Extending the Infusion Intervals of Tysabri – a Sensible Measure in MS?

Tysabri (active ingredient Natalizumab) is given for (highly-) active Multiple Sclerosis every 4 weeks. Recently, it has been frequently mentioned that extending the infusion interval – often the number 8 weeks is mentioned – reduces the risk of PML. What’s behind this statement? First of all, it must be said that this statement is certainly too general. On the other hand, there is a very interesting scientific discussion behind this topic. In fact, with increasing duration of therapy, the plasma levels of Tysabri continuously increase. To achieve sufficient saturation of Tysabri’s target structure (Tysabri binds to the VLA-4 molecule on the surface of T-lymphocytes, preventing these cells from migrating into the central nervous system), plasma levels of 1 µg/ml are required, which are still detectable at this level 8 weeks after a Tysabri infusion.
A multicentric American study therefore compared the data of Tysabri patients who had received the drug either in its standard dosage (every 4 weeks) or with extended infusion intervals (more than 4 weeks and less than 8 weeks). The results of the studies were recently presented to a wider audience. There was no difference in effect between the two groups in terms of relapse rate reduction and suppression of MR activity. Interestingly, however, the occurrence of PML in the group with extended infusion intervals was lower than expected, even though the group with extended infusion intervals had a higher proportion of JCV-positive patients and patients with prior immunosuppressive treatment, and the group also had a longer average duration of therapy. So this group ultimately had more risk factors for the occurrence of PML than the group that was infused according to the standard protocol and yet showed a lower PML incidence than expected. This is undoubtedly an interesting observation.
Does this mean that Tysabri should generally be administered at longer intervals? Rather no, because one must bear in mind that the results are based only on a small sample, even if each study group comprised almost 1,000 patients. It is still too early to make a final recommendation – one should, as the authors of the study also recommend, wait and continue to collect and evaluate the data. If the preliminary results now reported remain stable, then indeed a fundamental change in the dosage intervals would have to be made. Until then, however, it is advisable not to propagate any fundamental changes, as the study data on effects and side effects of the substance are based on the 4-weekly infusion interval.
The study does show, however, that it is possible in individual cases to extend the interval to 8 weeks without loss of effect, e.g. if a 4-weekly administration is not possible due to scheduling difficulties (vacation, stay in a rehab center etc.). Of course, against the background of the reported results, one can understand that some colleagues, especially in risk patients (JCV positive, high JCV index, long duration of therapy), apply an extended dosage interval. However, at this point in time this should be an individual decision. A general propagation of an extended interval is not yet indicated from my point of view due to the considerations mentioned above.