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The Role of Natalizumab in the Treatment of Multiple Sclerosis
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The Role of Natalizumab in the Treatment of Multiple Sclerosis

Patricia K. Coyle, MD

Abstract

Natalizumab is an α4-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 α4 subunit of α4β1-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, placebo-controlled 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 relapsing-remitting 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 therapy-would help define natalizumab's appropriate place in therapy.

(Am J Manag Care. 2010;16:S164-S170)

 

Multiple 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 macrophages-white blood cells that consume other cells that they "perceive" to be invasive or harmful. Resident macrophages in the brain and spinal cord-called microglia cells-are 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 lesions. These lesions can be visualized using MRI. While remyelination processes are activated to repair the damage to the myelin sheath, in MS, this process is inadequate.9 In addition to the gradual demyelination just described, there is neurodegeneration (damage to axons and neurons), with consequent emergent symptoms.





MS Lesions and Detection Using MRI

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 "gadolinium-enhancing" lesions.





Role of α4-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 α4β1-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 α4 subunit of α4β1-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 α4β1-integrin binds in the course of migrating to inflammatory sites as part of the immune response.16 By binding to fibronectin, natalizumab interrupts α4β1-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

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 relapse-free.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%, respectively-a 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 given 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], 0.43- 0.77; 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).





 
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