Dear Editor

We read the recently published article “Real-World Analysis Affirms the High Persistence and Adherence Observed with Diroximel Fumarate in Patients with Multiple Sclerosis” by Lager et al. [1], which shows real-world data on the adherence and persistence of diroximel fumarate (DRF). However, we believe that this work has some undisclosed limitations that we would like to address.

Clinical Trials

Lager et al. base their introduction on the premise that DRF has been shown to improve gastrointestinal tolerance compared to dimethyl fumarate (DMF) in two trials, namely EVOLVE-MS-1 [2] and EVOLVE-MS-2 [3]. However, this comparison has numerous limitations.

First, the EVOLVE-MS-1 study was an open-label, single-arm study that did not establish a direct comparison with DMF. Referencing this study as evidence that DRF is associated with better gastrointestinal tolerability compared to DMF is misleading, as these two drugs were not compared in the study. Therefore, in our opinion, this reference should be removed from that paragraph.

Furthermore, as indicated by the evaluators of the European Medicines Agency (EMA) in the European Public Assessment Report (EPAR) for DRF [4], the scales used in the EVOLVE-MS-2 study, IGISIS (Individual Gastrointestinal Symptom and Impact Scale) and GGISIS (Global Gastrointestinal Symptom and Impact Scale), were not validated at the time the data were submitted for EMA authorization and it was the first time these scales were used in a clinical trial setting. As stated in the EPAR, “The fact that these scales were not validated and used for the first time in a clinical setting in a questionable study design to perform a comparison between DMF and DRF cannot be supportive of a better GI tolerability of DRF.” Moreover, the selection of the endpoint as the “Number of Days with any IGISIS Symptom Intensity Score ≥ 2 relative to exposure days” seems somewhat result driven, as “the number of days with symptoms ≥ 3, 4, 5, and 6 was low, thus not allowing for clinically significant conclusions and raising questions about the validity of the scales”.

Another shortcoming is that the chosen method for reporting gastrointestinal adverse events, e-diaries, is subject to biases compared to other more reliable clinical methods that the researchers could have used. Considering the variable “Number of Days with any IGISIS Symptom Intensity Score ≥ 2” as acceptable for drawing clinically significant conclusions, the difference of 1 day of symptoms between DMF and DRF (2.5 vs. 1.5 days, respectively) does not seem clinically relevant enough to justify the use of one drug over another.

Finally, the mechanism of action for the supposed improvement of gastrointestinal events is not sufficiently clear. The proposed possibilities are speculative and not adequately proven.

Real-World Evidence

Before drawing conclusions based on real-world studies, the effects of a drug should be demonstrated in well-designed clinical trials. By disregarding the methodological limitations of the trials, this study aimed to assess the adherence and persistence of DRF in real-world settings. In this scenario, opting for a comparative arm comprising patients who continued treatment with DMF would have been a preferable choice. This approach would establish a comprehensive and long-term comparison of adherence and persistence between the two drugs.

Araujo et al. did not find such high rates of persistence at 12 months for DMF or DRF as estimated in this work (44% for DMF and 49% for DRF), nor for other oral treatments [5]. Additionally, these authors found identical persistence rates between DRF and DMF at 3 months of follow-up (79%), which is when most discontinuations occur due to GI symptoms.

Furthermore, the median treatment duration in this study with DMF before switching to DRF was 13.7 months, while the treatment time after the switch from DMF to DRF was only 6.9 months. Only 4.6% of patients in the DMF-to-DRF switch group had an exposure of > 1 year, and only 10% of the overall population. Therefore, the treatment duration seems insufficient to observe drops in adherence and persistence due to other adverse events or lack of efficacy which can be key in long-term treatments. In another real-world study on DMF, Thompson et al. found that discontinuations were due to lymphopenia (11.1%), efficacy (13.2%) and other adverse effects (10.4%), compared to gastrointestinal adverse effects (7%) [6].

Lastly, including all adverse effects occurring in the first month as gastrointestinal adverse events is an important shortcoming. Flushing is another adverse effect leading to discontinuation in the early months, which could be relevant in persistence drops at this time [6]. It does not seem appropriate to include non-gastrointestinal adverse effects to demonstrate the better gastrointestinal tolerability of one drug over another.

Therefore, establishing a presumed benefit of DRF over DMF requires better controlled clinical trials as well as real-world evidence studies that directly compare the alternatives for an adequate period.