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Abstract
Natalizumab is an 4-integrin antagonist, the first in its class for the treatment of multiple sclerosis (MS). Although multiple mechanisms have been proposed for the efficacy of natalizumab in MS, the most likely explanation is that it interferes with the migration of immune cells into the central nervous system. It does this by binding to the 4 subunit of 41-integrin and preventing leukocyte adhesion to endothelial vascular cell adhesion molecule-1. The efficacy of natalizumab in relapsing-remitting MS has been demonstrated in several double-blind, placebocontrolled trials. Natalizumab has been shown to slow the progression of disability in relapsing-remitting MS significantly better than placebo, and to reduce the number of new and enlarging T2 hyperintense and gadolinium-enhanced magnetic resonance imaging lesions. In a post hoc analysis, the proportion of patients with relapsingremitting MS free of disease activity was significantly greater with natalizumab compared with placebo. Due to the rare risk of progressive multifocal leukoencephalopathy as a complication, natalizumab is primarily recommended in patients who fail, or cannot tolerate, treatment with interferon (IFN) beta or glatiramer acetate (GA). Stratification of those patients most likely to benefit from natalizumab treatment such as those with highly active disease, severe disease, or extensive functional loss, or those who have failed or cannot tolerate IFN beta or GA therapywould help define natalizumabs appropriate place in therapy.
(Am J Manag Care. 2010;16:S164-S170)
ultiple sclerosis (MS) is a central nervous system (CNS) disease characterized by immune activation with damage to the CNS components including myelin, axons, oligodendrocytes, and neurons.1 The course of MS is quite variable. MS can range from very mild to very severe. The most common course of the disease in most untreated patients involves a relapsing pattern, which later transitions to a slow, worsening progressive pattern in most untreated patients.2 If initial onset is progressive, disability will typically occur more rapidly and with greater severity.3
The effect of MS on lifespan is also quite heterogeneous. The period from symptom onset to death has been estimated to range from 20 to 45 years.4 Ultimately, the average person with untreated MS may be expected to lose 5 to 10 years off their natural lifespan. Onset of MS generally occurs in young and early middle-aged adults, with peak onset between the ages of 20 and 40 years.5,6 Women are at least 2 times more likely than men to develop MS, and this trend is increasing.7
Pathophysiology of MS
MS is a chronic disease distinguished by waves of activity that damage the CNS. Disease activity is evident on a macroscopic level (ie, detection of MS lesions using magnetic resonance imaging [MRI]) and a cellular level. The process by which MS lesions form is complex and includes multiple factors (eg, cytokines, chemokines, and immunoglobulins). There is focal breach of the blood-brain barrier (BBB), penetration of systemic immune cells, and local immune activation and responses leading to damage of the CNS tissue.8,9 Microglial and oligodendrocyte changes may occur that prime this immune response. Permeability of the BBB allows more T cells to enter into the CNS.9 These T cells produce cytokines which activate macrophageswhite blood cells that consume other cells that they perceive to be invasive or harmful. Resident macrophages in the brain and spinal cordcalled microglia cellsare activated and attack the myelin sheath.10 The myelin sheath insulates nerve fibers (axons) and speeds up the impulses that travel along these axons. As the microglia cells attack the myelin sheath, it gradually breaks down in a process known as demyelination. Areas where the myelin sheath and surrounding tissue have been damaged form
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binding to fibronectin, natalizumab interrupts 41-integrin binding, thereby reducing the inflammatory response.17 Similarly, a reduction in the inflammatory response appears to result from the binding of natalizumab to osteopontin, a protein involved in endothelial cell and leukocyte adhesion.17,18 Finally, it has been suggested that the clinical efficacy of natalizumab in MS may be due to its ability to induce apoptosis in T cells.19
Clinical Efficacy of Natalizumab
MRI is used to visualize and determine the characteristics of MS lesions. T1-weighted imaging and T2-weighted imaging are the most common techniques employed to assess MS lesions. Scarred lesions are evident as white, bright (ie, hyperintense) areas on T2 images.11,12 T1 images identify areas where nerve fibers have died; these areas are less dense (ie, hypointense) and are commonly referred to as black holes. Gadolinium is used as a contrast agent to identify areas of active disease; it will leak into the brain tissue when there are breaks in the BBB.12 These areas will be hyperintense on T1-weighted images, and are referred to as gadoliniumenhancing lesions.
Role of 4-integrin Antagonism in the Treatment of MS
Although the exact mechanism of action of natalizumab in MS is unknown, several explanations have been suggested. New lesion development follows infiltration of activated lymphocytes through the BBB, which requires the adhesion of lymphocytes to vascular endothelial cells.9 This process involves binding of vascular cell adhesion molecule (VCAM)-1 to 41-integrin located on the lymphocytes, which facilitates lymphocytic penetration of the BBB.13 It is generally believed that the primary mechanistic explanation for the efficacy of natalizumab is that it interferes with the migration of immune cells into the CNS by binding to the 4 subunit of 41-integrin, thereby preventing leukocyte adhesion to endothelial VCAM-1. A murine version of natalizumab, AN100226m, has been shown to have a powerful limiting effect on leukocyte infiltration into the CNS of guinea pigs in a preclinical model of MS, experimental allergic encephalomyelitis (EAE).14 The rapid clearance of leukocytes from the CNS was associated with a reduction in disease progression and a substantial decrease in the incidence of demyelination. Similar results have been observed in studies of EAE in rats.15 Several other effects of natalizumab have been offered as explanations for its efficacy in MS. One such effect relates to the role of fibronectin, a component of the extracellular matrix to which 41-integrin binds in the course of migrating to inflammatory sites as part of the immune response.16 By
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The clinical efficacy of natalizumab was established in a double-blind, placebo-controlled trial: the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis study, known as AFFIRM.20 AFFIRM was a 2-year trial conducted in 99 clinical centers in North America, Europe, New Zealand, and Australia. A total of 942 patients between the ages of 18 and 50 years (mean age, 36 years), with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 6 (mean score, 2.3), were randomized in a 2:1 ratio to receive either natalizumab 300 mg (n = 627) or placebo (n = 315) intravenously every 4 weeks.20 Patients were evaluated every 12 weeks. The study design of AFFIRM included primary and secondary end points at years 1 and 2. At year 1, the primary end point was clinical relapse rate, and the secondary end points were: (1) number of new or enlarging MRI-detected hyperintense T2 lesions, (2) number of gadolinium-enhanced MRI lesions, and (3) proportion of patients who were relapsefree.20 At year 2, the primary end point was the cumulative probability of sustained disability progression over a 12-week period. Disability progression was defined as an increase of at least 1.0 on the EDSS among patients with a baseline EDSS score of at least 1.0. (Patients with a baseline EDSS score of 0 were defined as experiencing disability progression if their EDSS score increased by at least 1.5.) At year 2, secondary end points were: (1) clinical relapse rate, (2) volume of T2-weighted lesions, (3) number of new hypointense T1 lesions, and (4) disability progression as measured by the Multiple Sclerosis Functional Composite (MSFC). Natalizumab was significantly more effective than placebo. At year 1, 77% of patients given natalizumab were relapse free compared with 56% of those given placebo; at year 2, the proportions were 67% and 41%, respectivelya reduction of 59% over 2 years (P <.001 for both years).20 The annualized relapse rate at year 1 was significantly lower in the natalizumab group compared with the placebo group (0.26 vs 0.81, respectively; P <.001). This benefit was sustained over 2 years, with a 68% relative reduction in the relapse rate among patients given natalizumab compared with those giv-
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n Figure 1. Time to Sustained Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis Given Natalizumab in AFFIRM
Proportion of Patients With Sustained Progression of Disability 0.4
P <.001 Placebo
0.3
0.2
Natalizumab
0.1
0.0
Reprinted with permission from Polman CH, et al. N Engl J Med. 2006; 354:899-910.
en placebo (0.23 vs 0.73, respectively; P <.001). The 2-year primary end point, sustained disability progression rate, was also significantly lower in natalizumab-treated patients compared with those receiving placebo; the cumulative probability of 12-week sustained progression of disability was 17% in the natalizumab group versus 29% in the placebo group (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.430.77; P <.001) (Figure 1). This difference represents a 42% reduction in risk of disability progression with natalizumab. When a stricter definition of disability progression was applied (sustained progression for 24 weeks), natalizumab was associated with a 54% reduction in risk (HR, 0.46; 95% CI, 0.33-0.64; P <.001). In parallel with clinical measurements, the MRI data also reflected significantly better outcomes associated with nata l izumab treatment. The mean number of new or enlarging T2 hyperintense lesions was significantly less in the natalizumab group compared with the placebo group at years 1 and 2 (P <.001 for both).12,20 After 2 years, natalizumab was associated with an 83% reduction in the number of new or enlarging T2 hyperintense lesions compared with placebo. Similarly, there was a 92% reduction in lesions detected by gadolinium-enhancing MRI among natalizumab-treated patients compared with placebo at year 1 (0.1 natalizumab vs 1.3 placebo) and year 2 (0.1 natalizumab vs 1.2 placebo; P <.001 for both). After 2 years, mean T2 lesion volume was significantly lower in patients treated with natalizumab compared with those
given placebo, and the mean number of T1 hypointense lesions in the natalizumab group was 1.1 compared with 4.6 in the placebo group, a reduction of 76% (P <.001).12 Several post hoc analyses of data from the AFFIRM study have provided additional insight into the benefits of nata lizumab monotherapy in relapsing-remitting MS. One of the most compelling is an analysis conducted by Havrdova et al which examined the proportion of patients free of disease activity.21 A state of no overt disease activity is clearly an ideal treatment goal, but has not been an expected outcome for the majority of MS patients receiving therapy. In this post hoc analysis, no clinical disease activity was defined as the absence of both relapse and of disability progression (sustained for at least 12 weeks). No radiologic disease activity was defined as the absence of gadolinium-enhancing lesions and the absence of both new and enlarging T2 hyperintense lesions. (T1 hypointense lesions were excluded from these criteria due to challenges in their quantification and in the detection of lesion conversion based on annual MRIs.21) Of the original 942 patients enrolled in the AFFIRM trial, data from 917 patients were available for analysis of disease activity; patient characteristics were similar to those in the overall population.21 Natalizumab was associated with significant improvement compared with placebo for all measurements of disease activity. At 2 years, significantly more natalizumab-treated patients experienced no clinical disease activity compared with those given placebo (64% vs 39%, respectively; P <.0001).21 Differences were seen for each measure of disease activity; natalizumab was significantly better than placebo for the measures of no relapses and no disability progression for 12 weeks (P <.0001 for both).21 Even more pronounced was the absence of radiologic disease activity in patients given natalizumab compared with those given placebo (58% vs 14%, respectively; P <.0001). Compared with placebo, significantly fewer patients given natalizumab experienced either measure of radiologic disease activity (new gadolinium-enhancing lesions and new or enlarging T2 hyperintense lesions) (P <.0001 for both).21 Patients given natalizumab were also significantly more likely to have no evidence of either clinical or MRI disease activity (37%) than those given placebo (7%; P <.0001) (Figure 2).
Subgroup Analyses From AFFIRM
Hutchinson and colleagues conducted an extensive analysis of data from predefined patient subgroups in the AFFIRM trial. The subgroups were defined as follows: (1) number of relapses occurring during the year prior to enrollment (1, 2, >3); (2) EDSS score (<3.5, >3.5); (3) number of T2 lesions
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nTable. Adverse Events Occurring in the AFFIRM Trial
Adverse Reactions (Preferred Term) General Headache Fatigue Arthralgia Chest discomfort Acute hypersensitivity reactionsa Other hypersensitivity reactionsa Seasonal allergy Rigors Weight increased Weight decreased Infection Urinary tract infection Lower respiratory tract infection Gastroenteritis Vaginitisb Tooth infections Herpes Tonsillitis Psychiatric Depression Musculoskeletal/connective tissue disorders Pain in extremity Muscle cramp Joint swelling Gastrointestinal Abdominal discomfort Diarrhea NOS Abnormal liver function test Skin Rash Dermatitis Pruritus Night sweats Menstrual disorders b Irregular menstruation Dysmenorrhea Amenorrhea Ovarian cyst Neurologic disorders Somnolence Vertigo Renal and urinary disorders Urinary incontinence Urinary urgency/frequency Injury Limb injury NOS Skin laceration Thermal burn Tysabri (N = 627) Percentage 38 27 19 5 4 5 3 3 2 2 21 17 11 10 9 8 7 19 16 5 2 11 10 5 12 7 4 1 5 3 2 2 2 6 4 9 3 2 1 Placebo (N = 312) Percentage 33 21 14 3 <1 2 2 <1 <1 <1 17 16 9 6 7 7 5 16 14 3 1 10 9 4 9 4 2 0 4 <1 1 <1 <1 5 3 7 2 <1 <1
NOS indicates not otherwise specified. a Acute versus other hypersensitivity reactions are defined as occurring within 2 hours postinfusion versus more than 2 hours. b Percentage based on female patients only. Reprinted from Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc; 2009. .
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Safety results from AFFIRM were similar between nata lizumab and placebo. Nearly all patients in both groups experienced some type of adverse event (AE); however, only fatigue (natalizumab 27% vs placebo 21%; P = .048) and allergic reaction (natalizumab 9% vs placebo 4%; P = .012) were significantly different.20 The incidence of serious AEs was similar between natalizumab and placebo (19% vs 24%, respectively; P = .06).20 The Table provides a full list of AEs occurring in the AFFIRM trial. The most common serious AE was relapsing MS (6% with natalizumab, 13% with placebo; P <.001). All other serious AEs occurred in less than 1% of each treatment group.
Role of Natalizumab in Clinical Practice
May 6, 2010, there were49 confirmed cases of PML among patients who received natalizumab worldwide.33 Although the risk of PML may be a disincentive to treat with natalizumab, it is worth considering the benefits nata lizumab may provide in the treatment of MS. The efficacy of natalizumab in treating patients with MS is compelling, and clinicians must weigh this benefit against the risks of nata lizumab. With this in mind, patients with active disease may be considered a group for whom natalizumab therapy would be very beneficial, particularly in light of the post hoc analysis from AFFIRM, which demonstrated that natalizumab produced no overt disease activity in this subset of patients.22 Natalizumab therapy may be considered in patients with an inadequate response to IFN beta (-1a or -1b) or GA, or those who cannot tolerate such agents. The demonstrated efficacy of natalizumab in reducing relapses, as well as the risk of disability progression, substantiates its use in patients whose functionality has deteriorated and who may not have other promising treatment options.12,20 Ultimately, the place of natalizumab in therapy requires appropriate stratification of patients to identify those who will likely respond and benefit from natalizumab treatment. Such a stratification process would consider nata lizumab not simply as a backup treatment, but as a first-line therapy for those patients with greater disease severity, more disease activity, more functional loss, and perhaps those who are phenotypically less likely to respond to other treatments.
Conclusion
Natalizumab monotherapy is approved for the treatment of relapsing forms of MS. At present, natalizumab is widely regarded as a second-line therapy for MS that can be used if treatment with IFN beta or GA fails. Indeed, the US Food and Drug Administrationapproved labeling for natalizu mab recommends, although does not mandate, its use in cases of inadequate response or intolerability to alternate MS therapies.32 It should be noted that some practitioners do employ natalizumab as first-line therapy, and that the cate gorization of natalizumab as a second-line therapy is largely a consequence of the occurrence of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS caused by lytic infection of oligodendrocytes by the papovavirus JC that causes death or severe disability. As of
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Natalizumab is an effective agent in the treatment of relapsing-remitting MS. The status of natalizumab as a secondline therapy is based on the risk of PML, a rare but severe infection.33 Appropriate stratification of patients could better refine the place of natalizumab in MS treatment and identify those patients for whom first-line initiation of natalizumab therapy may be appropriate.
Acknowledgment: Editorial support for this manuscript was provided by James Borwick. Author Affiliation: From the Department of Neurology, Stony Brook University Medical Center and Stony Brook MS Comprehensive Care Center, Stony Brook, NY. Funding Source: Financial support for this work, including honoraria, was provided by Biogen Idec. Author Disclosures: The author reports board membership at Bayer and Novartis; consultancy/advisory board membership at Acorda, Bayer, Biogen Idec, EMD Serono, Pfizer, sanofi-aventis, and Teva. Dr Coyle has also received grants from Novartis and sanofi-aventis as well as honoraria and lectureship fees from Bayer, Biogen Idec, EMD Serono, Novartis, Pfizer, sanofi-aventis, and Teva. Authorship Information: Concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and approval of final version of manuscript.
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Address correspondence to: Patricia K. Coyle, MD, Department of Neurology, HSC T-12 20, State University of New York, Stony Brook, NY 11794-8121. E-mail: pcoyle@notes.cc.sunysb.edu.
18. Bayless KJ, Meininger GA, Scholtz JM, Davis GE. Osteopontin
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