Expert Opinion on Biological Therapy
ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: http://www.tandfonline.com/loi/iebt20
Natalizumab for multiple sclerosis: appraising risk versus benefit, a seemingly demanding tango Sahil Gupta MD & Bianca Weinstock-Guttman MD To cite this article: Sahil Gupta MD & Bianca Weinstock-Guttman MD (2014) Natalizumab for multiple sclerosis: appraising risk versus benefit, a seemingly demanding tango, Expert Opinion on Biological Therapy, 14:1, 115-126, DOI: 10.1517/14712598.2014.864634 To link to this article: http://dx.doi.org/10.1517/14712598.2014.864634
Published online: 02 Dec 2013.
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Date: 13 September 2015, At: 06:42
Drug Evaluation
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Natalizumab for multiple sclerosis: appraising risk versus benefit, a seemingly demanding tango 1.
Introduction
2.
Mechanism of action
3.
Pivotal studies
4.
Clinical indications
5.
Adverse effects associated with natalizumab therapy
6.
Alternative therapies
7.
Conclusion
8.
Expert opinion
Sahil Gupta & Bianca Weinstock-Guttman† SUNY University of Buffalo, Jacobs Neurological Institute, NY, USA
Introduction: Natalizumab is a highly effective monoclonal antibody used for the treatment of multiple sclerosis (MS). It reduces relapses, delays the onset of disease progression and improves disease outcomes in relapsing-remitting MS. However, treatment with natalizumab is associated with progressive multifocal leukoencephalopathy (PML), a severe opportunistic brain infection with John Cunningham virus. Areas covered: In this review, we discuss the mechanism of action, results of pivotal studies, clinical use and adverse effects associated with natalizumab therapy with emphasis on PML. A risk stratification strategy to optimize natalizumab therapy is included. This review also summarizes the alternative and upcoming therapies available for the treatment of MS. Expert opinion: Natalizumab is a very effective therapy for MS and has shown tremendous results in reducing the disease activity and improving patients’ quality of life. Serious adverse effect such as PML warrant extreme caution and heightened clinical vigilance while prescribing the drug. If used with prudence, the drug can be instrumental in treatment of patients with inadequate response to the first-line medications. Keywords: JC index, multiple sclerosis, natalizumab, progressive multifocal leukoencephalopathy risk stratification, progressive multifocal leukoencephalopathy Expert Opin. Biol. Ther. (2014) 14(1):115-126
1.
Introduction
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and a common cause of neurological disability in young adults [1]. Influx of T lymphocytes in the brain through interaction of integrins with the vascular cell adhesion molecule (VCAM1) on the endothelial cells is a prerequisite for the inflammatory process of MS [2]. Natalizumab is a recombinant humanized IgG4 antibody that interferes with the influx of inflammatory cells by binding to the a4 subunit of the a4b1 integrin [3] expressed on the surface of immune cells (Box 1). In 1992, researchers at Stanford University and Athena Neuroscience discovered the role of a4 integrin in lymphocyte migration into the brain tissue in animal models of MS called experimental autoimmune encephalomyelitis [4]. Only 12 years after cloning of its molecular target, natalizumab was approved by US FDA in 2004, due to the encouraging results of AFFIRM [5] (Natalizumab Safety and Efficacy in Relapsing-Remitting MS) and SENTINEL [6] (Safety and Efficacy of Natalizumab in Combination with Avonex in patients with Relapsing-Remitting MS) Phase III trials (Figure 1). Thereafter, natalizumab was suspended due to emerging reports of two recipients diagnosed with progressive multifocal leukoencephalopathy (PML) [7,8] and an additional patient with Crohn’s disease. After an independent review which revealed the risk of developing PML following treatment for 18 months was 1 in 1000 patients, the drug was reinstated in July 2006 with recommendations for monitoring of PML [9]. Since then more than 92,000 patients 10.1517/14712598.2014.864634 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase indication
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Mechanism of action Route of administration Pivotal trials
Natalizumab FDA approved prescription only drug Second line treatment of Relapsing-Remitting Multiple Sclerosis Humanized monoclonal antibody against cell adhesion molecule a4 integrin Intravenous infusion Phase 2: GLANCE Phase 3: AFFIRM, SENTINEL
have been treated with natalizumab revealing decreased relapse frequency and better quality of life [10]. Definite strides have also been made in risk stratification of patients on natalizumab to mitigate the threat of developing PML [11]. This has been possible only through recognizing the risk factors for development of PML like prior use of immunosuppressants and increased duration of treatment and, more recently, via use of laboratory test such as John Cunningham virus (JCV) antibody assay [12]. 2.
Mechanism of action
Inflammation and demyelination are the two hallmarks of MS pathophysiology, in addition to a neurodegenerative component. Demyelinating lesions of MS are primarily caused by infiltration of leukocytes especially T lymphocytes [13]. The transmigration of T lymphocytes is mediated by the interaction between the adhesion molecule (a4 integrin) on the lymphocyte and complementary ligand (VCAM1) on the endothelium. Leukocyte integrins are obligate heterodimers containing two chains, a and b subunits. Natalizumab is a humanized IgG4 monoclonal antibody against the a4 integrins, primarily a4b1 (mediating transmigration in the CNS) and a4b7 (mediating transmigration in the small intestine). By blocking the integrins, natalizumab inhibits the movement of leukocytes in the CNS, thereby attenuating inflammation in MS (Figure 2) [14]. Similarly, natalizumab also benefits Crohn’s disease patients preventing inflammation of the small intestine by binding to the a4b7 integrin. It is also shown that natalizumab modulate ongoing tissue inflammatory reaction by inhibiting binding of a4 positive leukocytes with fibronectin and osteopontin and hence reducing the survival, priming and activation of leukocytes that have gained access to CNS parenchyma [15]. No clear clinical data to support this in vivo mechanism is available. 3.
Pivotal studies
In 2000, pharmaceutical companies decided to develop and commercialize natalizumab for treatment of MS following the beneficial results of Phase I trials. Sheremata et al. tested 116
single intravenous infusion of natalizumab and Vollmer et al. studied natalizumab in combination with interferon (IFN)-b and both of these studies found natalizumab to be safe and well tolerated (Table 1). Phase II trials were subsequently commenced to evaluate the efficacy of natalizumab as compared to placebo. Its effect on preventing the development of new gadolinium-enhancing lesions was treated as a yardstick to measure its efficacy by Tubridy et al. [16]. The study was a randomized controlled trial in which the patients received two doses of placebo or natalizumab 1 month apart and were followed up with MRI scans for 6 months. The study revealed that patients treated with natalizumab had decreased number of new active lesions as compared to the placebo group (1.8 vs 3.6, p = 0.04) [16]. However, the most important Phase II trial was the Miller study which was a randomized controlled trial in which subjects were treated for 6 months with monthly doses of natalizumab or placebo and were monitored with monthly MRI scans. The study revealed decrease in the number of inflammatory brain lesion in patients receiving 3 and 6mg/kg natalizumab dosages as compared to placebo (0.7 and 1.1 vs 9.6, p < 0.001) (Table 2). An additional combination, Phase II, 6-month trial, evaluated safety and preliminary efficacy on natalizumab combined with glatiramer acetate (GA) versus GA alone in patients with suboptimal response on GA alone (GLANCE) [17]. The combination was safe and provided preliminary data suggesting benefit on MRI metrics versus GA alone. Combination therapy of natalizumab with GA resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p = 0.020) and new enlarging T2-hyperintense lesions (0.5 vs 1.3, p = 0.029). The incidence of infection and infusion reactions was similar in both groups, but no hypersensitivity reactions were observed. With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone [17]. Use of natalizumab as a monotherapy was investigated through AFFIRM study [5]. Another Phase 3 trial named SENTINEL was designed to investigate the possible synergistic effect of Natalizumab and Interferon [3]. The SENTINEL enrolled relapsing MS patients who demonstrated only a partial therapeutic response to IFN therapy. AFFIRM and SENTINEL were the two pivotal studies that provided the necessary data for acceptance of natalizumab as a very encouraging option for treatment of MS. AFFIRM and SENTINEL showed natalizumab to be effective in reducing annualized relapse rate (ARR), number of new T2 hyperintense lesions, gadolinium-enhancing lesions, expanded disability status scale (EDSS) worsening, new non-enhancing T1 hypointense lesions and brain atrophy (Table 3). Owing to the encouraging year 1 results of AFFIRM and SENTINEL, FDA approved natalizumab in November 2004 following an accelerated review just 12 years after the
Expert Opin. Biol. Ther. (2014) 14(1)
Natalizumab
2000 Commercial developement of natalizumab
1992 Discovery of α4 integrin important in CNS lymphocyte migration
1997 Phase I trials started
2004 FDA approval
2001 Phase III trials started
2006 Reintroduction to the market
2005 Voluntary suspension due to 3 PML cases
2012 US label lists 3 risk factors for PML
Figure 1. Timeline of natalizumab is shown.
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Adapted from [64].
T Lymphocyte
Natalizumab
Capillary lumen
α4 Intergrin
VCAM1
Endothelial cell Brain parenchyma
Figure 2. Representation of natalizumab inhibiting interaction between a4 integrin on the T-lymphocyte and VCAM1 on the capillary endothelial cell, thereby inhibiting the transmigration of T-lymphocyte in CNS. VCAM1: Vascular cell adhesion molecule 1.
discovery of the target molecule. This indicated that natalizumab provides promising advantages over any of the therapies existing at that time. 4.
Clinical indications
Today natalizumab is available as a treatment for relapsing MS under a restriction-distribution format, defined under the Tysabri Outreach Unified Commitment to Health (TOUCH) prescribing programs which require the drug to be provided by the infusion centers registered with the program. It also mandates regular evaluation by the medical professionals at 3 and 6 months and every 6 months subsequently. MRI imaging of the patient is also required prior to the initiation of the therapy and regularly (quarterly, 6 months or yearly) afterward and in
urgent basis if new symptoms become evident while being on natalizumab. More frequent testing should be considered if patients are on long-term therapy (over 2 years) and especially while being JC antibody positive (see further JC antibody status in Section 5.1.2) [12,14]. MS patients with active disease based on presence of continuous relapses or disease activity evident in MRI scans despite therapy with first-line agents such as IFN-b or GA are considered good candidates for initiation of natalizumab therapy [8]. Natalizumab is also favorable for patients with unreliable treatment adherence because of the close monitoring which follows its administration. Natalizumab also provides the benefits of being administered only once a month as compared to once a week for IFN and once daily for glatiramer. Therefore, it is a preferable drug for patients
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Table 1. Phase I trial publications with prespecified end points. Ref.
Trial
Patients
Sheremata et al. [57]
RCT; 5-level dose escalation
28
Vollmer et al. [58]
Open-label; natalizumab and IFN b 1-A
38
Result Safe and well tolerated; natalizumab detected in serum 3 -- 8 weeks after 1 to 3 mg/kg i.v. dose Safe and well tolerated
i.v.: Intravenous; RCT: Randomized controlled trials.
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Table 2. Phase II trial publications with prespecified end points and post-hoc analysis. Ref.
Trial
Patients
Tubridy et al. [16]
RCT, double-blind
72
Miller et al. [59]
RCT, double-blind
213
GLANCE [17]
RCT, double-blind
110
End point Mean active lesions Mean new lesions Inflammatory brain lesion; natalizumab (3 and 6 mg/kg) vs placebo Relapse (natalizumab 1 and 3 mg/kg) vs placebo New gadolinium-enhancing lesions evolving into T1 hypointense lesions [60] Cumulative new active lesions (natalizumab + GA vs GA) T2 hyperintense lesions (natalizumab + GA vs GA) Gadolinium-enhancing lesions (natalizumab + GA vs GA)
Result (natalizumab vs placebo) 1.8 vs 3.6 (p = 0.04) 1.6 vs 3.3 (p = 0.02) 0.7 and 1.1 vs 9.6 (p < 0.001) 19 vs 38% (p = 0.02) 26 vs 68% (p < 0.01)
0.9 vs 2.6 (p = 0.057) 0.5 vs 1.3 (p = 0.029) 0.6 vs 2.3 (p = 0.02)
GA: Glatiramer acetate; GLANCE: Glatiramer acetate and natalizumab combination evaluation; RCT: Randomized controlled trials.
with lower compliance because of its favorable dosage schedule. Although the use of natalizumab in active patients with negative JCV status or a low JCV antibodies (index < 0.9) as mentioned is usually considered in patients not responding to first-line therapies, the use of natalizumab as first-line therapy would be also considered in patients with clinical predictors of high-risk disease progression (i.e., African-American patients, active MRI [multiple white matter lesions and multiple gadolinium-enhancing lesions] or patients with severe relapses and incomplete recovery). In patients with coexisting conditions, which might suppress immunity such as hematological cancers or prior immunosuppressant use within the past 3 months, natalizumab therapy should be avoided or reconsidered and the risks and benefits should be discussed with the patients [18]. Natalizumab is also useful in treatment of Crohn’s disease in patients who are unresponsive to medications such as infliximab (TNF-a blocker). Some researchers have shown that combination therapy of natalizumab and infliximab in Crohn’s disease is effective in inducing remission [19]. In 2008, US FDA approved natalizumab for treatment of moderate-to-severe Crohn’s disease [20]. 118
Adverse effects associated with natalizumab therapy
5.
Natalizumab is a very well-tolerated drug for MS as demonstrated by the Phase III clinical trials [5,21]. Post-infusion reactions were reported in about 24% of the patients. The most common reactions were fatigue and arthralgia, which were treated symptomatically and did not necessitate discontinuation of therapy. Only 4% of the patients receiving natalizumab had hypersensitivity reactions and 1.3% of patients were deemed as serious. As per protocol, the study drug was discontinued in all patients who had hypersensitivity reactions. No significant difference was found between the infection rate in the placebo and the natalizumab group [5]. About 9% of the subjects were positive for anti-natalizumab antibodies at least once during the studies and 6% demonstrated permanent anti-natalizumab antibodies. These patients exhibited diminished clinical efficacy with natalizumab and had significantly worse outcomes both clinically and on MRI as compared to patients who did not develop these antibodies [3,5]. Evaluating for the presence of these antibodies in patients experiencing disease activity especially during the first 6 months and/or initial infusion allergic reaction is recommended.
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Natalizumab
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Table 3. Phase III prespecified end points and post-hoc analysis of SENTINEL and AFFIRM. Trial
Patients
AFFIRM [5,61]
942
SENTINEL [3,62]
1171
End point
Result
ARR Disability progression Gadolinium-enhancing lesion Mean change in EDSS New T1 hypointense lesions Visual loss ARR New T2 hyperintense lesions Number of gadolinium-enhancing lesion Mean T2 lesion volume Mean change in EDSS Visual loss
Decreased by 68% (p < 0.001) Decreased by 42% (p < 0.001) Decreased by 92% (p < 0.001) 0.04vs 0.41 (p < 0.001) Decreased by 76% (p < 0.001) Decreased by 35% (p < 0.001) Decreased by 55% (p < 0.001) Decreased by 83% (p < 0.001) Decreased by 89% (p < 0.001) Decreased by 11.8% (p < 0.001) 0.15 vs 0.30 (p = 0.01) Decreased by 28%
AFFIRM: Natalizumab safety and efficacy in RRMS; ARR: Annualized relapse rate; EDSS: Expanded disability status scale; SENTINEL: Safety and efficacy of natalizumab in combination with IFN-b-1a in patients with RRMS.
In 2005, after completion of AFFIRM and 1 month before completion of SENTINEL, two cases were reported to have PML while on natalizumab [7,8]. A third case of PML of a patient on natalizumab for Crohn’s disease was also reported [22]. Marketing of natalizumab was immediately halted and physicians prescribing the drug were notified [9]. A safety review was subsequently done which included MRI scans of all patients on the treatment and cases with symptoms similar to PML to be evaluated thoroughly. No more cases of PML were found following the safety review and natalizumab was reintroduced in the market in 2006 under the TOUCH program. Although the risk for developing PML was primarily associated with the use of natalizumab, sporadic cases have been described in patients treated with other immunosuppressive therapies, such as rituximab and mycophenolate mofetil, and more recently in psoriasis patients treated with Fumaderm, a compound similar but not identical with dimethyl fumarate (Tecfidera) [23]. A new case of PML treated with fingolimod was also identified, although the presentation was more atypical and FDA has been evaluating this specific case [24]. The additional information obtained from this case indicated that the patient did have neuromyelitis optica (NMO) with positive anti-NMO IgG antibodies. Vigilant assessment of the risk:benefit ratio for any of these interventions should be considered before initiating therapy. Progressive multifocal leukoencephalopathy PML is a CNS infection caused by the JCV. The JCV is prevalent in almost 50% of the population [25]. It remains latent in the body in kidneys, bone marrow and lymphoreticular system [26]. Mutation of the JCV capsid protein 1 (VP1) is believed to be responsible to transform JCV into a neurotropic strain. The exact cause of natalizumab-related JC virus is not clearly known as no systemic immunosuppression is seen. The possibility of a decreased CNS surveillance appears as the most acceptable theory (Figure 3) [27]. 5.1
Most common clinical symptoms of PML are cognitive and behavioral dysfunctions which occur in ~ 50% of PML patients (Figure 4) [28]. Motor deficits and dysphasia are also fairly common. Some patients also suffer from seizures and fever [28]. Mostly, the patients present with multiple neurological features which deteriorate over time. Sometimes the symptoms of MS and PML can be overlapping. The striking difference in symptoms of PML as compared to MS is that patients suffering from PML very rarely show any optic nerve or spinal cord involvement. On MRI imaging, the common findings are monofocal subcortical white matter lesions which are hyperintense on T2 and FLAIR (Figure 5). About 30 -- 40% might also show gadolinium enhancement, thus making it hard to differentiate from MS lesions [28,29]. On cerebrospinal fluid (CSF) analysis, 50% of patients demonstrated low JCV DNA levels (< 500 copies/ml) in the initial testing, thus requiring sensitive assays that can identify low levels of JCV [28]. Repeated CSF testing in negative cases but with high clinical/MRI suspicion as well as for monitoring the disease progression under therapeutic interventions is recommended. The clinical symptoms, MRI and CSF findings are summarized in Figure 4. Treatment of PML The fundamentals of management of PML are: 1) Immediate discontinuation of natalizumab and 2) drug removal from plasma through plasma exchange or immunoadsorption [28]. Although on some occasions, rapid removal of natalizumab may result in reconstitution of the immune system, associated with brain new inflammatory lesions referred to as immune reconstitution inflammatory syndrome (IRIS), causing worsening of symptoms and appearance of new gadoliniumenhancing lesions. IRIS is often difficult to differentiate from reactivation of MS, although the enhancing lesions may present with more speckled features [30]. Intravenous corticosteroid is the most common treatment available to PML-IRIS patients [28]. Most physicians also recommend an 5.1.1
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JCV INFECTION
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Latent JC virus in the body (bone marrow, tonsils, adrenals)
JCV infection of the peripheral blood mononuclear cells Systemic immunosuppression not clear if related to natalizumab
JCV mutations
Gliotropic Strain
NATALIZUMAB CNS entry through blood brain barrier
Failure of CNS surveillance
PML
Figure 3. Proposed pathogenesis of natalizumab-associated PML is shown. Adapted from [65]. JCV: JC virus; PML: Progressive multifocal leukoencephalopathy.
adjunctive antiviral treatment such as mefloquine or mirtazapine [31,32]. The prognosis of patients with Tysabri-related PML, although somber with a mortality rate of about 20% and the remaining 80% surviving with varying degrees of disability [28], appears less aggressive than the PML associated with other systemic immunosuppressive condition as in HIV patients [33]. Risk profiling and stratification On reviewing the patients who developed PML while on natalizumab, three risk factors were clearly identified: i) duration of treatment for more than 2 years; ii) prior use of immunosuppressant and iii) JCV-specific (anti-JCV) antibodies in the blood [34]. Natalizumab exposure for > 2 years increases PML to about 3.7 cases per 1000 patients [35]. Prior immunosuppression increases the risk of PML by approximately four times [36]. Of the 125 PML patients recognized till 2011, about 47 5.1.2
120
were treated with immunosuppressive agents such as mitoxantrone, methotrexate, azathioprine and cyclophosphamide. The most important risk indicator is JCV seropositivity [12]. A new two-stage optical enzyme-linked immunosorbent assay (ELISA) using recombinant VP1 protein conjoining it to a secondary ELISA test to categorize patients as negative or positive became clinically available [37]. After using this assay, it was revealed that all PML cases till date have been JCV seropositive. It was also shown that almost 50% of people tested were JCV positive and the rest were JCV negative. Patients who are JCV seronegative are at markedly lower risk of developing PML (0.09 per 1000 cases) and can be prescribed natalizumab with significant confidence [11]. The risk of a false negative testing and/or the risk of converting to a positive testing (JCV exposure) are estimated to be 2 -- 4% [12]. Contrastingly, JCV DNA polymerase chain reaction in blood and urine has not been found to be suggestive of PML and its clinical relevance is still unclear [37]. A more sensitive assay
Expert Opin. Biol. Ther. (2014) 14(1)
Natalizumab
PML
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Clinical features 1) cognitive 2) motor 3) Language 4) Visual 5) Ataxia 6) Seizures 7) Fever
MRI findings 1) Starting as usual monofocal lesions in subcortical White Matter affecting the U fibers 2) Hyperintense on T2 and FLAIR
CSF findings 1) JCV DNA as the confirmatory test
3) Hypointense lesions on T1 4) 30 – 40% showing contrast enhancement
Figure 4. Clinical features, MRI findings and CSF findings of natalizumab associated PML are shown. FLAIR: Fluid-attenuated inversion recovery; JCV: JC virus; PML: Progressive multifocal leukoencephalopathy.
A.
B.
Figure 5. A. MRI imaging of the patient 5 months before developing PML. B. Red arrow demonstrate the hyperintense subcortical lesions in the same patient after developing PML.
providing the JC antibody titers presented as an index value was shown recently to be associated with a low risk in antiJCV antibody positive patients (when the index < 0.9) for developing PML similar to the JC negative status [38]. Recent studies have revealed cell-based assessment of percentage of lselectin-expressing CD4 T cells as a possible additional biomarker for PML risk assessment [39]. However, further studies will still be required to validate this new diagnostic method. On identification of any of these risk factors, the patients should be subject to close monitoring and increased clinical and MRI vigilance for evidence of PML. Natalizumab should be immediately stopped and risks of discontinuation of natalizumab therapy should be discussed with the patient [33].
Alternative therapies should be recommended and a new treatment plan should be devised and discussed. An algorithm of risk profiling is presented in Figure 6. Discontinuation of natalizumab Natalizumab therapy may be discontinued especially if the stratification algorithm previously mentioned suggests high risk of PML [11]. Several reports have described worsening of MS to nearly pretreatment levels after withdrawing natalizumab (Table 4) [40-43]. O’Connor et al. evaluated patients from AFFIRM, SENTINEL and GLANCE trials who discontinued therapy [40]. Reactivation of the disease to near pretreatment levels was reported within 3 to 6 months of 5.2
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Natalizumab therapy
Baseline testing: EDSS, MRI, JC virus Serology
JCV serostatus
Low risk of PML 1:10,000
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Low risk of PML 1:10,000
Continue Rx with q 3 – 6 months JC virus Serology, clinical and MRI q 6 months-1 year or any time new symptoms become evident
Previous use of immunosuppressant
Continue treatment with caution after 1 year with very close (q 3 – 4 months) monitoring clinical and with MRI
JCV Serostatus
Consider other treatment after 12 months-2 years if seroconvertion occurs (index > 0.9)
Consider other treatment after 12 months-2 years if seroconvertion occurs and index > 0.9
Figure 6. Algorithm of PML risk profiling. EDSS: Expanded disability status scale; JCV: JC virus; MRI: Magnetic Resonance Imaging; PML: Progressive multifocal leukoencephalopathy.
therapy withdrawal. A concern for a rebound phenomenon mostly associated with MRI worsening was raised in patients discontinuing natalizumab therapy [40,44]. Most recently, a Randomized Natalizumab Interruption Study (RESTORE) was carried out to study effects of discontinuation of natalizumab therapy. A total of 175 patients already on natalizumab, stable clinically and as per MRI, were randomized into three groups. A total of 45 patients continued to be on natalizumab, whereas 42 patients were given intravenous (i.v.) placebo and the rest 88 patients were initiated on alternative therapies (i.e., monthly i.v. methyl prednisolone, IFN-b IM weekly or GA) based on patient and physician decision. Patients were followed clinically quarterly 3 months and with monthly MRIs for the first 6 months and at the end of the 52-week study. Of the 167 patients who completed the study, 46% of patients on placebo and 37% of patients on alternative therapy had worsening MRI disease activity, whereas none of the patients who were continued on natalizumab worsened, thus providing class 1 evidence that withdrawing of natalizumab therapy causes worsening of MS in a subset of patients [45]. Additional immunological and pharmacodynamics studies 122
supported the link between reactivation of the disease and decrease of VLA4 saturation < 75% along with natalizumab withdrawal [46]. 6.
Alternative therapies
MS is a rapidly advancing field with several new therapies on the horizon. Various treatments are in different phases of clinical trials and preliminary data are very promising. Ten FDAapproved disease-modifying therapies are available today for treating MS patients. GA and IFN-b (IFN-b-1-a IM, IFN-b-1-a SQ, IFN-b-1b-2 products) are considered as first-line therapies. They are injectable immunomodulating agents that alter the underlying immunological process without suppressing the immune system on a larger scale [13,47,48]. Mitoxantrone, a chemotherapy with immunosuppressive properties, was approved for secondary progressive MS and worsening relapsing-remitting MS (RRMS) but is rarely used today primarily related to its cardiac and leukemia complications, often encountered even below the maximum dose recommended [49,50].
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Natalizumab
Table 4. Treatment interruption trials. Type of study AFFIRM, SENTINEL and GLANCE [40] Elective interruption of natalizumab: post-marketing study [63] Course of RRMS during and after natalizumab: chart review [42]
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Natalizumab dosage suspension: chart review [44] RESTORE; randomized controlled trial
Patients
Results
1866 patients with relapse; 341 with contrast-enhancing lesions 21 48
84 175. Patients on natalizumab therapy were randomized to: continuing natalizumab, i.v. placebo or alternative therapy (monthly i.v. methylprednisolone, IM IFN or GA) in 1:1:2 and evaluated for worsening of disease activity.
ARR and contrast-enhancing lesions increased between 4 and 7 months 19% had relapses and 47% had increased MRI disease activity ARR during treatment: 0.08 ARR before treatment: 0.52 ARR after discontinuation: 0.35 27.9% experienced clinical relapse Median time for relapse: 3 months Worsening disease activity: Placebo: 46% IFN-b: 7% Glatiramer: 53% Methylprednisolone: 40% Natalizumab: 0%
AFFIRM: Natalizumab safety and efficacy in RRMS; SENTINEL: Safety and efficacy of natalizumab in combination with IFN-b1a in patients with RRMS; GA: Glatiramer acetate; GLANCE: Glatiramer Acetate and natalizumab combination evaluation study; MRI: Magnetic resonance imaging; ARR: Annualized relapse rate; RESTORE: Randomized natalizumab interruption study.
Three new oral interventions with different mechanism of action also became available recently. Since MS is a chronic disease, regular injectable treatments cause patient discomfort and decrease patient adherence. Therefore development of oral drugs can offer greater patient satisfaction and better compliance. Fingolimod, a sphingosine-1 phosphate receptor modulator, inhibits the egression of lymphocytes from lymph nodes, reducing the availability of activated lymphocytes and consequently impeding abnormal autoimmune processes [51-53]. Teriflunomide and dimethyl fumarate (BG12) represent the most recent oral drugs approved by the FDA. Teriflunomide, the active metabolite of leflunomide, approved as a therapy for rheumatoid arthritis since 1998, selectively and reversibly inhibits dihydroorotate dehydrogenase and inhibits the proliferation of stimulated T and B lymphocytes in the periphery that are thought to be responsible for the damaging inflammatory processes involved in MS [54]. BG-12 (dimethyl fumarate) is a modified fumaric acid ester that is used for the treatment of relapsing forms of MS and is thought to have primarily immunomodulatory and possible antioxidant properties that are considered responsible for its beneficial activity in MS patients [55]. New interventions include monoclonal antibodies: alemtuzumab, which is a humanized monoclonal antibody that targets the CD52 surface protein, has shown great benefit in controlling MS disease activity in large pivotal studies and awaits FDA approval; daclizumab, a recombinant humanized monoclonal anti-CD25 antibody that received FDA approval in 1997 for the prevention of renal allograft rejection; and ocrelizumab, a humanized IgG1 anti-CD20 antibody that targets mature B lymphocytes, all are currently being evaluated for the management of relapsing MS [56].
7.
Conclusion
Natalizumab is one of the most efficacious therapies for relapsing MS. The clinical benefit is hampered by the associated risk of a potentially fatal adverse event, the development of PML. Therefore, to better monitor the risk:benefit ratio, it is imperative to develop a strategy for appropriate patient selection. Three factors which are instrumental for selecting the appropriate patients for natalizumab therapy are i) duration of treatment; ii) prior use of immunosuppressant; and iii) JCV seropositivity. High-risk patients should be promptly identified and subjected to heightened clinical vigilance and regular monitoring. Risks and benefits of continuation of therapy should be discussed with the patient and the concerns of withdrawing natalizumab therapy should also be considered. In the unfortunate event of development of PML, urgent plasma exchange should be provided. Immune reconstitution syndrome in such patients should be anticipated as well. Natalizumab if used with appropriate caution and proper patient selection is a very effective drug for treatment of MS. 8.
Expert opinion
Natalizumab represents one of the most efficient therapeutic options available today for the treatment of relapsing MS. Natalizumab is the first selective adhesion molecule inhibitor approved for the treatment of relapsing MS and represents a novel approach for treating the disease. From its early discovery and development as a targeted monoclonal antibody that inhibits activated T cells transmigration into the CNS, positive research results became rapidly available and culminated
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with the significant positive outcomes from the two Phase III clinical trials that brought the FDA approval of the drug. The significant reduction in relapse rate, MRI activity and prevention of disability progression as well as the convenient monthly administration provided a very strong support for its use in active relapsing MS patients. Unfortunately, there was no warning and even no clear understanding of the PML complications that developed shortly after the study termination. The ongoing research to better characterize the patients’ risk for developing PML is substantial. The new algorithm that identified the three factors includes: JC positivity, therapy over 2 years and previous exposure to chemotherapy as significant for a high risk of developing PML is very helpful for the clinical practice. The development of a more sensitive test to identify the patients previously exposed to JCV also represent a very important step toward a safer use of natalizumab as the risk to develop PML in patients with negative JC stratify testing may be as low as 1/10,000. Nevertheless, further research is necessary to improve the PML diagnostic methods and hopefully more efficient therapeutic interventions for patients diagnosed with PML. As future MS therapeutics are developed pursuing specific immunological targets, the natalizumab experience has raised the cognizance for potential complications. There are many new monoclonal antibodies on the pipeline for the treatment of MS (i.e., alemtuzumab, ocrelizumab, daclizumab and Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Declaration of interest B Weinstock-Guttman has participated in speaker’s bureaus and served as a consultant for Biogen Idec, Teva Neurosciences, EMD Serono, Pfizer, Novartis, Genzyme and Sanofi, Mylan and Acorda. She also has received grant/research support from the agencies listed above as well as ITN, Questcor and Shire. No other industry financial relationships exist. S Gupta has no disclosures. leukoencephalopathy. N Engl J Med 2006;354(9):924-33
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Affiliation Sahil Gupta MD & Bianca Weinstock-Guttman† MD † Author for correspondence SUNY University of Buffalo, Jacobs Neurological Institute, 100 High Street, Buffalo NY 14051, USA E-mail: [email protected]
ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: http://www.tandfonline.com/loi/iebt20
Natalizumab for multiple sclerosis: appraising risk versus benefit, a seemingly demanding tango Sahil Gupta MD & Bianca Weinstock-Guttman MD To cite this article: Sahil Gupta MD & Bianca Weinstock-Guttman MD (2014) Natalizumab for multiple sclerosis: appraising risk versus benefit, a seemingly demanding tango, Expert Opinion on Biological Therapy, 14:1, 115-126, DOI: 10.1517/14712598.2014.864634 To link to this article: http://dx.doi.org/10.1517/14712598.2014.864634
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Drug Evaluation
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Natalizumab for multiple sclerosis: appraising risk versus benefit, a seemingly demanding tango 1.
Introduction
2.
Mechanism of action
3.
Pivotal studies
4.
Clinical indications
5.
Adverse effects associated with natalizumab therapy
6.
Alternative therapies
7.
Conclusion
8.
Expert opinion
Sahil Gupta & Bianca Weinstock-Guttman† SUNY University of Buffalo, Jacobs Neurological Institute, NY, USA
Introduction: Natalizumab is a highly effective monoclonal antibody used for the treatment of multiple sclerosis (MS). It reduces relapses, delays the onset of disease progression and improves disease outcomes in relapsing-remitting MS. However, treatment with natalizumab is associated with progressive multifocal leukoencephalopathy (PML), a severe opportunistic brain infection with John Cunningham virus. Areas covered: In this review, we discuss the mechanism of action, results of pivotal studies, clinical use and adverse effects associated with natalizumab therapy with emphasis on PML. A risk stratification strategy to optimize natalizumab therapy is included. This review also summarizes the alternative and upcoming therapies available for the treatment of MS. Expert opinion: Natalizumab is a very effective therapy for MS and has shown tremendous results in reducing the disease activity and improving patients’ quality of life. Serious adverse effect such as PML warrant extreme caution and heightened clinical vigilance while prescribing the drug. If used with prudence, the drug can be instrumental in treatment of patients with inadequate response to the first-line medications. Keywords: JC index, multiple sclerosis, natalizumab, progressive multifocal leukoencephalopathy risk stratification, progressive multifocal leukoencephalopathy Expert Opin. Biol. Ther. (2014) 14(1):115-126
1.
Introduction
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and a common cause of neurological disability in young adults [1]. Influx of T lymphocytes in the brain through interaction of integrins with the vascular cell adhesion molecule (VCAM1) on the endothelial cells is a prerequisite for the inflammatory process of MS [2]. Natalizumab is a recombinant humanized IgG4 antibody that interferes with the influx of inflammatory cells by binding to the a4 subunit of the a4b1 integrin [3] expressed on the surface of immune cells (Box 1). In 1992, researchers at Stanford University and Athena Neuroscience discovered the role of a4 integrin in lymphocyte migration into the brain tissue in animal models of MS called experimental autoimmune encephalomyelitis [4]. Only 12 years after cloning of its molecular target, natalizumab was approved by US FDA in 2004, due to the encouraging results of AFFIRM [5] (Natalizumab Safety and Efficacy in Relapsing-Remitting MS) and SENTINEL [6] (Safety and Efficacy of Natalizumab in Combination with Avonex in patients with Relapsing-Remitting MS) Phase III trials (Figure 1). Thereafter, natalizumab was suspended due to emerging reports of two recipients diagnosed with progressive multifocal leukoencephalopathy (PML) [7,8] and an additional patient with Crohn’s disease. After an independent review which revealed the risk of developing PML following treatment for 18 months was 1 in 1000 patients, the drug was reinstated in July 2006 with recommendations for monitoring of PML [9]. Since then more than 92,000 patients 10.1517/14712598.2014.864634 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase indication
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Mechanism of action Route of administration Pivotal trials
Natalizumab FDA approved prescription only drug Second line treatment of Relapsing-Remitting Multiple Sclerosis Humanized monoclonal antibody against cell adhesion molecule a4 integrin Intravenous infusion Phase 2: GLANCE Phase 3: AFFIRM, SENTINEL
have been treated with natalizumab revealing decreased relapse frequency and better quality of life [10]. Definite strides have also been made in risk stratification of patients on natalizumab to mitigate the threat of developing PML [11]. This has been possible only through recognizing the risk factors for development of PML like prior use of immunosuppressants and increased duration of treatment and, more recently, via use of laboratory test such as John Cunningham virus (JCV) antibody assay [12]. 2.
Mechanism of action
Inflammation and demyelination are the two hallmarks of MS pathophysiology, in addition to a neurodegenerative component. Demyelinating lesions of MS are primarily caused by infiltration of leukocytes especially T lymphocytes [13]. The transmigration of T lymphocytes is mediated by the interaction between the adhesion molecule (a4 integrin) on the lymphocyte and complementary ligand (VCAM1) on the endothelium. Leukocyte integrins are obligate heterodimers containing two chains, a and b subunits. Natalizumab is a humanized IgG4 monoclonal antibody against the a4 integrins, primarily a4b1 (mediating transmigration in the CNS) and a4b7 (mediating transmigration in the small intestine). By blocking the integrins, natalizumab inhibits the movement of leukocytes in the CNS, thereby attenuating inflammation in MS (Figure 2) [14]. Similarly, natalizumab also benefits Crohn’s disease patients preventing inflammation of the small intestine by binding to the a4b7 integrin. It is also shown that natalizumab modulate ongoing tissue inflammatory reaction by inhibiting binding of a4 positive leukocytes with fibronectin and osteopontin and hence reducing the survival, priming and activation of leukocytes that have gained access to CNS parenchyma [15]. No clear clinical data to support this in vivo mechanism is available. 3.
Pivotal studies
In 2000, pharmaceutical companies decided to develop and commercialize natalizumab for treatment of MS following the beneficial results of Phase I trials. Sheremata et al. tested 116
single intravenous infusion of natalizumab and Vollmer et al. studied natalizumab in combination with interferon (IFN)-b and both of these studies found natalizumab to be safe and well tolerated (Table 1). Phase II trials were subsequently commenced to evaluate the efficacy of natalizumab as compared to placebo. Its effect on preventing the development of new gadolinium-enhancing lesions was treated as a yardstick to measure its efficacy by Tubridy et al. [16]. The study was a randomized controlled trial in which the patients received two doses of placebo or natalizumab 1 month apart and were followed up with MRI scans for 6 months. The study revealed that patients treated with natalizumab had decreased number of new active lesions as compared to the placebo group (1.8 vs 3.6, p = 0.04) [16]. However, the most important Phase II trial was the Miller study which was a randomized controlled trial in which subjects were treated for 6 months with monthly doses of natalizumab or placebo and were monitored with monthly MRI scans. The study revealed decrease in the number of inflammatory brain lesion in patients receiving 3 and 6mg/kg natalizumab dosages as compared to placebo (0.7 and 1.1 vs 9.6, p < 0.001) (Table 2). An additional combination, Phase II, 6-month trial, evaluated safety and preliminary efficacy on natalizumab combined with glatiramer acetate (GA) versus GA alone in patients with suboptimal response on GA alone (GLANCE) [17]. The combination was safe and provided preliminary data suggesting benefit on MRI metrics versus GA alone. Combination therapy of natalizumab with GA resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p = 0.020) and new enlarging T2-hyperintense lesions (0.5 vs 1.3, p = 0.029). The incidence of infection and infusion reactions was similar in both groups, but no hypersensitivity reactions were observed. With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone [17]. Use of natalizumab as a monotherapy was investigated through AFFIRM study [5]. Another Phase 3 trial named SENTINEL was designed to investigate the possible synergistic effect of Natalizumab and Interferon [3]. The SENTINEL enrolled relapsing MS patients who demonstrated only a partial therapeutic response to IFN therapy. AFFIRM and SENTINEL were the two pivotal studies that provided the necessary data for acceptance of natalizumab as a very encouraging option for treatment of MS. AFFIRM and SENTINEL showed natalizumab to be effective in reducing annualized relapse rate (ARR), number of new T2 hyperintense lesions, gadolinium-enhancing lesions, expanded disability status scale (EDSS) worsening, new non-enhancing T1 hypointense lesions and brain atrophy (Table 3). Owing to the encouraging year 1 results of AFFIRM and SENTINEL, FDA approved natalizumab in November 2004 following an accelerated review just 12 years after the
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Natalizumab
2000 Commercial developement of natalizumab
1992 Discovery of α4 integrin important in CNS lymphocyte migration
1997 Phase I trials started
2004 FDA approval
2001 Phase III trials started
2006 Reintroduction to the market
2005 Voluntary suspension due to 3 PML cases
2012 US label lists 3 risk factors for PML
Figure 1. Timeline of natalizumab is shown.
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Adapted from [64].
T Lymphocyte
Natalizumab
Capillary lumen
α4 Intergrin
VCAM1
Endothelial cell Brain parenchyma
Figure 2. Representation of natalizumab inhibiting interaction between a4 integrin on the T-lymphocyte and VCAM1 on the capillary endothelial cell, thereby inhibiting the transmigration of T-lymphocyte in CNS. VCAM1: Vascular cell adhesion molecule 1.
discovery of the target molecule. This indicated that natalizumab provides promising advantages over any of the therapies existing at that time. 4.
Clinical indications
Today natalizumab is available as a treatment for relapsing MS under a restriction-distribution format, defined under the Tysabri Outreach Unified Commitment to Health (TOUCH) prescribing programs which require the drug to be provided by the infusion centers registered with the program. It also mandates regular evaluation by the medical professionals at 3 and 6 months and every 6 months subsequently. MRI imaging of the patient is also required prior to the initiation of the therapy and regularly (quarterly, 6 months or yearly) afterward and in
urgent basis if new symptoms become evident while being on natalizumab. More frequent testing should be considered if patients are on long-term therapy (over 2 years) and especially while being JC antibody positive (see further JC antibody status in Section 5.1.2) [12,14]. MS patients with active disease based on presence of continuous relapses or disease activity evident in MRI scans despite therapy with first-line agents such as IFN-b or GA are considered good candidates for initiation of natalizumab therapy [8]. Natalizumab is also favorable for patients with unreliable treatment adherence because of the close monitoring which follows its administration. Natalizumab also provides the benefits of being administered only once a month as compared to once a week for IFN and once daily for glatiramer. Therefore, it is a preferable drug for patients
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Table 1. Phase I trial publications with prespecified end points. Ref.
Trial
Patients
Sheremata et al. [57]
RCT; 5-level dose escalation
28
Vollmer et al. [58]
Open-label; natalizumab and IFN b 1-A
38
Result Safe and well tolerated; natalizumab detected in serum 3 -- 8 weeks after 1 to 3 mg/kg i.v. dose Safe and well tolerated
i.v.: Intravenous; RCT: Randomized controlled trials.
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Table 2. Phase II trial publications with prespecified end points and post-hoc analysis. Ref.
Trial
Patients
Tubridy et al. [16]
RCT, double-blind
72
Miller et al. [59]
RCT, double-blind
213
GLANCE [17]
RCT, double-blind
110
End point Mean active lesions Mean new lesions Inflammatory brain lesion; natalizumab (3 and 6 mg/kg) vs placebo Relapse (natalizumab 1 and 3 mg/kg) vs placebo New gadolinium-enhancing lesions evolving into T1 hypointense lesions [60] Cumulative new active lesions (natalizumab + GA vs GA) T2 hyperintense lesions (natalizumab + GA vs GA) Gadolinium-enhancing lesions (natalizumab + GA vs GA)
Result (natalizumab vs placebo) 1.8 vs 3.6 (p = 0.04) 1.6 vs 3.3 (p = 0.02) 0.7 and 1.1 vs 9.6 (p < 0.001) 19 vs 38% (p = 0.02) 26 vs 68% (p < 0.01)
0.9 vs 2.6 (p = 0.057) 0.5 vs 1.3 (p = 0.029) 0.6 vs 2.3 (p = 0.02)
GA: Glatiramer acetate; GLANCE: Glatiramer acetate and natalizumab combination evaluation; RCT: Randomized controlled trials.
with lower compliance because of its favorable dosage schedule. Although the use of natalizumab in active patients with negative JCV status or a low JCV antibodies (index < 0.9) as mentioned is usually considered in patients not responding to first-line therapies, the use of natalizumab as first-line therapy would be also considered in patients with clinical predictors of high-risk disease progression (i.e., African-American patients, active MRI [multiple white matter lesions and multiple gadolinium-enhancing lesions] or patients with severe relapses and incomplete recovery). In patients with coexisting conditions, which might suppress immunity such as hematological cancers or prior immunosuppressant use within the past 3 months, natalizumab therapy should be avoided or reconsidered and the risks and benefits should be discussed with the patients [18]. Natalizumab is also useful in treatment of Crohn’s disease in patients who are unresponsive to medications such as infliximab (TNF-a blocker). Some researchers have shown that combination therapy of natalizumab and infliximab in Crohn’s disease is effective in inducing remission [19]. In 2008, US FDA approved natalizumab for treatment of moderate-to-severe Crohn’s disease [20]. 118
Adverse effects associated with natalizumab therapy
5.
Natalizumab is a very well-tolerated drug for MS as demonstrated by the Phase III clinical trials [5,21]. Post-infusion reactions were reported in about 24% of the patients. The most common reactions were fatigue and arthralgia, which were treated symptomatically and did not necessitate discontinuation of therapy. Only 4% of the patients receiving natalizumab had hypersensitivity reactions and 1.3% of patients were deemed as serious. As per protocol, the study drug was discontinued in all patients who had hypersensitivity reactions. No significant difference was found between the infection rate in the placebo and the natalizumab group [5]. About 9% of the subjects were positive for anti-natalizumab antibodies at least once during the studies and 6% demonstrated permanent anti-natalizumab antibodies. These patients exhibited diminished clinical efficacy with natalizumab and had significantly worse outcomes both clinically and on MRI as compared to patients who did not develop these antibodies [3,5]. Evaluating for the presence of these antibodies in patients experiencing disease activity especially during the first 6 months and/or initial infusion allergic reaction is recommended.
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Table 3. Phase III prespecified end points and post-hoc analysis of SENTINEL and AFFIRM. Trial
Patients
AFFIRM [5,61]
942
SENTINEL [3,62]
1171
End point
Result
ARR Disability progression Gadolinium-enhancing lesion Mean change in EDSS New T1 hypointense lesions Visual loss ARR New T2 hyperintense lesions Number of gadolinium-enhancing lesion Mean T2 lesion volume Mean change in EDSS Visual loss
Decreased by 68% (p < 0.001) Decreased by 42% (p < 0.001) Decreased by 92% (p < 0.001) 0.04vs 0.41 (p < 0.001) Decreased by 76% (p < 0.001) Decreased by 35% (p < 0.001) Decreased by 55% (p < 0.001) Decreased by 83% (p < 0.001) Decreased by 89% (p < 0.001) Decreased by 11.8% (p < 0.001) 0.15 vs 0.30 (p = 0.01) Decreased by 28%
AFFIRM: Natalizumab safety and efficacy in RRMS; ARR: Annualized relapse rate; EDSS: Expanded disability status scale; SENTINEL: Safety and efficacy of natalizumab in combination with IFN-b-1a in patients with RRMS.
In 2005, after completion of AFFIRM and 1 month before completion of SENTINEL, two cases were reported to have PML while on natalizumab [7,8]. A third case of PML of a patient on natalizumab for Crohn’s disease was also reported [22]. Marketing of natalizumab was immediately halted and physicians prescribing the drug were notified [9]. A safety review was subsequently done which included MRI scans of all patients on the treatment and cases with symptoms similar to PML to be evaluated thoroughly. No more cases of PML were found following the safety review and natalizumab was reintroduced in the market in 2006 under the TOUCH program. Although the risk for developing PML was primarily associated with the use of natalizumab, sporadic cases have been described in patients treated with other immunosuppressive therapies, such as rituximab and mycophenolate mofetil, and more recently in psoriasis patients treated with Fumaderm, a compound similar but not identical with dimethyl fumarate (Tecfidera) [23]. A new case of PML treated with fingolimod was also identified, although the presentation was more atypical and FDA has been evaluating this specific case [24]. The additional information obtained from this case indicated that the patient did have neuromyelitis optica (NMO) with positive anti-NMO IgG antibodies. Vigilant assessment of the risk:benefit ratio for any of these interventions should be considered before initiating therapy. Progressive multifocal leukoencephalopathy PML is a CNS infection caused by the JCV. The JCV is prevalent in almost 50% of the population [25]. It remains latent in the body in kidneys, bone marrow and lymphoreticular system [26]. Mutation of the JCV capsid protein 1 (VP1) is believed to be responsible to transform JCV into a neurotropic strain. The exact cause of natalizumab-related JC virus is not clearly known as no systemic immunosuppression is seen. The possibility of a decreased CNS surveillance appears as the most acceptable theory (Figure 3) [27]. 5.1
Most common clinical symptoms of PML are cognitive and behavioral dysfunctions which occur in ~ 50% of PML patients (Figure 4) [28]. Motor deficits and dysphasia are also fairly common. Some patients also suffer from seizures and fever [28]. Mostly, the patients present with multiple neurological features which deteriorate over time. Sometimes the symptoms of MS and PML can be overlapping. The striking difference in symptoms of PML as compared to MS is that patients suffering from PML very rarely show any optic nerve or spinal cord involvement. On MRI imaging, the common findings are monofocal subcortical white matter lesions which are hyperintense on T2 and FLAIR (Figure 5). About 30 -- 40% might also show gadolinium enhancement, thus making it hard to differentiate from MS lesions [28,29]. On cerebrospinal fluid (CSF) analysis, 50% of patients demonstrated low JCV DNA levels (< 500 copies/ml) in the initial testing, thus requiring sensitive assays that can identify low levels of JCV [28]. Repeated CSF testing in negative cases but with high clinical/MRI suspicion as well as for monitoring the disease progression under therapeutic interventions is recommended. The clinical symptoms, MRI and CSF findings are summarized in Figure 4. Treatment of PML The fundamentals of management of PML are: 1) Immediate discontinuation of natalizumab and 2) drug removal from plasma through plasma exchange or immunoadsorption [28]. Although on some occasions, rapid removal of natalizumab may result in reconstitution of the immune system, associated with brain new inflammatory lesions referred to as immune reconstitution inflammatory syndrome (IRIS), causing worsening of symptoms and appearance of new gadoliniumenhancing lesions. IRIS is often difficult to differentiate from reactivation of MS, although the enhancing lesions may present with more speckled features [30]. Intravenous corticosteroid is the most common treatment available to PML-IRIS patients [28]. Most physicians also recommend an 5.1.1
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JCV INFECTION
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Latent JC virus in the body (bone marrow, tonsils, adrenals)
JCV infection of the peripheral blood mononuclear cells Systemic immunosuppression not clear if related to natalizumab
JCV mutations
Gliotropic Strain
NATALIZUMAB CNS entry through blood brain barrier
Failure of CNS surveillance
PML
Figure 3. Proposed pathogenesis of natalizumab-associated PML is shown. Adapted from [65]. JCV: JC virus; PML: Progressive multifocal leukoencephalopathy.
adjunctive antiviral treatment such as mefloquine or mirtazapine [31,32]. The prognosis of patients with Tysabri-related PML, although somber with a mortality rate of about 20% and the remaining 80% surviving with varying degrees of disability [28], appears less aggressive than the PML associated with other systemic immunosuppressive condition as in HIV patients [33]. Risk profiling and stratification On reviewing the patients who developed PML while on natalizumab, three risk factors were clearly identified: i) duration of treatment for more than 2 years; ii) prior use of immunosuppressant and iii) JCV-specific (anti-JCV) antibodies in the blood [34]. Natalizumab exposure for > 2 years increases PML to about 3.7 cases per 1000 patients [35]. Prior immunosuppression increases the risk of PML by approximately four times [36]. Of the 125 PML patients recognized till 2011, about 47 5.1.2
120
were treated with immunosuppressive agents such as mitoxantrone, methotrexate, azathioprine and cyclophosphamide. The most important risk indicator is JCV seropositivity [12]. A new two-stage optical enzyme-linked immunosorbent assay (ELISA) using recombinant VP1 protein conjoining it to a secondary ELISA test to categorize patients as negative or positive became clinically available [37]. After using this assay, it was revealed that all PML cases till date have been JCV seropositive. It was also shown that almost 50% of people tested were JCV positive and the rest were JCV negative. Patients who are JCV seronegative are at markedly lower risk of developing PML (0.09 per 1000 cases) and can be prescribed natalizumab with significant confidence [11]. The risk of a false negative testing and/or the risk of converting to a positive testing (JCV exposure) are estimated to be 2 -- 4% [12]. Contrastingly, JCV DNA polymerase chain reaction in blood and urine has not been found to be suggestive of PML and its clinical relevance is still unclear [37]. A more sensitive assay
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PML
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Clinical features 1) cognitive 2) motor 3) Language 4) Visual 5) Ataxia 6) Seizures 7) Fever
MRI findings 1) Starting as usual monofocal lesions in subcortical White Matter affecting the U fibers 2) Hyperintense on T2 and FLAIR
CSF findings 1) JCV DNA as the confirmatory test
3) Hypointense lesions on T1 4) 30 – 40% showing contrast enhancement
Figure 4. Clinical features, MRI findings and CSF findings of natalizumab associated PML are shown. FLAIR: Fluid-attenuated inversion recovery; JCV: JC virus; PML: Progressive multifocal leukoencephalopathy.
A.
B.
Figure 5. A. MRI imaging of the patient 5 months before developing PML. B. Red arrow demonstrate the hyperintense subcortical lesions in the same patient after developing PML.
providing the JC antibody titers presented as an index value was shown recently to be associated with a low risk in antiJCV antibody positive patients (when the index < 0.9) for developing PML similar to the JC negative status [38]. Recent studies have revealed cell-based assessment of percentage of lselectin-expressing CD4 T cells as a possible additional biomarker for PML risk assessment [39]. However, further studies will still be required to validate this new diagnostic method. On identification of any of these risk factors, the patients should be subject to close monitoring and increased clinical and MRI vigilance for evidence of PML. Natalizumab should be immediately stopped and risks of discontinuation of natalizumab therapy should be discussed with the patient [33].
Alternative therapies should be recommended and a new treatment plan should be devised and discussed. An algorithm of risk profiling is presented in Figure 6. Discontinuation of natalizumab Natalizumab therapy may be discontinued especially if the stratification algorithm previously mentioned suggests high risk of PML [11]. Several reports have described worsening of MS to nearly pretreatment levels after withdrawing natalizumab (Table 4) [40-43]. O’Connor et al. evaluated patients from AFFIRM, SENTINEL and GLANCE trials who discontinued therapy [40]. Reactivation of the disease to near pretreatment levels was reported within 3 to 6 months of 5.2
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Baseline testing: EDSS, MRI, JC virus Serology
JCV serostatus
Low risk of PML 1:10,000
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Low risk of PML 1:10,000
Continue Rx with q 3 – 6 months JC virus Serology, clinical and MRI q 6 months-1 year or any time new symptoms become evident
Previous use of immunosuppressant
Continue treatment with caution after 1 year with very close (q 3 – 4 months) monitoring clinical and with MRI
JCV Serostatus
Consider other treatment after 12 months-2 years if seroconvertion occurs (index > 0.9)
Consider other treatment after 12 months-2 years if seroconvertion occurs and index > 0.9
Figure 6. Algorithm of PML risk profiling. EDSS: Expanded disability status scale; JCV: JC virus; MRI: Magnetic Resonance Imaging; PML: Progressive multifocal leukoencephalopathy.
therapy withdrawal. A concern for a rebound phenomenon mostly associated with MRI worsening was raised in patients discontinuing natalizumab therapy [40,44]. Most recently, a Randomized Natalizumab Interruption Study (RESTORE) was carried out to study effects of discontinuation of natalizumab therapy. A total of 175 patients already on natalizumab, stable clinically and as per MRI, were randomized into three groups. A total of 45 patients continued to be on natalizumab, whereas 42 patients were given intravenous (i.v.) placebo and the rest 88 patients were initiated on alternative therapies (i.e., monthly i.v. methyl prednisolone, IFN-b IM weekly or GA) based on patient and physician decision. Patients were followed clinically quarterly 3 months and with monthly MRIs for the first 6 months and at the end of the 52-week study. Of the 167 patients who completed the study, 46% of patients on placebo and 37% of patients on alternative therapy had worsening MRI disease activity, whereas none of the patients who were continued on natalizumab worsened, thus providing class 1 evidence that withdrawing of natalizumab therapy causes worsening of MS in a subset of patients [45]. Additional immunological and pharmacodynamics studies 122
supported the link between reactivation of the disease and decrease of VLA4 saturation < 75% along with natalizumab withdrawal [46]. 6.
Alternative therapies
MS is a rapidly advancing field with several new therapies on the horizon. Various treatments are in different phases of clinical trials and preliminary data are very promising. Ten FDAapproved disease-modifying therapies are available today for treating MS patients. GA and IFN-b (IFN-b-1-a IM, IFN-b-1-a SQ, IFN-b-1b-2 products) are considered as first-line therapies. They are injectable immunomodulating agents that alter the underlying immunological process without suppressing the immune system on a larger scale [13,47,48]. Mitoxantrone, a chemotherapy with immunosuppressive properties, was approved for secondary progressive MS and worsening relapsing-remitting MS (RRMS) but is rarely used today primarily related to its cardiac and leukemia complications, often encountered even below the maximum dose recommended [49,50].
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Table 4. Treatment interruption trials. Type of study AFFIRM, SENTINEL and GLANCE [40] Elective interruption of natalizumab: post-marketing study [63] Course of RRMS during and after natalizumab: chart review [42]
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Natalizumab dosage suspension: chart review [44] RESTORE; randomized controlled trial
Patients
Results
1866 patients with relapse; 341 with contrast-enhancing lesions 21 48
84 175. Patients on natalizumab therapy were randomized to: continuing natalizumab, i.v. placebo or alternative therapy (monthly i.v. methylprednisolone, IM IFN or GA) in 1:1:2 and evaluated for worsening of disease activity.
ARR and contrast-enhancing lesions increased between 4 and 7 months 19% had relapses and 47% had increased MRI disease activity ARR during treatment: 0.08 ARR before treatment: 0.52 ARR after discontinuation: 0.35 27.9% experienced clinical relapse Median time for relapse: 3 months Worsening disease activity: Placebo: 46% IFN-b: 7% Glatiramer: 53% Methylprednisolone: 40% Natalizumab: 0%
AFFIRM: Natalizumab safety and efficacy in RRMS; SENTINEL: Safety and efficacy of natalizumab in combination with IFN-b1a in patients with RRMS; GA: Glatiramer acetate; GLANCE: Glatiramer Acetate and natalizumab combination evaluation study; MRI: Magnetic resonance imaging; ARR: Annualized relapse rate; RESTORE: Randomized natalizumab interruption study.
Three new oral interventions with different mechanism of action also became available recently. Since MS is a chronic disease, regular injectable treatments cause patient discomfort and decrease patient adherence. Therefore development of oral drugs can offer greater patient satisfaction and better compliance. Fingolimod, a sphingosine-1 phosphate receptor modulator, inhibits the egression of lymphocytes from lymph nodes, reducing the availability of activated lymphocytes and consequently impeding abnormal autoimmune processes [51-53]. Teriflunomide and dimethyl fumarate (BG12) represent the most recent oral drugs approved by the FDA. Teriflunomide, the active metabolite of leflunomide, approved as a therapy for rheumatoid arthritis since 1998, selectively and reversibly inhibits dihydroorotate dehydrogenase and inhibits the proliferation of stimulated T and B lymphocytes in the periphery that are thought to be responsible for the damaging inflammatory processes involved in MS [54]. BG-12 (dimethyl fumarate) is a modified fumaric acid ester that is used for the treatment of relapsing forms of MS and is thought to have primarily immunomodulatory and possible antioxidant properties that are considered responsible for its beneficial activity in MS patients [55]. New interventions include monoclonal antibodies: alemtuzumab, which is a humanized monoclonal antibody that targets the CD52 surface protein, has shown great benefit in controlling MS disease activity in large pivotal studies and awaits FDA approval; daclizumab, a recombinant humanized monoclonal anti-CD25 antibody that received FDA approval in 1997 for the prevention of renal allograft rejection; and ocrelizumab, a humanized IgG1 anti-CD20 antibody that targets mature B lymphocytes, all are currently being evaluated for the management of relapsing MS [56].
7.
Conclusion
Natalizumab is one of the most efficacious therapies for relapsing MS. The clinical benefit is hampered by the associated risk of a potentially fatal adverse event, the development of PML. Therefore, to better monitor the risk:benefit ratio, it is imperative to develop a strategy for appropriate patient selection. Three factors which are instrumental for selecting the appropriate patients for natalizumab therapy are i) duration of treatment; ii) prior use of immunosuppressant; and iii) JCV seropositivity. High-risk patients should be promptly identified and subjected to heightened clinical vigilance and regular monitoring. Risks and benefits of continuation of therapy should be discussed with the patient and the concerns of withdrawing natalizumab therapy should also be considered. In the unfortunate event of development of PML, urgent plasma exchange should be provided. Immune reconstitution syndrome in such patients should be anticipated as well. Natalizumab if used with appropriate caution and proper patient selection is a very effective drug for treatment of MS. 8.
Expert opinion
Natalizumab represents one of the most efficient therapeutic options available today for the treatment of relapsing MS. Natalizumab is the first selective adhesion molecule inhibitor approved for the treatment of relapsing MS and represents a novel approach for treating the disease. From its early discovery and development as a targeted monoclonal antibody that inhibits activated T cells transmigration into the CNS, positive research results became rapidly available and culminated
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with the significant positive outcomes from the two Phase III clinical trials that brought the FDA approval of the drug. The significant reduction in relapse rate, MRI activity and prevention of disability progression as well as the convenient monthly administration provided a very strong support for its use in active relapsing MS patients. Unfortunately, there was no warning and even no clear understanding of the PML complications that developed shortly after the study termination. The ongoing research to better characterize the patients’ risk for developing PML is substantial. The new algorithm that identified the three factors includes: JC positivity, therapy over 2 years and previous exposure to chemotherapy as significant for a high risk of developing PML is very helpful for the clinical practice. The development of a more sensitive test to identify the patients previously exposed to JCV also represent a very important step toward a safer use of natalizumab as the risk to develop PML in patients with negative JC stratify testing may be as low as 1/10,000. Nevertheless, further research is necessary to improve the PML diagnostic methods and hopefully more efficient therapeutic interventions for patients diagnosed with PML. As future MS therapeutics are developed pursuing specific immunological targets, the natalizumab experience has raised the cognizance for potential complications. There are many new monoclonal antibodies on the pipeline for the treatment of MS (i.e., alemtuzumab, ocrelizumab, daclizumab and Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Affiliation Sahil Gupta MD & Bianca Weinstock-Guttman† MD † Author for correspondence SUNY University of Buffalo, Jacobs Neurological Institute, 100 High Street, Buffalo NY 14051, USA E-mail: [email protected]
