4. Important Clinical Studies Involving MMF and MS
Data on the efficacy of Bafiertam™ (MMF) in patients with relapsing forms of multiple sclerosis come from the results of several clinical trials, to date including DEFINE, CONFIRM, their ongoing extension ENDORSE, and retrospective analyses of pooled trial data [75
]. It is important to note that monomethyl fumarate (MMF; Bafiertam™) is the sole active metabolite detectable in plasma of dimethyl fumarate (DMF; Tecfidera®
) and diroximel fumarate (DRF; Vumerity®
). For this reason, efficacy data for monomethyl MMF are based on bioequivalence with dimethyl fumarate (DMF) preapproval clinical trial data for DMF, and post-market monitoring of patients treated with DMF.
Phase I studies compared the safety profile of DMF and DRF, both prodrugs of MMF, and recent head-to-head phase I trials have more directly investigated the tolerability of MMF versus DMF in healthy volunteers (see also above, Safety, Adverse Events) [95
]. In an early pilot study, the effects of fumaric acid esters (FAEs) were investigated in 10 patients with a diagnosis of definite relapsing active multiple sclerosis (RRMS) [97
]. The FAE preparations administered to MS patients in this study contained high amounts of DMF and were originally approved in Germany for the treatment of severe plaque psoriasis (Fumaderm®
; Fumapharm, Muri, Switzerland). Enrolled patients had active lesions on MRI and showed reductions in the mean number and total volume of gadolinium enhancing lesions (GdE) on T1 MRI after 18 weeks of treatment with 720 mg oral FAE [97
]. A more recent phase I comparative study of monomethyl fumarate (MMF) evaluated the side effects and safety profile of MMF in healthy volunteers [95
]. In this study, 210 healthy volunteers (159 female) were administered equal molar weights of MMF (190 mg) and DMF (240 mg) twice daily over a 5 week treatment period. The gastrointestinal tolerability profile of MMF, assessed by the Modified Overall Gastrointestinal Symptom Scale (MOGISS), showed no statistically significant differences in terms of primary study endpoints, i.e., area under the curve (AUC), over the 5 week treatment period. The study authors noted statistically significant differences in mean worst severity MOGISS scores overall, with lower scores for vomiting and diarrhea with Bafiertam™.
For phase II studies of dimethyl fumarate (DMF), an early phase IIb multicenter, randomized, double-blind, placebo-controlled trial of oral DMF investigated safety and efficacy of 120 mg QD, 240 mg TID, and 240 mg TID doses in patients with RRMS compared to placebo [86
]. It was found that the 240 mg TID dose reduced the mean number of GdE lesions by 69% over a 12-week period (primary endpoint), reduced the number of new or enlarging T2 MRI hyperintense lesions, number of new T1-hypointense lesions, and reduced annual relapse rate (ARR) by 32%. The authors also noted that the study was not adequately powered for relapse endpoints.
Two large phase III trials of DMF were conducted in 2012, one comparing DMF to placebo and the other comparing DMF to glatiramer as active comparator [75
]. The first multicenter, randomized, double-blind, placebo-controlled trial was Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS (DEFINE) [76
]. This study investigated the use of oral DMF (BG-12) in RRMS patients (n
= 1234) by giving them 240 mg of DMF twice daily, 240 mg of DMF thrice daily, or placebo. A significantly lower estimated proportion of relapse was found in the DMF groups, 27% in patients taking BID DMF, and 26% in patients taking TID DMF, versus 46% with placebo. The annualized relapse rate (ARR) at two years was 0.17 with BID, 0.19 with TID, and 0.36 with placebo (annualized relapse rate defined by the total number of relapses divided by the number of patient years). The rate of disability progression, as measured by the Expanded Disability Status Scale (EDSS), was 16% with BID, 18% with TID, and 27% with placebo. Additionally, there were significant reductions in the number of Gd+ T2 MRI hyperintensities with both DMF regimens compared to placebo.
The second randomized, multicenter, double-blind trial to evaluate the efficacy of DMF was Comparator and an Oral Fumarate in Relapsing–Remitting Multiple Sclerosis (CONFIRM) [75
]. This study investigated the use of oral DMF (BG-12) in RRMS patients (n
= 1417) by giving them 240 mg of DMF twice daily, 240 mg of DMF thrice daily, 20 mg of glatiramer acetate (GA) subcutaneously daily, or placebo. The annualized relapse rate at 2 years was 0.22 with BID DMF, 0.20 with TID DMF, 0.29 with glatiramer acetate, and 0.40 with placebo. Significant reductions were found in the number of new or enlarging T2 hyperintensities, and reductions in new T1 hypointensities with both DMF and GA. No significant reductions in disability progression were found between the DMF regimens and GA. Overall, the DEFINE and COMPARE trials found that treatment regimens of DMF significantly reduced the proportion of relapses, disability progression, and the number of MRI lesions in RRMS patients compared to placebo.
Additional information about the efficacy of DMF comes from retrospective data analyses from the DEFINE, CONFIRM, and now ENDORSE clinical trials, plus analyses of real-world comparative clinical data from several large MS clinics and national registries [88
]. In further analyses of the randomized controlled clinical trials, retrospective studies consider subgroups of RRMS patients or combined patient data from multiple studies. For example, analysis of MRI data from a small group of patients in the abovementioned phase IIb trial showed a significantly lower percentage of evolution of Gd+ lesions to T1 hypointense lesions [98
]. Patients who had received 240 mg of BG-12 (DMF) thrice daily (TID, n
= 18) versus placebo (n
= 38) showed reduced lesion evolution, even after adjusting regression models for disease duration and relapse activity. In another analysis of the same phase IIb trial, baseline characteristics and demographic data of 108 patients (240 mg DMF TID, n
= 54; placebo, n
= 54) showed reductions in the number of new Gd+ lesions among numerous subgroups [88
]. Subgroups with significant reductions included EDSS score ≤ 2.5, EDSS > 2.5, no Gd+ lesions, ≥ 1 Gd+ lesion, age < 40 years, age ≥ 40 years, female patients, disease duration ≤ 6 years, and disease duration > 6 years. It was noted that only the male subgroup showed no significant reductions in the number of new Gd+ lesions. In subgroup analyses of the DEFINE clinical trial data, it was found that for all subgroups, DMF BID and TID reduced the proportion of patients who relapsed, and the annualized relapse rate (ARR), compared to placebo [92
]. Further analyses of the CONFIRM trial data revealed that health-related quality of life (HRQoL) measures had improved significantly at two years from baseline scores [90
]. These HRQoL measures included the Physical Component Summary (PCS), Mental Component Summary (MCS), and Short Form-36 (SF-36). Statistically significant improvements were noted for both DMF BID and glatiramer acetate (GA) compared to placebo, with a trend towards improvement with DMF TID. Similar results were also shown for patient-perceived health status measures such as PCS, MCS, and SF-36 with an analysis of the DEFINE trial data [91
]. In post hoc analyses of pooled data from the DEFINE and CONFIRM trials, newly diagnosed patients (n
= 678) naïve to MS disease-modifying therapy showed statistically significant clinical and neuroradiological outcomes at 2 years [89
]. For patients diagnosed with RRMS within 1 year of study entry, 240 mg of DMF BID (n
= 221) reduced the ARR by 56%, and 240 mg of DMF TID (n
= 234) reduced the ARR by 60%, compared to placebo. Another subset of patients with available MRI data (n
= 308) analyzed for neuroradiological progression of disease showed relative reductions in adjusted mean number of new or enlarging T2-hyperintense lesions at 2 years, 80% with 240 mg of DMF BID (n
= 221), and 81% with 240 mg of DMF TID (n
= 234), compared to placebo.
Several real-world clinical studies and retrospective analyses of patient data have provided additional efficacy information for DMF treatment in MS patients. These studies have considered MS patient sub-populations and/or data for active comparators such as fingolimod (FTY) and teriflunomide (TRF) [99
]. In a retrospective chart review of RRMS patient (n
= 390) initiating DMF treatment at US tertiary clinics, the efficacy of DMF was found not to differ among White Americans, African Americans, and Hispanic Americans [99
]. A study of real-world efficacy of DMF in RRMS patients at a large academic MS center found that DMF (n
= 458) and fingolimod (FTY) (n
= 317) had comparable clinical efficacy [100
]. MRI activity and rates of discontinuation between patients taking DMF and FTY in this study were also comparable. A real-world study of 119 patients (59.7% female) from the national MS registry of Kuwait evaluated MS patients taking 240 mg DMF BID for at least six months (mean duration 20.5 ± 9.5 months) [101
]. In this study, the proportion of relapse-free patients increased significantly from 51.2% to 89.9%, and the proportion of patients with MRI activity decreased significantly from 61.1% to 15.1%. Analysis of combined patient data from two US academic MS centers showed the proportion of relapse was similar for those prescribed DMF (n
= 737) compared to FTY (n
= 535) [102
]. Patients taking DMF in this study were more likely to discontinue treatment (n
= 326) than patients taking FTY (n
= 186). The study authors cited intolerability as the likely main factor responsible for this difference. Retrospective analysis of data from six MS centers in Italy (n
= 456) showed an ARR reduction of 75% compared to baseline ARR during DMF treatment, and DMF discontinuation significantly associated with a higher baseline EDSS [104
]. Finally, a recent comparative trial provided Class III evidence for similar clinical effectiveness of DMF and teriflunomide (TRF) in RRMS patients at 2 years post-initiation [103
]. In this study, patients taking DMF (n
= 1057) and patients taking TRF (n
= 713) had similar relapse rates and disability progression, but the proportion of patients with at least one new T2 lesion was significantly lower with DMF (60.8%) compared to TRF (72.2%). In the context of these and other trials, a large database study also raised the issue of the lack of comparative evidence and data on clinical effectiveness for the use of DMF in MS patients in the post-approval period, citing a lack of direct comparison, from analysis of 16 trials of MS disease-modifying drugs compared to placebo (11) and to interferon-β-1a (5) [79
Interim analysis of ENDORSE, the ongoing 12-year extension of DEFINE and CONFRIM, now provides data on the extended use of DMF in RRMS patients for up to 5 years [87
]. In patients continuing to take 240 mg of DMF BID (BID/BID), cumulative ARR during years 0–5 was 0.163. For patients taking glatiramer acetate (GA) in CONFIRM (GA/BID), cumulative ARR during years 0–5 was 0.199. Detailed analysis of early ARRs was also reported for DMF, compared to both placebo and GA. The study authors reported consistently low clinical MRI activity with analysis at 5 years, i.e., in the succeeding 3 years after 2 years of DEFINE and CONFIRM. The more recent analyses of ENDORSE reported sustained efficacy of DMF for up to 11 years, i.e., in the succeeding 9 years after DEFINE and CONFIRM [93
]. Over the approximately 9 years of ENDORSE, 47% of patients initially randomized to placebo who switched to DMF were relapse free, as were 53% of patients randomized to DMF who continued taking DMF. The authors also noted that 86% of patients had two or fewer relapses. Detailed yearly and other interim analyses of ARRs, EDSS, MRI changes (MRI cohort), and disability progression were also reported (see Gold et al. 2020) [93
]. More detailed information regarding safety is also detailed in these analyses, especially regarding absolute lymphocyte count (ALC) and incidence of infection and malignancy (see above Safety, Adverse Events) [93
Safety, Adverse Events
The safety profile of monomethyl fumarate (MMF) comes largely from clinical trials of dimethyl fumarate (DMF) in MS patients, and the tolerability profile of MMF thus far comes from head-to-head comparison of MMF with DMF in healthy volunteers [94
]. Common treatment-related adverse events in MS patients have included flushing, diarrhea, nausea, abdominal pain, vomiting, proteinuria, and pruritis [75
]. Flushing and gastrointestinal events have been of mild or moderate severity, and were found to be highest in the first month of treatment by patient self-report [105
]. Phase II trials also reported adverse events, including headache, fatigue, and feeling hot [86
]. In phase III trials comparing DMF to glatiramer acetate (GA), no opportunistic infections or malignant neoplasms were reported, but there were decreased lymphocyte counts with DMF [75
]. The issue of leukopenia and dimethyl fumarate-associated lymphopenia has since been investigated more closely [106
]. In a cohort of 221 patients, 17% developed grade 2–3 lymphopenia, which did not resolve with DMF treatment, and smaller cohorts have shown similar results [106
]. Patients over the age of 55 undergoing DMF treatment were found to be at increased risk of developing moderate to severe lymphopenia. In a 2-year prospective study of 456 MS patients treated with DMF, there were 95 cases of lymphopenia, with 13% grade 1, 7% grade 2, and 1% grade 3 [104
]. A small number of cases of PML have been reported in MS patients taking DMF, including a patient without lymphocytopenia [87
]. A small number of neoplasms were reported [110
]. Clinically significant liver injury has been reported in more than 20 cases of MS patients treated with DMF [110
]. FDA guidelines for Bafiertam™ (MMF) advise caution as opportunistic infections have occurred during DMF treatment, specifically herpes zoster, but also other viral, fungal, and bacterial pathogens [5
]. Interim data analyses and follow-up on the long-term treatment continuation (~9 years) of the ENDORSE clinical trial (continuation of DEFINE and CONFIRM) appear to support a favorable risk-benefit profile of oral DMF [87
]. Post-marketing data have noted DMF discontinuation due to lymphopenia and elevated transaminases, along with milder, transient reactions that did not result in discontinuation such as arthralgias, alopecia, and myalgias, and asymptomatic eosinophilia [110
]. Among the pregnancies reported in the post-marketing setting and ongoing MS registries, there appears to be no increased risk of fetal abnormalities or adverse pregnancy outcomes [110
Contraindications to MMF therapy include hypersensitivity (e.g., anaphylaxis or angioedema) to MMF, DMF, DRF, or any component of their formulations, or concomitant treatment with DMF or DRF, See and .
Table 1. Clinical efficacy and safety.
||Groups Studied and Intervention
||Results and Findings
|Schimrigk et al. 2006 
|10 patients with definite RRMS, relapse in the year prior to enrollment, active lesion on MRI, active EDSS score 2.0–6.0; oral FAE * (Fumaderm initial®, Fumaderm forte®) 720 mg/day for 18 weeks, followed by 360 mg/day for 48 weeks
||Reductions in mean number and total volume of gadolinium enhancing lesions (GdE) on T1 MRI after 18 weeks of treatment
||Fumaric acid esters reduced radiologic progression of MS lesions in a small group of patients. Some FAE preparations contain more than 55% DMF and may be useful for RRMS patients.
|Kappos et al. 2008 
|257 patients with RRMS; 120 mg of DMF QD, 120 mg of DMF TID, 240 mg of DMF TID, or placebo.
||DMF 240 TID reduced mean number of GdE lesions (69%) over a 12 week period, number of new or enlarging T2-hyperintense lesions, new T1-hypointense lesions, and annual relapse rate (32%).
||DMF can reduce radiologic progression of disease in RRMS patients. Consider DMF 240 mg TID for prevention of radiological progression of disease in RRMS patients.
|Gold et al. 2012 
|1234 RRMS patients; 240 mg DMF twice daily, 240 mg DMF thrice daily, or placebo.
||Significantly lower estimated proportion of relapse: 27% in patients taking BID DMF, 26% taking TID DMF, and 46% with placebo. Annualized relapse rate at 2 years: 0.17 with BID, 0.19 with TID, and 0.36 with placebo. Rate of disability progression: 16% with BID, 18% with TID, and 27% with placebo. Significant reduction in number of Gd+ T2 MRI hyperintensities with each DMF regimen compared to placebo.
||DMF regimens reduced MS relapses and imaging findings compared to placebo. Consider 240 mg DMF twice or thrice daily for MS patients unable to tolerate other MS treatments.
|Malllucci et al. 2018 
|Records of 720 MS patients (478 female) treated with DMF: 25.8% treatment-naïve; 19.5% discontinued another DMF treatment >12 months prior; 54.6% switched from another disease-modifying treatment (DMT): (IFN (45.8%), GA (27.2%), TFU (5.8%), FTY (7.3%), NTZ (6.6%). Median DMF exposure 17 months.
||Reduction in ARR by 63.2% (mean ARR before DMF vs. mean ARR at least follow-up). 85% of patients relapse-free at 12 months, 76% of patients relapse-free at 24 months. 89% continued DMF at 12 months, and 70% continued DMF at 24 months.
||DMF may be considered in patients who must switch from another disease-modifying therapy due to tolerance issues, lack of efficacy, or safety concerns.
|Sabin et al. 2020 
|886 MS patients (629 female) treated with DMF: 25.3% treatment-naïve; 74.7% switched from another DMT. Median exposure 39.5 months. 56.2% completed at least 3 years DMF treatment.
||Tolerability and safety study. 71.2% experienced adverse events (flushing 44.1%, grade III lymphopenia 5.4%). 11.7% discontinued in the first year. No safety problems reported.
||DMF may be considered a generally safe alternative to existing DMT for RRMS patients. Acknowledge that adverse effects are relatively common and there may occasionally be the need for discontinuation.
|Gold et al. 2020 
|1736 patients taking 240 mg of DMF who completed CONFIRM/DEFINE. Patients having taken GA or TID DMF excluded. Median follow-up 8.5 years (range 2.0–11.3).
||ARR remained low (<0.20) over ~9 year treatment period. Approximately 70% patients had no new or enlarging MRI lesions compared to baseline after 7 years of DMF treatment. Of 2470 patients had ≥ lymphocyte assessment, 53 developed severe prolonged lymphopenia.
||There is support for long-term safety and efficacy of DMF in RRMS patients.