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Natalizumab (Tysabri) - factsheet

Revised: October 2008


1. Introduction

Natalizumab (Tysabri) is the first in a new class of drugs known as selective adhesion molecule (SAM) inhibitors. It is also the first monoclonal antibody to be licensed for MS, although monoclonal antibodies are licensed for use in other areas such as cancer. Antibodies are proteins produced by the immune system to fight foreign substances, such as infections. Monoclonal antibodies can be produced in large quantities in cell culture in a laboratory. They can be designed to bind to proteins on the body's normal cells, altering the immune response.

In MS, it is believed that immune cells pass through the blood-brain barrier into the central nervous system (brain and spinal cord) where they can cause inflammation and potentially damage nerves and their surrounding myelin sheath. Adhesion molecules on the surface of immune cells play an important role in this process. Natalizumab binds to a specific adhesion molecule on the immune cell surface known as alpha-4 integrin and it is thought to act by preventing the cells from passing into the central nervous system via the blood-brain barrier.


2. Natalizumab approved in the European Union

In June 2006, the European Commission approved the marketing of natalizumab as a single disease modifying therapy for relapsing/remitting MS to prevent relapses and delay progression of disability. However, in practice, treatment with natalizumab has been restricted to the following patient groups:

  • people with highly active relapsing/remitting MS who have failed to respond to treatment with beta interferon (sub-optimal therapy group). Patients should have had at least one relapse in the previous year whilst on therapy and have evidence of lesions on their MRI scan; or
  • people with rapidly evolving severe relapsing/remitting MS (RES group). Defined as having two or more disabling relapses in one year and with evidence of increasing lesions on two consecutive MRI scans.

Treatment has been restricted to the above groups due to safety concerns (see section 2.2).


2.1. Assessment of natalizumab for availability on the NHS

2.1.1. England and Wales

On 3 July 2007, NICE published their decision around access to natalizumab on the NHS in England and Wales. The Final Appraisal Determination (FAD) states that:

'Natalizumab (Tysabri) is recommended as an option for the treatment only of rapidly evolving severe relapsing-remitting multiple sclerosis (RES). RES is defined by two or more disabling relapses in one year, and one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared with a previous MRI.

People currently receiving natalizumab, but for whom treatment would not have been recommended according to section 1.1 of this guidance, should have the option to continue therapy until they and their clinicians consider it appropriate to stop.'

This means that anyone currently receiving natalizumab in England and Wales should continue to get it until their neurologist considers it is no longer being effective. From now natalizumab should also be available to individuals who experience multiple disabling relapses in one year, where their neurologist considers it is the most appropriate treatment.

The full guidance can be found on the NICE website.


2.1.2. Scotland

On 10 September 2007, the Scottish Medicines Consortium (SMC) announced that they had approved natalizumab for use within NHS Scotland.

As in England and Wales, use of natalizumab is restricted to the people with rapidly evolving severe relapsing-remitting multiple sclerosis.

The full guidance can be found on the Scottish Medicines Consortium website

The MS Trust is delighted with these Determinations, as it will allow people with this severe form of MS access to treatment. We are also pleased that both NICE and SMC listened to rational argument from ourselves and others, in overturning their preliminary recommendations that natalizumab was not considered to be cost-effective, and are now supportive of natalizumab being available on the NHS.


2.1.3. Northern Ireland

Under a previous administration, the Northern Ireland health minister confirmed that they would follow the NICE decision on funding, and we anticipate that the current government will honour that commitment.


2.2. Safety concerns - natalizumab and PML

The Food and Drug Administration (FDA), the body that regulates drugs in the USA, granted the first licence for natalizumab in November 2004 for the US market. However, the drug was voluntarily withdrawn from the US market and European clinical trial programme only three months later. This followed reports of two cases, one fatal, of progressive multifocal leukoencephalopathy (PML) in two patients who had received natalizumab in combination with Avonex as part of a two-year clinical trial.

PML is a rare demyelinating disorder of the central nervous system (brain and spinal cord) that primarily affects individuals with a weakened immune system, for example transplant recipients and individuals with Aids. Symptoms include vision and speech problems, ataxia and eventually paralysis. PML is a very aggressive condition for which there is no known effective treatment. Although not always fatal, it can cause death as little as one to six months after onset of symptoms.

In light of the two cases of PML, the manufacturers initiated a safety review of all natalizumab clinical trial patients. They also worked with experts in PML and neurology to better understand the potential risk of PML and reviewed all the clinical data from the patients involved in their MS, Crohn's disease and rheumatoid arthritis trials.

The review identified a third case of PML, which involved a patient who had received natalizumab in an open label trial in Crohn's disease. The patient, who died in December 2003, was originally diagnosed with a form of brain cancer. When the case was re-examined as part of the review, the diagnosis was reassessed as PML.

The natalizumab safety evaluation is now complete and the data was published in March 2006[1]. No further cases of PML were found in the 2,000 people involved in the MS clinical trials or the 1,500 patients who participated in the Crohn's disease and rheumatoid arthritis trials.

Following the completion of the safety evaluation, the FDA authorised the return of natalizumab to the US market in June 2006. However, because there is not enough information about how the use of other immune modifying drugs with natalizumab could affect the risk of developing progressive multifocal leukoencephalopathy (PML) or other opportunistic infections, a series of restrictions were imposed as to the groups of patients eligible for treatment. These restrictions are similar to those that were also adopted in Europe.

Two further cases of PML were identified in Europe in July 2008 and a third in the USA in October 2008 - the first instances since the safety review. Each had been treated with natalizumab monotherapy for between 14 and 17 months. Two had histories of previous treatment with immune suppressing drugs.

While these cases bring the total of people developing PML to six, they do not change the risk profile currently reflected in the license; nor do they warrant a change in the treatment recommendations.

To put these cases into perspective, a recent quantitative risk-benefit analysis of natalizumab that modelled the long-term risks and benefits of the therapy in individuals with relapsing/remitting MS, indicated that the health gains or benefits outweigh the risks by a ratio of 7:1[2].


2.3. PML and the beta interferons

The two people with MS who developed PML were also taking Avonex as part of the trial. Therefore, the FDA reviewed its post-marketing safety databases* of patients on beta interferon to determine whether any cases of PML had been reported in patients receiving Avonex or any other beta interferon drug alone. It has not found any cases in more than 10 years of post-marketing data.

*Note - Post-marketing databases contain information from studies that are conducted after a product has been approved for marketing. They are used to gather additional information about a product's safety, efficacy or optimal use. They can also be used to demonstrate clinical benefit of a product following accelerated approval.


2.4. Natalizumab and potential risk of liver injury

Following regulatory review of the drug either side of the Atlantic, a liver damage warning was added to the prescribing information for natalizumab. Patients receiving natalizumab therapy need to be made aware of the potentially increased risk of liver damage while health professionals are urged to be extra vigilant in monitoring for liver function abnormalities. Signs of liver damage or hepatoxicity are indicated by an increased count of serum hepatic enzymes and elevated levels of bilirubin. Liver function generally recovers when therapy is stopped.


3. Clinical trials of natalizumab in MS

The FDA originally granted a licence following accelerated approval based on positive one-year results from two large phase III trials^ of natalizumab in MS:

  • The AFFIRM trial evaluated the effect of natalizumab on the progression of disability and the rate of clinical relapses.
  • The SENTINEL trial evaluated the effect of the addition of natalizumab treatment in participants who were receiving Avonex.

As part of the initial approval process, the manufacturers were required to continue the trials for a further year as originally planned. Both trials are now complete and the results have been published[3,4].


3.1. AFFIRM trial results

AFFIRM was a two-year, randomised, multi-centre, placebo-controlled, double-blind study of 942 people conducted in sites in America, Europe and Australasia. Participants received either a 300mg intravenous (IV) infusion dose of natalizumab or placebo every four weeks.

The two-year data showed that natalizumab reduced the rate of clinical relapses by 67% relative to placebo[3]. The annualised relapse rate was 0.22 for people on treatment compared with 0.67 for those receiving placebo. The proportion of people who remained relapse free was 67% in the treatment group compared to 41% in the placebo group.

Natalizumab treatment also reduced the risk of progression of disability. After two years, 29% of placebo-treated patients had progressed, compared to 17% of natalizumab-treated patients. Progression was pre-defined as at least a one-point increase in the Expanded Disability Status Score (EDSS) sustained for six months.

Benefits were also seen on the Quality of Life (QoL) measures used in the study. A significant improvement was observed on both the physical wellbeing and mental wellbeing components of the Short Form-36 Health Survey (SF-36). General wellbeing also increased, as measured on a Visual Analogue Scale (VAS).


3.2. SENTINEL trial results

SENTINEL was a two-year, randomised, multi-centre, placebo-controlled, double-blind study of 1,171 people taking Avonex (beta interferon 1a) who continued to experience disease activity. Participants received either natalizumab or placebo in addition to Avonex.

At two years, the addition of natalizumab to Avonex resulted in a 24% reduction in the risk of disability progression compared to the effect provided by Avonex plus placebo[4]. The trial data also revealed a 56% reduction in the rate of clinical relapses in those receiving natalizumab plus Avonex compared with those receiving Avonex plus placebo. The reduction in relapse rate was statistically significant and sustained over the two-year period. Improvements in QoL were also observed in this study.


3.3. Safety extension study

Following their suspension in February 2005, clinical trials of natalizumab were allowed to restart in March 2006. The first participants have already been enrolled and dosed in an open-label, multi-centre natalizumab monotherapy safety extension study programme in MS. People with MS who previously participated in the phase III trials and subsequent safety evaluation are eligible to be screened for entry into this study. Sites throughout the United States, Europe, Canada, Australia, New Zealand and Israel are enrolling participants in this study.


4. References

  1. Yousry TA, Major EO, Ryschkewitsch C, et al.
    Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy.
    New England Journal of Medicine 2006; 354(9): 924-933.
  2. Thompson JP, Noyes K, Dorsey ER et al.
    Quantitative risk-benefit analysis of natalizumab.
    Neurology 2008; 71(5): 357-364.
  3. Polman CH, O'Connor PW, Havrdova E, et al.
    A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.
    New England Journal of Medicine 2006; 354(9): 899-910.
  4. Rudick RA, Stuart WH, Calabresi PA, et al.
    Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.
    New England Journal of Medicine 2006; 354(9): 911-923.

5. Further reading

Reports of earlier stages of research on natalizumab and MS are also available.

  • O'Connor P, Miller D, Riester K, et al.
    Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis.
    Multiple Sclerosis 2005; 11(5): 568-572.
  • O'Connor PW, Goodman A, Willmer-Hulme AJ, et al.
    Randomized multicentre trial of natalizumab in acute MS relapses: clinical and MRI effects.
    Neurology 2004; 62(11): 2038-2043.
  • Miller DH, Khan OA, Sheremata WA, et al.
    A controlled trial of natalizumab for relapsing multiple sclerosis.
    New England Journal of Medicine 2003; 348(1): 15-23.
  • Minagar A, Sheremata WA, Vollmer TL, et al.
    Reduction of relapses in multiple sclerosis after anti-alpha4 integrin antibody (natalizumab).
    International Journal of MS Care 2000; 2(1): 2.

^ Note - Drug trials

Phase I studies primarily assess the safety of a drug or procedure. They usually involve a small number of healthy volunteers (10-100) all of whom are given the same treatment.

Once a medical intervention has been proven safe, phase II trials test its effectiveness and whether it has the potential to be of benefit. These trials are larger, typically involving 100-300 people with the condition for which the intervention has been developed - in this case MS.

If the phase II study shows the treatment to be beneficial, phase III studies are conducted to gain a definitive understanding of the effectiveness, benefits and potential side effects in a large group of people (300-3,000) with the condition to be treated. Interventions have to successfully complete a phase III trial before they can be considered for a licence by regulatory authorities.