The objective of this investigation is to: comparatively assess the benefits of the drugs alemtuzumab, cladribine, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, ofatumumab, ozanimod, ponesimod, and teriflunomide with each other; in the treatment of adult patients with highly active relapsing-remitting multiple sclerosis despite complete and adequate treatment with at least 1 disease-modifying therapy. The assessment was conducted based on patient-relevant outcomes. Due to the highly variable clinical courses of multiple sclerosis (MS) as discussed in Section 1 of the report, different treatment strategies are conceivable in the comparison of benefit: escalation from basic therapy (e.g. interferons or glatiramer acetate) to high-efficacy therapy (e.g. fingolimod, ocrelizumab); deescalation, i.e. treatment pause or switch to a basic therapy in the absence of disease activity or in case of intolerable side effects, planned pregnancy, or advanced age; switch to another basic or escalation therapy. This results in the following research questions:
COMPARISON OF THE TREATMENT STRATEGIES OF ESCALATION THERAPY VERSUS BASIC THERAPY (RESEARCH QUESTION 1): For research question 1, meaningful data are available from only 1 study which compares escalation therapy with alemtuzumab versus interferon-beta 1a. The results for patients who switched from another basic therapy to interferon-beta 1a at the start of the study are decisive for answering the research question. The overall analysis of all outcomes for which results are available shows superiority of escalation to alemtuzumab versus switching to the basic therapy of IFN-β 1a. On the basis of the available data, no conclusions can be drawn for other escalation therapeutics. RESEARCH QUESTIONS ON ESCALATION THERAPIES WITH THE POSSIBILITY OF DEESCALATION (QUESTIONS 2 AND 3): No relevant studies were identified for the following research questions of the present benefit assessment: Research question 2: escalation therapy with the possibility of deescalation versus basic therapy. Research question 3: escalation therapy versus escalation therapy with the possibility of deescalation. For these 2 care-relevant research questions, it therefore remains unclear whether there is an advantage for one of the treatment strategies mentioned or, within one of the treatment strategies, for one of the drugs investigated. COMPARISON OF DIFFERENT DRUGS WITHIN A TREATMENT STRATEGY (RESEARCH QUESTION 4): Based on the available data, a comparison of different drugs within a treatment strategy was possible only for escalation therapy. Within escalation therapy, study data were available on the drugs alemtuzumab, cladribine, fingolimod, ofatumumab, ozanimod, ponesimod, and teriflunomide. For the drugs dimethyl fumarate and ocrelizumab, the manufacturers submitted no data for the present assessment. No relevant studies were identified for the drug natalizumab. Direct comparative studies were available for the drugs ofatumumab and ponesimod, each in comparison with teriflunomide. Based on the available data, greater or lesser benefit or harm can be derived only from the direct comparisons of the escalation therapies. For the majority of the other comparisons, data are either completely missing or were not provided by the responsible manufacturers. In some cases, relevant outcomes were not recorded in individual studies, or no advantages or disadvantages were found between the investigated drugs. For the comparison of ofatumumab versus teriflunomide, there are only indications in favour of ofatumumab, namely in the outcomes of confirmed relapses (annual relapse rate, patients with confirmed relapse), confirmed disability progression, and discontinuation due to adverse events. Altogether, this results in an indication of greater harm from ofatumumab in comparison with teriflunomide. For the comparison of ponesimod versus teriflunomide, this results in (1) a hint of greater benefit for the outcome of confirmed relapses (annual relapse rate) and (2) a hint of a greater harm from ponesimod for the outcome of discontinuation due to adverse events. However, only a few events occurred overall for the outcome of discontinuation due to adverse events. All things considered, this results in a hint of greater benefit of ponesimod in comparison with teriflunomide.
