ORATORIO is the first study that was able to show a significant influence on primary chronic progressive MS by an MS drug. The effects are not overwhelming, but the antibody Ocrelizumab is nevertheless the first effective therapy for this special course of MS.
At the beginning of 2018, Ocrelizumab was approved in the European Union for the treatment of primary chronic progressive MS. Accordingly, the question now arises as to which patient group benefits from this therapy. Therefore, at this year’s ECTRIMS, there was intense discussion about what characteristics qualify a chronically progressive patient for therapy with Ocrlizumab.
Prof. Xavier Montalban (Barcelona/Toronto), the study leader of the ORATORIO study, therefore analyzed the data of the study in context with other studies on chronic MS, with a special focus on the studies on Siponimod and Natalizumab for secondary chronic progressive MS. Considering the study data, it becomes clear that particularly chronically progressive patients with superimposed relapse activity, rapid progression and MR activity benefit, especially if they are of a younger age, have a shorter duration of illness and a low EDSS score at the start of treatment. Therefore, Prof. Montalban also emphasized the meaningfulness of the “new” classification of MS into active and inactive courses and advocated treating chronically progressive MS patients with signs of disease activity.
Nevertheless, the question remains open as to what can be offered to chronically progressive MS patients who are “inactive” according to the new definition – and this is still a relatively large group. Against this background, Prof. Robert Fox (Cleveland) presents the newer therapeutic developments in progressive MS. Worth mentioning here is Ibudilast, a phosphodiesterase inhibitor (PDE4 subtype), for which the phase II study (SPRINT-MS) was able to show a significant slowing down of brain atrophy. The antibody Opicinumab, which in initial studies has given indications that remyelination could be promoted, certainly also has potential – but further studies must be awaited for both substances. The approaches to axon protection with fluoxetine, amiloride and riluzole, which were investigated within the MS SMART study, a multi-arm study (3 concepts in one study with a comparison group), are also interesting.
The outlook for the future is promising, but much more important at present seems to be a consideration that both speakers also brought up in their lectures – namely, why so many drug approaches in studies have shown a negative outcome. It is possible that we are starting from false assumptions and the pathogenesis of chronic progressive MS follows completely different laws than assumed. However, I consider this theory to be not quite as likely in view of the histopathological data on progressive MS.
It seems more likely to me that the chosen clinical outcome parameters are not sensitive enough to detect relevant changes through therapy – the key word here is always the lack of sharpness of differentiation of the EDSS in later disease phases.
Against this background, it is worth mentioning that the ASCEND study, which examined Natalizumab in secondary chronic progressive MS, was negative in terms of the primary study endpoint, but a clear effect on the 9-hole pegboard test (secondary endpoint), i.e. hand function, was shown in the treated patients. This effect on hand function could also be traced across all subgroups in a post-hoc analysis of the ORATORIO study. Accordingly, it is indeed crucial when assessing “effectiveness” which study endpoint is chosen – and for a large number of patients, maintaining the function of the upper extremity through medication is likely to be of great importance.
The discussion about the right target group for drugs for the treatment of chronic progressive MS is therefore far from over.
