Supplements Best Practices for Natalizumab Utilization in the Treatment of Multiple Sclerosis
Recommendations for the Selection, Treatment, and Management of Patients Utilizing Natalizumab Therapy for Multiple Sclerosis
Natalizumab is an integrin receptor antagonist indicated for the treatment of multiple sclerosis (MS). Natalizumab is indicated as monotherapy in patients who have had an inadequate response to other forms of MS treatment and is not recommended as first-line treatment because of the potential for serious adverse events associated with its use. It is critical for both physicians and patients to understand the benefits as well as the potential risks of treating MS with natalizumab. One of the serious adverse events associated with treatment with natalizumab is the possibility of developing progressive multifocal leukoencephalopathy (PML). Physicians and patients must weigh the benefits of treatment against the possibility of developing PML before undergoing treatment. Proper clinical vigilance, via the Tysabri Outreach: Unified Commitment to Health (TOUCH) Prescribing Program, is currently the best method to minimize the risk of PML, associated with natalizumab therapy.
(Am J Manag Care. 2010;16:S178-S183)
Natalizumab (Tysabri; Biogen Idec, Inc, Elan Pharmaceuticals, Inc) is an integrin receptor antagonist indicated for the treatment of relapsing multiple sclerosis (MS).1 Natalizumab binds to the α4 subunit of α4β1- and α4β7-integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to specific receptors (ie, vascular cell adhesion molecule-1 on vascular endothelial cells and connecting segment-1 and/or osteopontin expressed by parenchymal cells).1
The exact mechanism by which natalizumab exerts its effects in MS is unknown. However, it is postulated that by binding to the α4-integins, natalizumab reduces the migration of lymphocytes into the central nervous system (CNS) of patients with MS and inhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation of MS lesions.2
Natalizumab is indicated as monotherapy for the treatment of patients with relapsing forms of MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. Natalizumab is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy.1
Advanced MS is a serious condition requiring an assertive stance to therapy. Natalizumab is an effective option to delay progression of advanced MS but it is also associated with a risk of developing progressive multifocal leukoencephalopathy (PML), which is a demyelinating disease of the CNS caused by lytic infection of oligodendrocytes by the papovavirus JC that causes death or severe disability. Consequently, patients and clinicians need to understand the risks and benefits of natalizumab therapy and compare them against the effects of not treating the disease. Below is a review of the efficacy and safety of natalizumab monotherapy for the treatment of MS.
Efficacy of Natalizumab and the AFFIRM Trial
The AFFIRM (Natalizumab Safety and Efficacy in Relapsing- Remitting Multiple Sclerosis) trial3 established natalizumab as an effective therapy for patients with relapsing MS. This 2-year phase 3 trial compared natalizumab (300 mg every 4 weeks; n = 627) to placebo (n = 315) in patients with relapsing MS. The primary end points were the rate of clinical relapse at 1 year and the rate of 3-month sustained progression of disability at 2 years. Results from this study were impressive. Natalizumab reduced the rate of clinical relapse at 1 year by 68% (P <.001) and reduced the risk of 3-month sustained progression of disability by 42% over 2 years (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.43-0.77; P <.001). The sensitivity analysis for 6-month sustained progression of disability was a 54% risk reduction in the natalizumab group (HR, 0.46; 95% CI, 0.33-0.64; P <.001).3
Patients receiving natalizumab also had 83% fewer new or enlarging T2 hyperintense lesions detected by magnetic resonance imaging (MRI) over 2 years compared with those given placebo (1.9 ± 9.2 lesions [mean ±SD] vs 11.0 ± 15.7, respectively [P <.001]) and reduced the mean number of lesions as detected by gadolinium-enhanced MRI by 92% as compared with placebo at both 1 year and 2 years (P <.001).3
In a post hoc subgroup analysis of data from the AFFIRM trial, natalizumab was effective in patients with highly active MS (2 or more relapses within a year and 1 or more gadolinium-enhancing [Gd+] lesions at study entry). Natalizumab, compared with placebo, reduced the risk of disability progression by 64% (vs 39%; P <.0001) and relapse rate by 81% (0.28 vs 1.46, respectively; P <.001).4
Safety of Natalizumab, the SENTINEL Trial, and Patient Selection
Natalizumab is associated with an increased risk of PML. This condition was first reported during a second phase 3 trial, the SENTINEL (Safety and Efficacy of Natalizumab in Combination with Interferon beta-1a) trial.5 This trial randomly assigned 1171 patients on interferon (IFN) beta-1a therapy who had at least 1 relapse to receive either continued IFN-beta therapy plus natalizumab (n = 589) or IFN beta plus placebo (n = 582) for up to 116 weeks. Results from this trial showed that the combination of IFN beta and natalizumab was efficacious (ie, combination therapy had a lower annualized rate of relapse over a 2-year period compared with IFN beta alone [0.34 vs 0.75, respectively; P <.001]) and was associated with fewer new or enlarging lesions on T2-weighted MRI (0.9 vs 5.4; P <.001). However, the trial was terminated early when 2 cases of PML, 1 fatal, were diagnosed in natalizumab-treated patients.
As of May 6, 2010, a total of 49 cases of PML were identified among approximately 67,700 patients who have received natalizumab worldwide.6
Due to the seriousness of PML, an expert panel was recently assembled to develop best practice recommendations for the use of natalizumab in patients with MS.7-9 The panel determined that natalizumab should only be given to patients who (1) have had a suboptimal response to standard treatment (eg, IFN beta or glatiramer acetate [GA]), (2) cannot tolerate standard treatment, or (3) have a poor prognosis (Table 1).9 For patients switching from IFN beta or GA to natalizumab, no washout period is necessary.
The expert panel further noted that a poor response to IFN beta or GA should be defined as 2 or more relapses within a year of treatment, 1 significant relapse in the past year, a single relapse accompanied by new MRI activity (eg, new Gd+ lesions, new or enlarging T2 hyperintense lesions, or new T1 black holes) within 1 year, or a significant increase in MRI activity even in the absence of clinical activity.9 Natalizumab can also be given to patients who cannot tolerate IFN beta or GA (ie, those who develop flulike symptoms or injection-site reactions). Finally, patients fitting into a poor prognosis category may also benefit from natalizumab (Table 1). In these groups of patients, natalizumab as firstline therapy can be considered. For example, first-line therapy with natalizumab is recommended for patients with a devastating first relapse, or accompanying poor prognosis MRI activity (eg, T1 black hole formation, high number and volume of Gd+ lesions).9
Natalizumab is not appropriate for some patients (Table 2).9 Patients who are immunocompromised should not receive natalizumab because they may be at increased risk for developing PML. Therefore, patients suspected of having a compromised immune system due to previous long-term use of immunosuppressive agents, chronic medical comorbidities, and/or recurrent or a recent history of opportunistic infection should be screened for immune competency prior to receiving natalizumab.9 The package insert for natalizumab does not require or recommend a washout period prior to initiation of therapy; however, the panel recommended that patients previously given immunosuppressants, such as azathioprine, mycophenolate mofetil, cyclophosphamide, mitoxantrone, and methotrexate, should undergo a 3- to 6-month washout period before beginning treatment with natalizumab. The panel felt that no washout period is necessary following IFN beta, GA, or corticosteroid treatment.9
The panel also stated that since MRI at baseline is essential for monitoring treatment efficacy, natalizumab should only be given as a last option in patients who cannot receive an MRI.9
Monitoring Patients Using Natalizumab
In order to assess efficacy of natalizumab therapy, the panel recommended that prior to beginning therapy, baseline clinical (physical exam, medical history, cognitive function), laboratory (human immunodeficiency virus and CD4 counts [if appropriate], complete blood count; liver function tests), and image testing (MRI with contrast) should be performed. After initiating treatment, routine follow-up should include a neurologic exam and MRI at 6 months, with subsequent exams and MRIs every 12 months thereafter. These recommendations are related to assessing symptoms and status of MS; monitoring for PML, as outlined below, differs slightly but generally overlaps with this schedule. Additionally, other tests may be performed if necessary (Table 3).9