Dear Editor,


We thank Mr. Nieto-Gomez and his colleagues for their interest in our article titled “Real-World Analysis Affirms the High Persistence and Adherence Observed with Diroximel Fumarate in Patients with Multiple Sclerosis.” Our response to the letter is below.

Response to Comments on the Introduction Section

In acknowledgement of the comment regarding the reference to the EVOLVE-MS-1 study in the introduction:

The sentence in the introduction stating “Two phase 3 clinical studies of DRF in patients with MS have demonstrated favorable GI tolerability and low (< 1%) treatment discontinuation due to GI AEs” does indeed reference both the EVOLVE-MS-1 and EVOLVE-MS-2 studies [1, 2]. Although EVOLVE-MS-1 did not contain a comparator arm, it did demonstrate a low (< 1%) discontinuation rate due to gastrointestinal adverse events (AEs) with diroximel fumarate (DRF). Both studies had < 1% discontinuation rate due to GI AEs in patients treated with DRF. Therefore, although the sentence is accurate, it could benefit from improved grammar, to state “Two phase 3 clinical studies of DRF in patients with MS were conducted; one of these studies demonstrated favorable GI tolerability of DRF versus DMF, while both studies demonstrated a low (< 1%) treatment discontinuation due to GI AEs in DRF-treated patients.”

In acknowledgement of the comment regarding the scales used in the EVOLVE-MS-2 study and the clinical meaningfulness of those scales:

We would first like to explain that the EVOLVE-MS-2 study is not the focus of this article. While we can offer an opinion on that study, the authors of the EVOLVE-MS-2 study publication [1] may be better suited to respond to the comments on the scales used in the EVOLVE-MS-2 study. Based on our review of that peer-reviewed publication, the lack of validation of the scales is a limitation that is already discussed by the authors in the EVOLVE-MS-2 study publication, yet the authors still concluded that the study results demonstrated improved GI tolerability for DRF versus dimethyl fumarate (DMF). Based on the information contained in the Naismith et al EVOLVE-MS-2 study publication, the conclusions of that study have been summarized accurately within the introduction section of our article. Regarding the clinical meaningfulness of the results of the EVOLVE-MS-2 study, this is outside the scope of our article: our article is focused on summarizing the results from the analysis of DRF in the AcariaHealth Specialty Pharmacy Program, and the aim of our study was to characterize the early real-world experience with DRF.

In acknowledgement of the comment “…the mechanism of action for the supposed improvement of gastrointestinal events is not sufficiently clear. The proposed possibilities are speculative and not adequately proven”:

This proposed mechanism of the differences in GI tolerability between DRF and DMF was briefly mentioned in the introduction section of our article to summarize the information that was found in the literature. Our summary clearly states that these proposed mechanisms are hypotheses. It is accepted practice to discuss hypotheses in the scientific literature as long as they are clearly described as such.

Response to Comments on the Study Design

In acknowledgement of the comment suggesting that this analysis should have included a comparator arm:

Our study aimed to assess the adherence and persistence of DRF in a real-world setting. The aim of our study was not to compare DRF versus other therapies. As we highlighted in the discussion section, the AcariaHealth Specialty Pharmacy Program lacks detailed baseline characteristics and demographics that are available through other types of data sources. Chart review studies, or even retrospective analyses of claims databases, would allow researchers to capture significantly more baseline variables (e.g., time since diagnosis, prior MS therapies, concomitant therapies, and comorbid health conditions, etc). The lack of these variables in our dataset limits the ability to conduct fair comparisons between treatment groups because we would have been unable to adjust for differences between groups. The extent to which we felt comfortable making comparisons was in relation to comparing outcomes before versus after switching from a therapy, as this type of analysis allowed patients to serve as their own control.

In acknowledgement of the comment referencing a different study [3] that demonstrated a lower rate of DRF persistence at 12 months than what was observed in our study:

Based on the date of publication, it appears that study was published after our article had already been submitted for publication, so we thank Mr. Nieto-Gomez and colleagues for bringing that study to our attention. Importantly, that study had a different design than our study and utilized administrative claims data, which is a distinctly different type of real-world data source. Administrative claims data have some advantages (i.e., more extensive baseline characteristics); however, claims data also have key limitations, especially when trying to estimate persistence outcomes. The claims data source cannot provide any details on reasons for discontinuation. Importantly, the claims data source can also characterize a patient as “non-persistent” if they have gaps in therapy but then return to the treatment after the gap period. This approach is necessary when using claims to estimate persistence due to the difficulty in distinguishing between a patient who has truly discontinued versus a patient who has a drug holiday or temporary drug interruption due to a clinical decision by their prescriber. In addition, the study referenced included patients who initiated treatment between 1 January 2020 through 30 June 2020, which was the first 6 months after DRF was approved in the USA. Therefore, the results could depend largely on which specific health insurance plans are included within the claims database being used for this study. There are several different claims databases in the US, each of which captures claims from a subset of health insurance plans. If some of the larger health plans that were included within the claims database used for that study did not cover DRF during this time, or if they initially covered DRF but then changed their coverage, then it is possible that non-clinical reasons (e.g., financial reasons or administrative reasons such as prior authorizations) could be significantly influencing the persistence rate. Similar limitations may also apply for the relatively low DMF persistence rates observed in that study, as the time frame used for the study follow-up period also coincided with the introduction of generic versions of DMF in the US. Many patients may have been forced to switch from brand TECFIDERA to generic DMF during this time. While some of those patients may have remained on generic DMF, it is possible that many patients who were forced to switch to a generic version of DMF may have instead opted to switch to a different drug class all together to remain on a branded medication if they were interested in retaining access to patient support programs or financial patient assistance programs. Unfortunately, there is no way to determine the extent to which these factors may have influenced the results of the referenced study because the reasons for starting, stopping, or switching therapy are not captured in claims data. Lastly, regarding the comment about the similar persistence rates between DMF and DRF that were observed in the referenced study, the authors of that study do state “…our outcomes are largely reported using descriptive measures, and no adjustments were made for possible confounding variables, such as any potential baseline differences between groups, e.g., age or MS severity." Without adjusting for potential confounders, it is difficult to draw conclusions from that study related to the comparisons between different groups.

In acknowledgement of the comment regarding adherence rates in patients who switched from DMF to DRF:

It is true that the average treatment duration on DMF was longer than the average treatment duration on DRF after switching. In the overall DMF-to-DRF switch subgroup (n = 433), we did conduct a sensitivity analysis evaluating adherence only in a subgroup of 326 patients with ≥ 6 months of DRF treatment: in this subgroup analysis (referred to as “sensitivity analysis 2” in our original article), there was a similarly high rate of adherence as observed in the primary analysis. Additional studies with longer follow-up will help to further characterize longer-term rates of adherence in DRF-treated patients.

In acknowledgement of the comment stating that “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 and it could be relevant in persistence drops at this time. It does not seem appropriate to include non-gastrointestinal adverse effects to demonstrate the better gastrointestinal tolerability of one drug over another.”

The overall persistence rate calculation did include patients who discontinued because of flushing or other AEs, in addition to GI-related AEs. Our article highlighted and emphasized GI-related discontinuation rates as a data point of special interest, but the overall persistence estimates and the overall discontinuation rates included patients who discontinued for other reasons, as well. In Table 3, we report the overall discontinuation rate for any reason was 12%. The footnote of Table 3 notes that 6% of patients discontinued because of an AE that was not GI related (69/1143). Regarding the definition used for GI-related AEs, GI-related AEs included those that were documented as being GI related, but also included any unknown AE (i.e., an AE lacking details regarding the nature of the event) that occurred within 90 days of initiating DRF therapy because this is when GI AEs are most common with fumarate treatments. We recognize that some of those “unknown AEs” were likely not GI related; however, this approach was used to avoid underestimation of the GI AE discontinuation rate. We erred on the side of overestimating the GI discontinuation rate rather than underestimating it. If we were to change this definition and only include AEs that were documented as being GI related, then the GI-related AE discontinuation rate with DRF would have been lower than what was reported in this analysis.

In acknowledgement of the comment stating that “…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”:

Regarding the design of the phase 3 DRF clinical trials, we have responded to those comments to the best of our ability; it is important to reiterate that, while we developed the study design of this DRF real-world study, we did not design the phase 3 DRF clinical trials. The authors of those phase 3 DRF clinical trial publications may be better suited to respond to the comments on their work. Regarding our real-world DRF study, this study was not designed to be a head-to-head comparison of DRF versus DMF for the reasons discussed in the publication and for the reasons previously described in this response letter. Our study sought to characterize the real-world experience with DRF, in both an overall population and a population of patients who switched from DMF to DRF as this is a common treatment switch that occurs in the real-world setting. Our results demonstrated high persistence and adherence with DRF as well as a low discontinuation rate due to GI AEs. Due to the lack of real-world data with DRF, this study aimed to address this data gap and provide data that could be informative to healthcare professionals.