Natalizumab: a potent treatment for highly active relapsing-remitting multiple sclerosis
Submitting InstitutionUniversity College London
Unit of AssessmentPsychology, Psychiatry and Neuroscience
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Neurosciences
Summary of the impact
Multiple Sclerosis (MS) is the most common disabling neurological disease
of young adults in the UK, affecting 1 in 800 of the population. In most
patients the early years are characterised by relapse and remissions;
relapses are often disabling and permanent disability occurs when
remissions fail to recover fully. Research at the UCL Institute of
Neurology — from early MRI studies through phase 1-3 clinical trials — has
resulted in the licensing of natalizumab for highly active relapsing
remitting MS. Natalizumab is now widely used to treat such patients with
very good efficacy and close monitoring. Natalizumab is a potent treatment
that has reduced relapse rate by two-thirds and relapse-related disability
by 50%. By July 2013, over 115,000 patients around the world had received
Serial magnetic resonance imaging (MRI) studies at the Institute of
Neurology showed that blood-brain barrier (BBB) breakdown is a key early
event in new lesion formation in relapsing remitting MS , and
the work of the Unit played a lead role in defining protocols for using
MRI in proof-of concept trials of potential new disease modifying
treatments . The evidence for the important role of BBB leakage
provided a rationale for investigating natalizumab, a monoclonal
anti-adhesion molecule antibody that was shown to prevent trafficking of
mononuclear white blood cells from blood to brain in an experimental model
Members of the Nuclear Magnetic Resonance (NMR) Unit, led by Professor
David Miller, 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 phase 1/2a study was a UK-based, parallel-group, placebo-controlled
trial in which Miller was the principal investigator. Study subjects
received two doses of placebo or natalizumab one month apart and were
followed up with regular MRI scans for six months. The study reached its
primary end point: the adjusted mean cumulative number of new active
lesions was lower after three months in the natalizumab-treated group than
in the placebo group (1.8 vs 3.6; P=.04, analysis of covariance) .
In an accompanying editorial, the trial finding was described as a "near
hit." Had the study not reached its primary end point, one could speculate
that it would have been a near miss and that the drug would not have been
A subsequent phase 2b multicentre, multinational study was undertaken in
patients with relapsing remitting MS or secondary progressive MS that
tested placebo vs. natalizumab in two doses given intravenously every
month for six months, followed by a six-month observation, and was
robustly powered to detect an effect on MRI lesion activity. This study
demonstrated profound (90%) suppression of new gadolinium-enhancing
lesions during a six-month treatment phase. Although not powered to do so
it showed a significant reduction in relapse rate in the
natalizumab-treated arms. Magnetic resonance imaging activity returned to
baseline levels during the six-month post-treatment observation period .
Together with Dr Gavin Giovannoni (also UCL), Miller was leading
investigator in the large phase 3, multicentre, placebo-controlled trial
that followed, with Miller's group providing central MRI analysis for the
trial. This trial showed that natalizumab treatment was associated with a
two-thirds reduction in relapse rate compared with placebo and a reduction
in the accumulation of disability by 50% . It also reduced the
rate of new lesion formation by ~90%.
The phase 3 trials of natalizumab did, however, identify a serious
adverse effect: about one person in 1,000 developed progressive multifocal
leucoencephalopathy (PML), a severe and sometimes fatal viral brain
disease. Professor Tarek Yousry (Department of Brain Repair and
Rehabilitation, UCL Institute of Neurology) led an international group
that defined the risk for PML  and he and Miller have since
contributed to subsequent guidelines for monitoring natalizumab-treated
patients for early detection of PML. Risk counselling and monitoring for
PML is an extremely important part of current treatment with natalizumab
and is discussed in a recent review by Miller and Dr Jeremy Chataway (also
References to the research
 Miller DH, Barkhof F, Nauta JJP. Gadolinium enhancement increases the
sensitivity of MRI in detecting disease activity in multiple sclerosis.
Brain. 1993 Oct;116(Pt. 5):1077-94.
 Miller DH, Albert PS, Barkhof F, Francis G, Frank JA, Hodgkinson S,
Lublin FD, Paty DW, Reingold SC, Simon JH. Guidelines for using magnetic
resonance techniques in monitoring the treatment of multiple sclerosis.
Annals of Neurology. 1996 Jan;39(1):6-16.
 Tubridy N, Behan PO, Capildeo R, Chaudhuri A, Forbes R, Hawkins CP,
Hughes RAC, Palace J, Sharrack B, Swingler R, Young C, Moseley IF,
MacManus DG, Donoghue S, Miller DH, and the UK Antegren Study group. The
effect of anti-alpha-4 integrin antibody on brain lesion activity in MS.
Neurology. 1999 Aug;53(3):466-72. http://dx.doi.org/10.1212/WNL.53.3.466
 Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice G, Libonati LA,
Wilmer-Hulme A, Dalton C, Miszkiel K, O'Connor PW. A controlled trial of
natalizumab for relapsing multiple sclerosis. N Engl J Med. 2003 Jan
 Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller
DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara
MA, Sandrock AW; AFFIRM Investigators. A randomized, placebo-controlled
trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006
Mar 2;354(9):899-910. http://dx.doi.org/10.1056/NEJMoa044397
 Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J,
Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E, Barkhof F, Radue EW,
Jäger HR, Clifford DB. Evaluation of patients treated with natalizumab for
progressive multifocal leukoencephalopathy. N Engl J Med. 2006 Mar
The MS NMR Research Unit at UCL Institute of Neurology has received
continuous peer-reviewed programme grant support since 1990 from the UK MS
Society to support MR imaging research in MS. The Unit has also been
supported during this time by peer-reviewed project, fellowship, PhD and
other smaller grants from multiple bodies including the Wellcome Trust,
Medical Research Council, UK National Institute for Health Research and US
National MS Society. The funded research has underpinned the development
of imaging protocols that are now routinely used to identify potential new
disease-modifying treatments for MS.
Details of the impact
Multiple sclerosis (MS) is the most common disabling neurological disease
of young adults in the UK, affecting 1 in 800 of the population. It is
associated with high health care 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 proved to have only limited effectiveness in preventing relapses and
with only equivocal effects on related disability, and there remained a
pressing need for more effective treatments. Furthermore, a NICE
technology appraisal in 2002 found that these first-line treatments were
not cost effective for use in the NHS and since then they have only been
available to treat MS patients through a unique Department of Health Risk
Sharing Scheme that was designed to ensure, through long term monitoring
over ten years of a large patients cohort (2002-15), that cost
effectiveness is achieved.
Following the pivotal phase 3 trial of natalizumab described
above, a full UK National Institute of Health and Clinical Excellence
(NICE) technology appraisal of natalizumab was undertaken in 2007. The
outcome was that natalizumab became the first NICE-recommended
disease-modifying treatment for MS available in the UK National Health
Service. The drug was also approved by regulatory authorities for the
treatment of active relapsing remitting MS in many countries around the
world (see full details below).
Key impacts: benefits for MS patients
The following major clinical benefits of natalizumab for people with MS
were identified in the phase 3 trial [see 5, above]:
- Relapse rate was reduced by two thirds in natalizumab-treated compared
to placebo-treated patients; in a subgroup of patients with highly
active relapsing remitting MS (who had had at least two relapses in the
prior 12 months), the reduction in relapse rate achieved by natalizumab
was 81%; furthermore, natalizumab reduced the rate of hospitalisations
by 64% and the need of steroid treatment for relapses by 69% [a].
- 50% fewer people treated with natalizumab developed a persistent
increase in disability when compared with those treated with placebo.
This reduction in disability accrual was even higher at 64% in the
subgroup with highly active disease. Natalizumab is the first treatment
for MS to show a large and unequivocal effect in preventing irreversible
disability. A substantial number of natalizumab-treated patients
actually experienced a reduction in their level of disability when
compared with their status before entering the trial.
- Clinically significant visual loss during the trial was reduced by 35%
in natalizumab-treated patients compared to placebo, and overall visual
function remained stable in natalizumab-treated patients whereas it
deteriorated in placebo-treated subjects [b]
- Health-related quality of life, which is often substantially impaired
in people with MS, was significantly improved in patients treated with
natalizumab [c]. The improvements were seen in both physical and
mental components of quality of life measures.
- Natalizumab also reduced the risk of a confirmed worsening of
cognitive function by 43% compared with placebo [a].
Licensing and prescription of natalizumab
Following the phase 3 clinical trials, natalizumab (trade name Tysabri)
was granted regulatory approval in the United States (FDA, 2006) [d],
European Union (EMEA, 2006) [e], Canada [f] and Australia
[g]. It was recommended in 2007 by the UK National Institute for
Health and Clinical Excellence as a clinically and cost effective
treatment in the NHS for patients with rapidly evolving severe relapsing
remitting MS [h]. The Medical Director (UK) at Biogen (the
manufacturers of natalizumab) has confirmed that there is "No doubt
that the input from Dr Miller's research collaboration was an important
contribution to the regulatory license application for Marketing
approval by the relevant regulatory authorities" [i].
As a result of these approvals, natalizumab is now widely used to treat
patients with highly active relapsing remitting MS. By December 2011, over
99,000 people worldwide had been treated with natalizumab [j].
Since that time, usage has continued to grow, with Biogen reporting sales
of $1.6bn (an increase of 8%) for 2012 [k]. By July 2013, over
115,000 patients had been treated [l].
As well as the direct financial benefits to Biogen in terms of sales, the
licensing of natalizumab has resulted in increased employment and economic
benefits in the US and Europe [m].
Contribution to guidelines
Due to the rare complication of PML, natalizumab is largely used as a
second-line treatment in highly active MS. Guidelines have been developed
for treatment and monitoring of people who are treated with natalizumab
and Yousry and Miller have contributed to these guidelines [n]. A
key part of clinical monitoring of patients treated with natalizumab is to
perform regular MRI scans looking for evidence of PML. Yousry has headed
an international panel that has identified the radiological features
typical of PML in natalizumab-treated patients; the panel has also
recommended MRI protocols for monitoring patients [o].
Sources to corroborate the impact
[a] Weinstock-Guttman B, Galetta SL, Giovannoni G et al. Additional
efficacy endpoints from pivotal natalizumab trials in relapsing-remitting
MS. J Neurol 2012;259:898-905.
[b] Balcer LJ, Galetta SL, Calabresi PA et al. Natalizumab reduces visual
loss in patients with relapsing multiple sclerosis. Neurology
[c] Rudick RA, Miller D, Hass S, et al.; AFFIRM and SENTINEL
Investigators. Health-related quality of life in multiple sclerosis:
effects of Natalizumab. Ann Neurol. 2007;62:335-46.
[d] FDA approval:
[e] EMEA approval: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000603/WC500044686.pdf
[f] Canadian approval: http://www.health.gov.on.ca/en/pro/programs/drugs/ced/pdf/tysabri2.pdf
[g] Australian approval: http://www.mssociety.org.au/documents/TreatmentsForMS-Tysabri-natalizumab.pdf
[h] NICE guidelines: http://www.nice.org.uk/nicemedia/live/11822/36136/36136.pdf
[i] Email from Biogen. Copy available on request.
[j] Data from drug company website: http://www.tysabri.com/treating-multiple-sclerosis.xml
"Last year (2012), Tysabri sales were $1.6 billion, up 8% from 2011."
[l] Chalkley JJ, Berger JR. Progressive multifocal leukoencephalopathy in
multiple sclerosis. Curr Neurol Neurosci Rep. 2013 Dec;13(12):408. http://dx.doi.org/10.1007/s11910-013-0408-6.
[m] Kappos L, Bates D, Hartung HP, Havrdova E, Miller D, Polman
CH, Ravnborg M, Hauser SL, Rudick RA, Weiner HL, O'Connor PW, King J,
Radue EW, Yousry T, Major EO, Clifford DB. Natalizumab treatment
for multiple sclerosis: recommendations for patient selection and
monitoring. Lancet Neurol. 2007;6:431-41. http://dx.doi.org/10.1016/S1474-4422(11)70149-1
[n] Yousry TA, Pelletier D, Cadavid D, Gass A, Richert ND, Radue
EW, Filippi M. Magnetic resonance imaging pattern in
natalizumab-associated progressive multifocal leukoencephalopathy. Ann
Nerol. 2012;72:779-87. http://dx.doi.org/10.1002/ana.23676
"Biogen Idec's production facilities in Hillerød (Denmark) are
preparing for production of TYSABRI® in 2013. The production facility,
which is identical to and has the same production capacity as Biogen's
facility in North Carolina, USA, will deliver to Biogen's market outside
the USA. The present staff numbers about 180 and will be increased by
120 new employees ...."