Natalizumab, also known as Tysabri, is an important addition to the therapies available for treating serious, active multiple sclerosis.
How does it work?
Natalizumab works by specifically targeting and inhibiting alpha 4 integrin - a protein present on the surface of immune system cells. This protein helps them attach to blood vessel walls and enter the brain.
The drug has been used in the animal model of MS, where it is effective, and in human studies.
Recent animal work shows that inhibiting alpha 4 integrin, not only reduces damage to myelin (demyelination) but also allows the body to repair or replace previously damaged myelin sheaths (remyelination).
The difficulty with drugs of this type is that they don’t just affect the immune response in MS, but in all conditions where immune response is required.
As a result, they tend to cause other problems related to underactivity of the immune system.
In a 2003 study published in in the New England Journal of Medicine, a randomized controlled trial on Tysabri in MS randomly assigned 213 patients to receive a low dose, a high dose, or a placebo.
The drug was given intravenously once every 4 weeks for 6 months. Patients were followed with MRI scanning and clinical assessment, which found at the end of the 6 months that:
- The placebo patients had on average nearly 10 new brain lesions
- The low-dose group had 0.7 new brain lesions
- The high-dose group had just over 1 new lesion.
Twice the number of patients in the placebo group had relapses than in either of the treatment groups.
Those taking the drug generally reported improvement in their sense of well-being, and those in the placebo group reported the reverse.This suggests the drug is well tolerated and its side effects are not too unpleasant.
At the meeting of the American Academy of Neurology in Honolulu in 2003, findings were presented on a number of related drugs that had proven beneficial for people with MS.
Other related drugs
Unfortunately, side effects were a major problem, with a third of patients treated developing Graves’ disease, a severe thyroid disorder, and many others developing an autoimmune blood-clotting disorder.
This drug was licensed for use in MS in several countries as Lemtrada. On 12th April 2019, the European Medicines Agency recommended a temporary restriction on the use of Lemtrada.
Another related drug, daclizumab (trade name Zenapax), looked more promising.
Two US groups reported results in 10 and 11 patients with relapsing-remitting and secondary progressive MS, either alone or in combination with interferon beta, with dramatic effects on MRI-demonstrated disease activity.
One group found no new lesions and the other found more than a 70% reduction in the number of lesions.
But the Tysabri MS story has been soured by events which led the US FDA to remove the drug from general use just three weeks after fast-tracking it to market in November 2004.
Two patients who had taken natalizumab in combination with an interferon in MS trials developed a condition called progressive multifocal leukoencephalopathy (PML).
This illness is similar to very aggressive MS, and it had previously only been reported in AIDS patients.Shortly after, a third patient, taking natalizumab alone in a trial for inflammatory bowel disease, died of the illness.
Following suspension, there was very careful investigation of all patients who had taken the drug in clinical trials to see if there were any unreported cases of PML.
This detailed review revealed no new cases and concluded that the risk of PML was about 1 in 1,000 for patients treated for about 18 months. The longer-term risk was unknown.
At around the same time, two further Tysabri MS papers were published, one featuring Tysabri in combination with an interferon, the other alone.
The former was the trial in which the 2 cases of PML were initially discovered. It showed that the combination of natalizumab and interferon was significantly better than interferon alone, with the annual relapse rate dropping to 0.34 per year on the combination, compared with 0.75 on the interferon alone, and less progression to disability.
In the latter study, 627 patients receiving natalizumab alone had a 68% reduction in annual relapse rate, as well as less progression to disability, than those receiving placebo.
More recent MRI studies confirm that natalizumab is highly effective at preventing new MRI lesions, with between 76% and 92% fewer lesions (depending on lesion type) in those on natalizumab versus placebo.
Recent updates from the company reported through the National Multiple Sclerosis Society website in 2009, reveal that, out of the 60,700 people worldwide receiving the drug, there had at that point been 24 cases of PML in both men and women receiving Tysabri from 1 year to 3.5 years, with an average of 2 years.
It was reported that 16 cases had occurred in Europe and 8 in the US, and that 4 of the 24 people had died.
Among the 20 survivors, some recovered enough to return to work, while at the other extreme, some were markedly disabled and confined to bed, requiring extensive assistance with daily living.
Five years later, a study released in March 2014 noted that since Tysabri’s return to the U.S. market in 2006, upwards of 440 cases of PML have been reported in patients taking the drug.
Conducted at the U.S. National Institute of Neurological Disorders and Stroke, the study noted that 30% to 50% of patients with PML die within a few months of diagnosis.
The study found that in patients taking Tysabri, the ‘JC virus,’ which is usually harmless, attacks the brain’s white matter, stripping insulation from nerve cells so they can’t transmit brain signals. Testing patients for the JC virus may help predict who is at risk for PML.
It is important that people taking this drug, and their doctors as well, be vigilant for any occurrence of new, unusual symptoms that might indicate PML.
It is currently impossible to predict who will get PML, although half the people who developed it had previously been on immunosuppressive therapies such as mitoxantrone, azathioprine or methotrexate.
When PML was suspected, Tysabri infusions were stopped.
There is no treatment for PML, but once the drug is stopped, as the immune system begins to recover, a condition called IRIS (immune reconstitution inflammatory syndrome) usually occurs about 4 weeks later.
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