Is There a Role for Planned Natalizumab Dosage Suspension in Mitigating Progressive Multifocal Leukoencephalopathy risk?

Abstract

ISSN 1758-2024 10.2217/NMT.10.4 © 2011 Future Medicine Ltd Neurodegen. Dis. Manage. (2011) 1(1), 11–14 Natalizumab is a humanized anti-a4 integrin monoclonal antibody that decreases lymphocyte trafficking into the CNS. It is US FDA approved for treatment of relapsing–remitting multiple sclerosis (MS) and is proven to reduce relapse rate, progression of disability and accumulation of brain MRI lesions [1,2]. Shortly after FDA approval in 2004, two patients in the SENTINEL trial developed progressive multifocal leuko encephalopathy (PML), resulting in natalizumab’s voluntary withdrawal from the market by Biogen Idec. Following a comprehensive safety reevaluation and development of a risk evaluation mitigation strategy natalizumab was reintroduced to the market in 2006 with a black box warning regarding PML risk. As of November 2010, approximately 75,500 patients have been treated with natalizumab worldwide. There are 75 confirmed cases of natalizumab-associated PML, with 15 fatalities. The duration of exposure to natalizumab is associated with increased PML risk [3,4]. The incidence of PML in the first year of treatment is estimated to be less than 1 in 70,000. In the second year of treatment the incidence rises to 1 in 2700 and in the third year of treatment the risk increases further to 1 in 670 [Biogen Idec Medical Affairs, Pers. Comm.]. Fewer data are available for patients receiving continuous natalizumab treatment beyond 3 years; however, the risk seems to decrease in the fourth year of treatment to 1 in 1000. Scheduled dosage interruptions have been proposed to decrease the cumulative risk of developing PML [5]. The rationale for this intervention is to allow reconstitution of lymphocyte trafficking into the CNS. In theory, PML infections might be cleared by trafficking lymphocytes prior to the onset of clinical manifestations. In practice, dosage interruptions typically occur for a period of 3–6 months following at least 12 months of continuous natalizumab treatment. A 3-month dosage interruption was proposed based on the Phase II natalizumab trial in which patients received monthly natalizumab or placebo infusions for 6 months and were then observed for an additional 6 months following discontinuation of the study drugs [6,7]. During the active treatment period natalizumab treatment was associated with a 90% reduction in the cumulative number of