Researchers Suggest Short Transition Period Between Natalizumab and Fingolimod Therapies to Control RRMS Disease Activity

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An international team led by researchers at the University Hospital Basel in Switzerland revealed that a short period of 8 to 12 weeks is the optimal timing to be considered when patients with relapsing-remitting multiple sclerosis (RRMS) are switched from natalizumab to fingolimod therapy. The study was recently published in the journal Neurology and is entitled “Switching from natalizumab to fingolimod, A randomized, placebo-controlled study in RRMS.

MS is a chronic, progressive neurodegenerative autoimmune disorder that results from an attack on the central nervous system (brain, spinal cord and optical nerves) by the body’s own immune system, causing inflammation and damage to the myelin layer that covers and protects neurons. Myelin loss leads to impairment in signal transmission along the nerve fibers, affecting motor function (coordination, balance, speech and vision), causing irreversible neurological disability and paralysis. It is estimated that more than 2.3 million people in the world suffer from the disease.

The most frequent form of multiple sclerosis is RRMS, which is clinically characterized by recurring episodes of neurological symptoms. Natalizumab is a humanized monoclonal antibody used in the treatment of RRMS patients. However, its use is associated with some clinical complications such as persistent anti-natalizumab antibodies (natalizumab has a long elimination half-life and prolonged immunosuppressive effects), suboptimal efficacy, tolerability issues, and the development of progressive multifocal leuko-encephalopathy (PML, a severe opportunistic brain infection by the JC virus). As natalizumab has an intravenous formulation, patients often prefer an oral therapy. Due to these factors, a switch from natalizumab to other therapies is therefore often considered. Natalizumab discontinuation can, in turn, lead to a rapid return of relapse activity and magnetic resonance imaging (MRI) lesions to levels similar to the ones prior to the treatment.

Oral fingolimod (0.5 mg, once-daily) is an efficient therapy for relapsing forms of MS. Previous studies have suggested that fingolimod has a beneficial effect in terms of relapses in patients who discontinued natalizumab treatment, and could therefore be considered a potential suitable switch therapy from natalizumab.

In this study, researchers conducted a randomized, multicenter, double-blind, placebo-controlled trial (TOFINGO) to determine the optimal timing for initiating fingolimod therapy after natalizumab discontinuation in 142 RRMS patients. The goal is to maintain disease control and avoid potentially harmful additive effects on immune surveillance. The team tested the intervals of 8, 12 and 16 weeks between the last natalizumab infusion and fingolimod treatment over 32 weeks. Brain MRI recurrence and clinical disease activity were evaluated.

Researchers found that in total, 78.9% (112) of the patients completed the study. The number of active MRI lesions was found to increase according with the duration of the interval between the two therapies. More patients were found to be relapse-free in the 8-week (88%) and 12-week (91%) periods in comparison to the 16-week period (84%). Of the cohort, 68% of the patients experienced mild or moderate adverse events with no major differences between the groups analyzed. No unusually severe relapses or opportunistic infections were reported.

The team concluded that patients with RRMS switching from natalizumab to fingolimod therapy should undergo a short period of 8 to 12 weeks between therapies, as this time interval is associated with less MRI disease activity than longer periods. The authors suggest that additional studies should be performed to determine whether an interval shorter than 8 weeks would further improve disease control with reasonable risks.

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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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