab [Hauser et al. 2008]. However, humanized antibodies seem to reduce the risk of anti-mAb development. In the phase II evaluation, the incidence of anti-ocrelizumab antibodies was up to 3% overall [Kappos et al. 2011b] and the incidence of neutralizing antibodies with daclizumab was up to 2% overall [Gold et al. 2013]; further evaluation in phase III trials is necessary to determine the clinical impact of immunogenicity with these antibodies.
Use during pregnancy
Findings to date from the natalizumab and alemtuzumab clinical trial programs indicate that neither treatment is teratogenic in humans [Ebrahimi et al. 2015; McCombe et al. 2014] or associated with rates of spontaneous abortion that are higher than those observed in MS patients receiving other DMTs [Giannini et al. 2012; Hellwig and Gold, 2011; Jung Henson et al. 2014; Karlsson et al. 2014] or the general population [Garcia-Enguidanos et al. 2002]. Natalizumab and alemtuzumab are both classified as pregnancy category C [Biogen Idec, 2013; European Medicines Agency, 2013b]. Alemtuzumab-treated women of childbearing potential should continue to use contraception for 4 months after receiving a treatment course [McCombe et al. 2014]. Natalizumab can pass into breast milk, and effects of natalizumab in this situation are unknown [Biogen Idec, 2013]. It is unknown if alemtuzumab passes into breast milk [Genzyme, 2014].
Conclusion
The development of new effective therapies, including mAbs, for RRMS has been motivated mainly by the modest efficacy of IFNβs and glatiramer acetate [Gensicke et al. 2012]. mAb therapies hold significant promise for the treatment of MS; however, individual therapies have distinct targets and mechanisms of action and, therefore, a wide spectrum of benefit-risk profiles. Immunogenicity profiles and effector functions also vary with antibody type. Thus, the mAbs for MS cannot be considered a single class of agents. Careful consideration of the numerous, unique characteristics of each mAb therapy for MS is necessary to select the appropriate treatment for each individual patient. Appropriate screening and routine monitoring should enable the optimal use of these therapies to achieve improved outcomes in patients with RRMS.
Footnotes
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:J.L. reports having received travel support and/or lecture honoraria from Bayer Schering Pharma, Biogen Idec, Novartis and Genzyme/Sanofi Aventis, served on scientific advisory boards for Almirall, Teva, Biogen Idec and Genzyme/Sanofi Aventis, and received unconditional research grants from Biogen Idec and Novartis. Editorial support for this manuscript was provided by Aji Nair, PhD, Genzyme Corporation, and Amy Zannikos, PharmD, CMPP, and Kristen W. Quinn, PhD, of Peloton Advantage, LLC, and was funded by Genzyme, a Sanofi company. The author was responsible for all content and editorial decisions and received no honoraria related to the development of this publication.