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Tysabri: reducing the risk of PML with extended interval dosing

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  1. The study in brief
  2. The study in more detail
  3. Find out more about PML
  4. Browse more from the latest research

The study in brief

Tysabri (natalizumab) is very effective for people with highly active relapsing remitting MS but it carries the risk of developing a rare but very serious brain infection called progressive multifocal leukoencephalopathy (PML).

Measures are taken to minimise the risk of PML and monitor for early signs of the infection. It has been suggested that a longer time between infusions might further reduce the risk of PML. But would Tysabri still be effective and how would this suit people who feel that the effects of Tysabri wear off just before their next infusion? Three recently published studies have looked at these issues.

Researchers analysed data collected through the TOUCH program which monitors treatment with Tysabri and PML risk in the United States. Records of 35,521 people were analysed. The risk of developing PML was between 88% and 94% lower for people on EID compared to SID.

To evaluate effectiveness of the two dosing patterns, Italian researchers reviewed medical records from 14 MS clinics and identified 360 people who had taken Tysabri for more than two years. They were grouped according to the average number of weeks between doses; less than 5 weeks, SID; more than 5 weeks, EID. Relapse rates for both groups were very low and the researchers concluded that both dosing patterns were equally effective at reducing relapses.

People taking Tysabri often report that symptoms, particularly fatigue and cog fog, are worse in the days leading up to their next infusion. Dutch researchers studied this in a group of 93 people. Just over a half (54%) of the group had experienced a wearing off effect at some point since they had started taking Tysabri and about one third (32%) reported a wearing off effect at the time of the study. The wearing off effect was more frequently reported with SID (39%) than with EID (19%) and was not associated with reduced Tysabri blood levels or binding to immune cells.

Overall, these studies do suggest that increasing the gap between Tysabri infusions from four to six or eight weeks does reduce the risk of PML, without loss of effectiveness. The wearing off effect was not related to blood levels of Tysabri, and does not appear to increase with EID.

The study in more detail

Background

Tysabri (natalizumab) has proved to be a very effective for people with highly active relapsing remitting MS but it carries a risk of developing a rare but very serious brain infection called progressive multifocal leukoencephalopathy (PML) which can cause severe disability or even death.

Measures are routinely taken to minimise the risk of PML and monitor for early signs and symptoms of the infection. It has been suggested that a longer time between Tysabri infusions (currently every four weeks) would reduce blood levels of Tysabri sufficiently to allow some immune cells to pass into the brain and prevent PML from developing. But with a bigger gap between infusions, would Tysabri still be effective? And how would this suit people who feel that the effects of Tysabri wear off just before their next infusion? Three recently published studies have looked at these issues.

1. Extended interval dosing and PML risk

Researchers analysed data collected through the TOUCH program which monitors treatment with Tysabri and PML risk in the United States. Records of 35,521 people who had a positive test for the JC virus and therefore at risk of developing PML were selected. The investigators used three definitions of extended interval dosing (EID) to identify people who had received less than the official number of infusions and compared their risk of PML with those receiving standard interval dosing (SID).

What was found?

For all three definitions, people who were treated with Tysabri EID were significantly less likely to develop PML. The risk of developing PML was between 88% and 94% lower for people on EID compared to SID. For one definition of EID (people who had received EID for the duration of their Tysabri treatment) there were no cases of PML.

2. Is Tysabri still effective with a longer interval between infusions?

Italian researchers reviewed medical records from 14 MS clinics and identified 360 people who had taken Tysabri for more than two years. People were grouped in two categories according to the average number of weeks between doses; less than 5 weeks, SID; more than 5 weeks, EID.

What was found?

The average relapse rates for SID group was 0.06 relapses per year, for the EID group 0.039 relapses per year. The researchers concluded that both dosing patterns were equally effective at reducing relapses.

3. Do the effects of Tysabri wear off?

People taking Tysabri often report that symptoms, particularly fatigue and cog fog, are worse in the days leading up to their next infusion; would this be worse if the interval between doses was longer? Dutch researchers studied this in a group of 93 people who had received at least six infusions. Participants were asked to complete questionnaires about their symptoms and blood levels of Tysabri were measured just before their next infusion.

What was found?

Just over a half (54%) of the group had experienced a wearing off effect at some point since they had started taking Tysabri and about one third (32%) reported a wearing off effect at the time of the study. The wearing off effect was more frequently reported with SID (39%) than with EID (19%); the duration of symptoms was similar for the two groups. The wearing off effect was not associated with reduced Tysabri blood levels or binding to immune cells.

What does it mean?

Overall, the studies do suggest that increasing the gap between Tysabri infusions from four to six or eight weeks does reduce the risk of PML, without loss of effectiveness. The wearing off effect does not appear to be related to blood levels of Tysabri, and does not appear to increase with EID.

Some commentators were surprised by the dramatic reduction in PML risk achieved by a small difference in dosing intervals and have urged caution in drawing conclusions from the study. One explanation could be that the JC virus that causes PML is very susceptible to a small increase in the number of immune cells passing into the brain.

Another criticism was that these studies are retrospective, in other words they use historical medical records, which can introduce bias into the results. To obtain more reliable data, a new study is recruiting 480 participants to compare the effectiveness of Tysabri SID and EID over two years, measuring relapse rates, lesions seen on MRI scans and disability worsening. The number of participants in the study will be too small to give data on the risk of PML; because PML is a rare side effect, it can be evaluated only by analysing data from thousands of people.

Ryerson LZ, et al.
Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing.
Neurology 2019;93(15):e1452-e1462.
Read the full study

Clerico M, et al.
Extending the interval of natalizumab dosing: is efficacy preserved?
Neurotherapeutics. 2019 Aug 26. [Epub ahead of print]
Read the summary

van Kempen ZLE, et al.
The natalizumab wearing-off effect: end of natalizumab cycle, recurrence of MS symptoms.
Neurology. 2019 Oct 22;93(17):e1579-e1586.
Read the full study

Find out more about PML

The JC virus is a common infection carried by the majority of the general population and completely unrelated to MS. The JC virus is normally kept under control by the immune system and does not cause any problems.

However, if your immune system is weakened, the JC virus can become active and cause inflammation and damage to the brain, known as progressive multifocal leukoencephalopathy (PML).

Treatment with some of the more effective disease modifying drugs, in particular Tysabri (natalizumab), but also very rarely Gilenya (fingolimod) and Tecfidera (dimethyl fumarate) can increase the risk of developing PML. This is because they work by suppressing your immune system.

Several factors are known to increase the risk of developing PML while taking Tysabri:

  • Infection with the JC virus – this can be detected with a blood test
  • Amount of JC virus antibody (titre) in your blood
  • Previous treatment with other drugs which suppress the immune system
  • How long you have been taking Tysabri (risk increases after two years)

With different combinations of these factors the risk of developing PML ranges from less than 1 in 10,000 up to 1 in 125.

Read more about JC virus and PML

Browse more from the latest research

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