In an invited lecture, Prof. Xavier Montalban (Vall d’Hebron University Hospital, Barcelona) discussed management of primary and secondary progressive MS (PPMS and SPMS) with approved disease-modifying treatment . Especially for PPMS, treatment options are very limited.
Drugs considered for active SPMS in the 2018 ECTRIMS/EAN MS treatment guidelines are interferon-1a or -1b, taking into account the dubious efficacy as well as the safety and tolerability profile . Other options for active SPMS that are mentioned are mitoxantrone, ocrelizumab, or cladribine. Possible additions to this list are siponimod and ozanimod, which were recently approved for relapsing MS, and ofatumumab, which was approved for relapsing MS by the FDA in August 2020.
For PPMS, 1 disease-modifying treatment (DMT) has been approved specifically, which is ocrelizumab. Prof. Montalban pointed out a number of reasons why drugs fail in PPMS trials. First, pathogenic mechanisms in the progressive phase are completely different from the relapsing phase. Second, patient populations included in PPMS trials are generally not appropriate. Third, clinical outcome measures are not sensitive enough, meaning clinical trials are not “smart” enough, to detect PPMS worsening over a relatively short time span. Among the drugs that failed to show any effect on PPMS are fingolimod and glatiramer acetate.
More DMTs have been tested in SPMS in the past decade, from interferon-β to agents that are not registered for any form of MS. For example, MD1003 (biotin) showed very positive results in 1 trail that could not be replicated in a second pivotal phase 3 trial [3,4]. A phase 3 trial of high-dose simvastatin in SPMS (n=1,180) is ongoing. A potentially promising therapy in both PPMS and SPMS is ibudilast . The potential benefit of opicinumab is less clear ; an additional phase 2b trial is underway. Clemastine showed short-term improvement in visual evoked potentials , but the clinical relevance of these results is as yet unclear. Amiloride, fluoxetine, and riluzole yielded basically negative results in the MS-SMART study . Lipoic acid showed a “very important” 68% reduction in annualized percentage change in brain volume , but these results will have to be replicated in a larger trial.
Prof. Montalban stressed that a major complicating factor in treating progressive MS is the lack of consensus on the definition of treatment failure. In active progressive MS, is it persistence of relapses, or disability worsening? In progressive, non-active PPMS, is it disability worsening and/or appearance of relapses? How long should the time on treatment be when evaluating efficacy? Can only improvement be considered as proof of efficacy? All these questions are still waiting to be answered.
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