The effectiveness of natalizumab vs fingolimod–A comparison of international registry studies

Abstract

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at reevaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/ exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The ontreatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion:The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.with the Center for Data Review applications (j. nr. 2012-58-0004/VD-2018-121 I-suite 6361). Declaration of Competing InterestJ.B. Andersen received travel grant and congress participation support from Merck.N. Koch-Henriksen received support for participation in congresses and symposia by Biogen, Merck, Novartis, and Teva.F. Sellebjerg served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, Merck, Novartis, Roche, Sanofi Genzyme and Teva. P. S. Sørensen received personal compensation for serving on scientific advisory boards, steering committees, independent data monitoring committees or have received speaker honoraria for Merck, Novartis, TEVA, GlaxoSmithKline, MedDay Pharmaceuticals, SanofiAventis/Genzyme, and Celgene.C. Hilt received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genzyme, Biogen, Roche, Novartis, and Merck P.V. Rasmussen received speaker honoraria from TEVA, Biogen, Roche and Novartis, support for congress participation from Merck, Roche, Sanofi and TEVA, fees for serving on advisory boards from Merck, Roche, Novartis, Biogen, and Sanofi.M.B. Jensen served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roch...

Systematic review and network meta-analysis (NMA) for cladribine tablets in achieving sustained disability improvement (SDI) in multiple sclerosis

“…The systematic review resulted in eight publications included in the analysis: in two of them, the results of SDI assessment coming from randomised controlled trials were Neurologia i Neurochirurgia Polska 2022 www.journals.viamedica.pl/neurologia_neurochirurgia_polska presented: CAMMS223 [18] and CARE-MS II [19], while the remaining six publications stated SDI results from cohort studies, where the propensity score matching method was applied with matching the characteristics of the assessed cohorts [13,[20][21][22][23][24]. The results for cladribine tablets were presented only in Kalincik 2018 [13], where the total cohort comprised only 37 patients.…”

“…In addition to the direct comparisons present in Kalincik 2018 [13] (CT vs. FTY or vs. IFNβ or vs. NAT), the remaining studies incorporated into the NMA comprised the following comparisons: NAT vs. FTY -Andersen 2021 [20], Baroncini 2016 [21], Guger 2018 [22] and Kalincik 2015 [24], ALE vs. NAT and vs. IFNβ -CAMMS223 [18] and Kalincik 2017 [23], and ALE vs. FTY -Kalincik 2017 [23] and CARE-MS II [19]. Kalincik 2018 [13] reported the sustained improvement in disability defined as: reduction in EDSS score ≥ 1 point (1.5 points if the baseline value was 1.5 and 0.5 points if the baseline value was > 6) confirmed in an interval of ≥ 6 months.…”

“…A change from 1 to 0 EDSS was not interpreted as an improvement in disability. A similar definition was adopted in Andersen [20] and Kalincik 2017 [23], except that it did not specify the criteria for patients with a baseline EDSS 1 score. The definition of the sustained improvement in disability in other included studies differed slightly in details -they are presented in Table S.2 in the Supplement.…”

“…To avoid multiple inclusion of the same patients, studies other than Kalincik 2018 [13] were removed from the calculations in the second sensitivity analysis, because those might in part include the same patients from the MS Base registry -Kalincik 2015 [24] and Kalincik 2017 [23] -that were already covered by Kalincik 2018 [13]. In the case of Andersen [20], the main results obtained in the population comprising the MS Base registry were excluded as well. However, the results of additional analysis restricted to DMSTR and OFSEP registries data were included in this NMA.…”

“…Only two RCT trials were found [18,19], and for this reason, we decided to include non-randomised controlled studies with lower reliability, according to the hierarchy of evidence. The six remaining included studies were conducted based on registry data, and groups for comparison were created under the propensity score matching method, based on many potential confounding factors, including age, sex, duration of illness, baseline EDSS, number of relapses in the past, or previous DMTs used [13,[20][21][22][23][24]. This technique minimises the differences between the groups in terms of known confounders as much as possible and is intended to bring the study as close as possible to an RCT trial [31,32].…”