In addition to the study data from Ofatumumab, which I had already reported on (see DocBlog post from September 2019), another new study program was presented at ECTRIMS 2019 in Stockholm. It is the so-called OPTIMUM study, which tested the effect of the new active ingredient Ponesimod against the active comparator Teriflunomide (Aubagio). Ponesimod, like Fingolimod (Gilenya) and Siponimod (Mayzent), belongs to the group of S1P (Spingosin 1 Phosphate) modulators. The S1P receptor is required by activated inflammatory cells to move from the secondary lymphatic organs (e.g. lymph nodes) into the bloodstream and cause inflammation in the brain. Taking it thus leads to a reduced CNS inflammation and efficient control of active MS courses.
In contrast to Fingolimod (Gilenya), which still binds to various subgroups of the S1P receptor and can thus cause a relatively broad spectrum of side effects, the newer substances bind relatively specifically to the S1P1 receptor, which is predominantly found on the surface of inflammatory cells (and is responsible for the immunomodulatory effect). The new active ingredients of the substance group of S1P modulators are therefore considered better tolerated.
In the aforementioned OPTIMUM study, more than 1000 patients were included and treated over 108 weeks either with the new substance Ponesimod or with the established oral MS drug Teriflunomide (Aubagio). Ponesimod was significantly superior to treatment with Teriflunomide in terms of annual relapse rate and MRI activity. However, there was no difference between the two treatment groups in influencing disability progression. Both substances were well tolerated, there was no difference in dropout rates, and there was no difference in side effects and serious side effects between the two substances. The study thus not only confirmed the good anti-inflammatory effect of the S1P modulator Ponesimod, but also the good tolerability of the substance. In particular, the bradycardia and arrhythmias discussed in connection with Fingolimod were not a problem in the current study.
The OPTIMUM study is thus another study that demonstrates the value of the newer S1P modulators. The results of two Phase III approval studies (SUNBEAM and RADIANCE) on the effect of Ozanimod in relapsing MS were recently published in the medical journal Lancet Neurology (Comi G et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1009-1020 and Cohen et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1021-1033).
Yes – you guessed it right, considering the characteristic name of the substance, this is also an S1P modulator – and also an S1P modulator with a high specificity for the subgroup of S1P1 receptors. Ozanimod was tested in two different dosages against interferon-beta 1a intramuscularly (Avonex). Here too, the new substance was superior to the established MS drug in terms of reducing the annual relapse rate and MRI activity. However, disability progression did not differ between the treatment groups. Fortunately, in these studies too, the side effects were comparable between the study groups, so this study program supports the good tolerability of the new S1P modulator.
It is expected that Ozanimod, which is currently in the approval process, will receive approval for the treatment of relapsing MS in 2020. The approval of Ponesimod, the results of which were first presented at ECTRIMS 2019, will probably follow.
In contrast to the precursor substance Fingolimod, which is used rather in more active MS courses due to its history, the newer S1P modulators are likely to establish themselves more in the area of first-line therapy. I think this is quite good news, because better efficacy with the same tolerability is certainly desirable in this segment. On the other hand, one must also counteract the euphoria a bit, because a really new concept is not introduced by the studies – it is rather (sorry for the analogy to the automotive industry) a “facelift” of a known model.
