These days, Ponvory® (Ponesimod), another drug from the group of S1P modulators for the treatment of relapsing MS, has arrived in pharmacies. This group includes, in addition to the “mother substance” Fingolimod, also Siponinmod and Ozanimod – with Siponimod only having been tested in SPMS patients and only being approved in Europe for this group of patients. All S1P modulators approved for MS therapy have common side effects. All remaining S1P modulators have in common that they were better in terms of their effectiveness than established comparative substances. In the case of Fingolimod (Gilenya®) and Ozanimod (Zeposia®) as Interferon-beta 1a i.m. (Avonex®) and in the case of the new Ponesimod (Ponvory®) they were more effective than Teriflunomide (Aubagio®). Accordingly, it is also welcome that both Ozanimod and the new Ponesimod have been approved as “first line” therapy for relapsing MS, so they can be prescribed directly at diagnosis. With Fingolimod, there was more restraint in 2011. Back then, the experience was still less, which is why Fingolimod is only approved for use after the failure of a first-line therapy. For very active patients, it can of course also be given from the start. This progress in terms of approval is very welcome. (Profiles and animation films of all approved MS therapies on www.amsel.de)
New S1P modulators act more specifically
Nevertheless, one can of course ask why there must be so many substances from one category of active ingredients. This is a legitimate question and the answer is that the new S1P modulators (Ponesimod, Ozanimod and Siponimod) bind more specifically to the S1P receptors (S1P1 and S1P5) relevant for the effect in multiple sclerosis. They also have little or no affinity for the receptors S1P2, 3 and 4. They are responsible for some of the unwanted side effects of the original substance Fingolimod. Therefore, it can be assumed that with the new developments the tolerability and safety increase, which is basically to be welcomed.
However, this should not obscure the fact that there are side effects common to all S1P modulators. In medicine, we speak of so-called class effects. These include the possible increase in liver values or the macular edema. First and foremost, however, the sometimes significant drop in lymphocytes in the peripheral blood count, the so-called lymphopenia, must be mentioned. This lymphopenia is observed when using all S1P modulators and can fall quite significantly individually (unpredictably). This often leads to a lot of agitation and thus to sometimes hasty measures. Personally, I am not overly disturbed by lymphopenia, because ultimately it reflects the mechanism of action of the group of substances. They hold back inflammatory cells in the lymph nodes so that they cannot trigger inflammation in the brain. The cells are therefore still existent, but not measurable, because they are redistributed. And this is a major difference to a lymphopenia caused by other immunotherapies or infectious diseases such as HIV.
Accordingly, I see crossing the “threshold” of 200/µl initially with composure. This value was arbitrarily adopted from HIV therapy with antiviral substances and does not exist in other countries such as the USA or Switzerland. I am concerned when patients who are stable and free of side effects (sometimes already for a longer period of time) with an S1P agonist are asked by colleagues to stop the substances immediately, if, for example, the arbitrary limit mentioned above is touched only once. This exposes patients to the risk of recurring disease activity. Also, the information often spread (in this context) that patients treated with S1P modulators and pronounced lymphopenia have a higher risk of opportunistic infections, especially for PML, is wrong. No correlation could be shown between the occurrence of PML and the lymphocyte count under S1P modulation. It is true that there is a low risk of developing PML in principle when treated with S1P modulators – this is also a class effect – but the risk does not depend on the level of lymphocytes in the peripheral blood.
Now that Ponesimod is another S1P modulator available for MS therapy and this class of substances is increasingly used earlier in the course of the disease, it is important to me to clarify this point again. Because the uncritical discontinuation of these effective substances solely based on (arbitrarily) established laboratory values often causes more problems in our patients than we would like. In case of doubt, one should get a second opinion on the lymphopenia before facts are created.
Normally, lymphopenia recedes after a maximum of 6 weeks. In rare cases, however, it can take longer, which does not play a role in terms of side effects, but is relevant in terms of follow-up therapy.
