Research Impact


Natalizumab: a potent treatment for highly active relapsing-remitting multiple sclerosis

12 December 2014


Research at the UCL Institute of Neurology has resulted in the licensing of natalizumab (Tysabri), a potent treatment for highly active relapsing remitting multiple sclerosis. By 2013, over 115,000 patients had received natalizumab, which has been shown to reduce relapse rate by two-thirds and relapse-related disability by 50%.

Multiple sclerosis (MS) is the most common disabling neurological disease of young adults in the UK, where it affects one in 800 of the population. It is associated with high healthcare and socioeconomic costs and a markedly reduced quality of life. The first available disease-modifying treatments - beta interferon and glatiramer acetate - were introduced in the 1990s, but their utility in preventing relapses and reducing related disability proved limited.

The subsequently pressing requirement for more effective treatments was compounded by the findings of a 2002 National Institute for Health and Clinical Excellence (NICE) technology appraisal, which showed that these first-line treatments were not cost effective for NHS use. Since then, they have been available to MS patients only through a unique Department of Health Risk Sharing Scheme designed to ensure cost-effectiveness through the long-term (2002-2015) monitoring of a large patient cohort.

Research at UCL has helped tackle this problem by supporting the development and licensing of natalizumab (trade name Tysabri), a monoclonal anti-adhesion molecule antibody shown to prevent trafficking of mononuclear white blood cells from blood to brain. Serial magnetic resonance imaging (MRI) studies conducted at the UCL Institute of Neurology identified blood-brain barrier (BBB) breakdown as a key early event in new lesion formation in relapsing remitting MS. As well as playing a key role in defining protocols for using MRI in proof-of concept trials of potential new disease modifying treatments, this provided a rationale for investigating natalizumab.

Under the leadership of Professor David Miller, members of the UCL Nuclear Magnetic Resonance Research Unit investigated the efficacy of natalizumab by performing central MRI analysis of multicentre Phase 1/2a and Phase 2b placebo-controlled trials in relapsing MS, using MRI lesion activity as the primary outcome measure. The large phase 3, multicentre, placebo-controlled trial that followed showed that, compared with placebo, natalizumab:

  • reduced relapse rate by two thirds, and by 81% in a subgroup of patients with highly active relapsing remitting MS
  • reduced the rate of hospitalisations by 64% and the need for steroid treatment for relapses by 69%
  • reduced by 50% (and by 64% in the subgroup with highly active disease) the development of irreversible disability; indeed, not only was it the first treatment for MS to show a large and unequivocal effect in preventing disability, but a substantial number of natalizumab-treated patients actually experienced a reduction in their level of existing disability
  • reduced by 43% the risk of a confirmed worsening of cognitive function
  • significantly improved both physical and mental health-related quality of life, which is often substantially impaired in people with MS.

The phase 3 trials did also identify a serious adverse effect of natalizumab: about one person in 1,000 developed progressive multifocal leucoencephalopathy (PML), a severe and sometimes fatal viral brain disease. This rare complication means that natalizumab is largely used as a second-line treatment in highly active MS. Professor Tarek Yousry (UCL Institute of Neurology) led an international group that defined the risk for PML and he and Professor Miller have since contributed to guidelines relating to the monitoring of natalizumab-treated patients for early detection of PML.


This pivotal phase 3 trial led to a full NICE technology appraisal of natalizumab in 2007, the outcome of which was that it became the first NICE-recommended disease-modifying treatment for MS available via the UK National Health Service.

The drug was also approved by regulatory authorities for the treatment of active relapsing remitting MS in many other parts of the world, including in the United States (FDA, 2006), European Union (EMEA, 2006), Canada and Australia. In 2007 NICE recommended natalizumab as a clinically and cost-effective treatment in the NHS for patients with rapidly evolving, severe relapsing remitting MS.

As a result of these approvals, natalizumab is now widely used to treat patients with this type of MS: by 2011, over 99,000 people worldwide had been treated and usage has continued to grow. Biogen reported sales of $1.6 billion (an increase of 8%) for 2012, and by 2013 more than 115,000 patients had been treated, with direct - and significant - financial benefits to Biogen, on top of the many benefits to the patients treated.