Tysabri® (Natalizumab) is undoubtedly a very effective and well-tolerated drug for the treatment of active Multiple Sclerosis. Many patients have benefited from the treatment in the past and were satisfied with the effects and individual therapeutic success. Unfortunately, Natalizumab has one significant and serious side effect – patients with positive JC virus detection in the blood carry the risk of progressive multifocal leukoencephalopathy (PML) due to the JC virus.
The risk of this severe viral disease of the brain can increase up to approximately 1:100 depending on individual circumstances – this cannot be overlooked. Therefore, many patients, as well as many of their attending neurologists, despite the often good therapeutic effect, want to get rid of the drug as quickly as possible. But this is not so simple, because there are not so many alternatives with such good efficacy – and also when switching to another preparation there are some things to consider. Therefore, discontinuing Natalizumab therapy often results in problems.
For this reason, scientists are doing a lot to reduce the PML risk of JC virus-positive Natalizumab patients. One approach is the “extended interval dosing” – i.e., extending the dose intervals. Natalizumab is typically given every four weeks as an infusion with 300 mg, regardless of how large or heavy a patient is. It has been known for some time that this regime is more than sufficient to saturate the target structure of Natalizumab (VLA4 on the surface of activated lymphocytes), for small and light people this dose can be described as very “generous”.
Therefore, scientists in the USA have investigated some time ago whether the PML risk can possibly be reduced by extending the dose intervals beyond the usual 4 weeks. During these investigations, it was observed that the group of patients who had received Natalizumab less often than every 4 weeks actually had fewer cases of PML. However, the sample size was too small to reliably answer this important question.
Nevertheless, the approach was so interesting that the manufacturer, together with the aforementioned American scientists, examined a large Natalizumab database in this regard. This database – the so-called TOUCH register – includes more than 90,000 MS patients, of whom over 35,000 were positive for the JC virus. In these “risk patients”, three different definitions were then applied, distinguishing treatment with extended dosing intervals (>5 and < 12 weeks) from standard dosing (> 3 and < 5 weeks).
The result of this investigation was presented at the last meeting of the American Academy of Neurology (AAN) in Los Angeles and showed that the extended dosing interval (EID = extended interval dosing) is associated with a clinically and statistically significantly lower PML risk than the standard dosing (SID = standard interval dosing) in Anti-JC Virus (JCV) antibody-positive patients. In most cases, patients switched to the extended dosing interval after about 2 years, with the average dosing interval for EID being 35-43 days compared to 30-31 days for SID.
The problem is that the TOUCH registry does not capture efficacy data – therefore it cannot be definitively stated whether the efficacy of Natalizumab is maintained with the extended dosing interval. Further prospective studies are required for this. However, it is also expected – considering the previous clinical experience – that an extension of the dosing interval by about 2 weeks will probably have no impact on the effect of Natalizumab.
So how should we deal with these data? The problem of PML is not solved by this observation, of course. On the other hand, these data are so interesting that one cannot avoid considering an extended dosing interval. I think it could help to alleviate pressure in JCV-positive patients. In case of a desire to switch medication, one could certainly first extend the dosing intervals and thereby possibly gain some time to plan the switch. Perhaps there will even be some patients who feel safe continuing Natalizumab with extended dosing and appropriate safety checks.
Nevertheless, it would be desirable, especially in view of the efficacy of Natalizumab, if we had stable parameters in the future to minimize the individual PML risk.
