Natalizumab (Tysabri®) inhibits the migration (transmigration) of inflammatory cells into the central nervous system and was the first monoclonal antibody approved for the treatment of relapsing multiple sclerosis. This was more than 15 years ago and it can rightly be said that Natalizumab was a real “game changer” for the treatment of relapsing MS. A high percentage of patients were stabilized both clinically and by MRI, including and especially patients with more aggressive courses.
Serious Side Effect PML
Given its high efficacy, Natalizumab was also very well tolerated. Headaches, fatigue, joint pain and nausea may occur during the infusion, but are only temporary and do not occur in everyone. Rarely, allergic reactions can occur (as with other infusions of proteins). These allergic reactions are most often observed at the second/third dose – which is why the first infusion cycles should always be carried out in areas with emergency care. If an allergic reaction occurs or if the infusions are generally poorly tolerated, it should always be checked whether a patient has formed antibodies against Natalizumab. These so-called Anti-Drug Antibodies (ADA) are a problem insofar as they neutralize the effect of the substance. In such a case, continuing therapy makes no sense.
More findings on side effects were actually not reported from the approval studies. Therefore, it was all the more disappointing when it turned out that this effective and ultimately well-tolerated drug can be associated with a very serious side effect with prolonged use. Natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection caused by the JC virus. The JC virus is ubiquitously present and usually harmless, the risk of infection increases proportionally with age (so the older you get, the more likely you are positive for the JC virus).
Keep an eye on JC virus and duration of therapy
We now know that the risk of PML is particularly high in MS patients who have tested positive for the JC virus and have been treated with Natalizumab for more than two years. For JCV-positive patients with a JCV antibody index of > 1.5 (for the specific meaning of the JC antibody index DocBlog: Natalizumab – what does the JCV antibody index mean), who have been treated with Natalizumab for longer than 2 years, it is about 1 in 90, while the risk for JCV-positive patients who have been treated for less than 2 years is about 1:1000. To minimize the PML risk in JCV positive patients, administration with extended intervals (Extended Interval Dosing, EID) is recommended as an alternative dosing strategy. EID involves extending the interval between Natalizumab infusions from every 4 weeks to every 5 or 6 weeks. It has been shown that this approach can reduce the risk of PML without compromising the effectiveness of Natalizumab. In JCV-negative MS patients, however, the risk of PML is very low, but not zero.
The risk of PML has led to JCV positive MS patients nowadays hardly being prescribed Natalizumab anymore, even though it is still a very efficient and above all fast-acting drug. In JCV negative MS patients, however, Natalizumab can be used safely, but there is the problem of seroconversion – i.e., negative individuals can be tested positive at some point – and then something must be done to minimize the risk.
One hope for a revival of Natalizumab would be to precisely determine who is at risk for PML and why – and then to forego therapy only in these individuals. Another possibility would be the establishment of a vaccination against the JC virus. It is much more likely, however, that new similarly effective concepts will be approved – as is already the case – and Natalizumab will therefore no longer be needed as urgently as it was a few years ago.
