Delayed-release Dimethyl Fumarate Research Articles

Long-Term Safety and Effectiveness of Delayed-release Dimethyl Fumarate in Multiple Sclerosis Patients Treated in Routine Medical Practice, an updated analysis of the ESTEEM Study (P7-3.009)

Long-Term Safety and Effectiveness of Delayed-release Dimethyl Fumarate in Multiple Sclerosis Patients Treated in Routine Medical Practice, an updated analysis of the ESTEEM Study (P7-3.009)

Final Analysis of Pregnancy Outcomes Following Exposure to Dimethyl Fumarate in a Prospective International Registry (S31.004)

Final Analysis of Pregnancy Outcomes Following Exposure to Dimethyl Fumarate in a Prospective International Registry (S31.004)

Metabolism, pharmacokinetics and excretion of [14C]dimethyl fumarate in healthy volunteers: an example of xenobiotic biotransformation following endogenous metabolic pathways

Delayed–release dimethyl fumarate (DMF), Tecfidera ® , is approved globally for treating relapsing-remitting multiple sclerosis. The disposition of DMF was determined in humans after administration of a single oral dose of [14C]DMF, and the total recovery was estimated to be between 58.4% to 75.0%, primarily through expired air. The absorption of [14C]DMF-derived radioactivity was rapid, with Tmax at 1h postdose. Glucose was the predominant circulating metabolite, accounting for ∼60% of the total extractable radioactivity. Cysteine and N-acetylcysteine conjugates of mono- or di-methyl succinate were found to be the major urinary metabolites. In vitro studies showed that [14C]DMF was mainly metabolised to MMF, and fumarase exclusively converted fumaric acid to malic acid and did not catalyse the conversion of fumaric acid esters to malic acid. DMF was observed to bind with human serum albumin through Michael addition to the Cys-34 residue when exposed to human plasma. These findings indicate that DMF undergoes metabolism via hydrolysis, GSH conjugation, and the TCA cycle, leading to the formation of citric acid, CO2, and water. These ubiquitous and well-conserved metabolism pathways minimise the risk of drug-drug interactions and reduce variability related to pharmacogenetics and ethnicity.

Pregnancy outcomes in a dimethyl fumarate exposure registry

IntroductionThe delayed-release dimethyl fumarate (DMF) label recommends use during pregnancy only if potential benefit justifies the potential risk. Given limited pregnancy data, United Kingdom (UK) and Ireland are enrolling DMF-exposed pregnant women into an ongoing international registry assessing pregnancy outcomes. Pregnancies end in live birth (62%), abortion (22%), and fetal loss (16%) in general, with similar rates in MS patients.MethodsPregnant women with MS exposed to DMF since the first day of their last menstrual period prior to conception/during pregnancy were included. The UK/Ireland Coordinating Centres liaise directly with patients and HCPs.ResultsAs of April 2019, 263 patients (14 patients from UK/Ireland) were enrolled. Of the 214 pregnancy outcomes (12 UK/Ireland) reported to date, 197(92%) were live births (12 UK/Ireland) and 17(8%) foetal loss. Of infants with known gestational age (n=197), 176(89%) births were full-term (12 UK/Ireland) and 18(9%) premature (<37 weeks). There were 16 spontaneous abortions (1 ectopic pregnancy), and 1 foetal death at ≥28 weeks of gestation. No molar pregnancies or infant or maternal deaths were reported. Seven(4%) infants (1 UK/Ireland) had confirmed birth defects.ConclusionNo safety signal was observed, consistent with MS and general populations. Support: Biogen; disclosures detailed on poster.david.rog@srft.nhs.uk

Long-Term Safety and Effectiveness of Delayed-release Dimethyl Fumarate in Multiple Sclerosis Patients Treated in Routine Medical Practice (P7-4.009)

Long-Term Safety and Effectiveness of Delayed-release Dimethyl Fumarate in Multiple Sclerosis Patients Treated in Routine Medical Practice (P7-4.009)

Characterizing Long-term Disability Progression and Employment in NARCOMS Registry Participants with Multiple Sclerosis Taking Dimethyl Fumarate.

Delayed-release dimethyl fumarate (DMF) is effective in relapsing-remitting multiple sclerosis (RRMS), but long-term effects of DMF on disability and disease progression in clinical settings are unknown. We evaluated disability and employment outcomes in persons with RRMS treated with DMF for up to 5 years. This longitudinal study included US North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants with RRMS reporting DMF initiation in fall 2013 through spring 2018 with 1 year or more of follow-up. Time to 6-month confirmed disability progression (≥1-point increase in Patient-Determined Disease Steps [PDDS] score) and change in employment status were evaluated using Kaplan-Meier analysis. Participants were censored at last follow-up or at DMF discontinuation, whichever came first. During the study, 725 US participants with RRMS had at least 1 year of DMF follow-up data, of whom most were female and White. At year 5, 69.9% (95% CI, 65.4%-73.9%) of these participants were free from 6-month confirmed disability progression, and 84.7% (95% CI, 78.6%-89.2%) were free from conversion to secondary progressive MS. Of 116 participants with data at baseline and year 5, most had stable or improved PDDS and Performance Scales scores over 5 years. Of 322 participants 62 years and younger and employed at the index survey, 66.0% (95% CI, 57.6%-73.1%) were free from a negative change in employment type over 5 years. Most US NARCOMS Registry participants treated up to 5 years with DMF remained free from 6-month confirmed disability progression and conversion to secondary progressive MS and had stable disability and employment status. These results support the long-term stability of disability and work-related outcomes with disease-modifying therapy.

A pharmacokinetic and biomarker study of delayed-release dimethyl fumarate in subjects with secondary progressive multiple sclerosis: evaluation of cerebrospinal fluid penetration and the effects on exploratory biomarkers

BackgroundBiomarkers are a useful and reliable measure of disease activity in many fields of medicine. Axonal and glial biomarkers in multiple sclerosis (MS) are being applied more often as technology is improving and becoming increasingly reliable. Nonclinical studies have shown dimethyl fumarate (DMF) to have cytoprotective and anti-inflammatory effects. The purpose of this study is to explore the pharmacokinetics (PK) of DMF (by measuring MMF, the active compound) in serum and cerebrospinal fluid (CSF) as well as relevant biomarker data for patients with secondary progressive MS (pwSPMS) and whether there is objective evidence for neuroprotection in pwSPMS treated with DMF. MethodsSixteen pwSPMS had serum and cerebrospinal fluid (CSF) evaluation for PK studies levels of MMF at various time points after ingestion of DMF. The CSF biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxyo-terminal hydrolase isozyme L1 (UCH-L1) and total tau (T-tau) were measured at baseline, week 6 and week 28 after initiating DMF with a starting dose of 120 mg twice daily for 4 weeks, followed by a maintenance dose of 240 mg twice daily. Clinical correlation of these patients with EDSS and MRI at these same time periods were made with the biomarkers. Four normal human volunteers had CSF studies for biomarkers at baseline. ResultsPK data showed CSF MMF concentration 11% of plasma with Tmax of plasma at 5 hr and Tmax of CSF at 7 hr. Biomarker data showed that CS NfL and to a lesser extent, GFAP, but not UCH-L1 nor T-tau showed relevant changes with clinical data. Some pwSPMS receiving DMF showed clinical improvements in Expanded Disability Status Scale (EDSS). Biomarker changes, but not MRI, correlated with clinical measures in this group of pwSPMS over the observation period. ConclusionsPK data showed that the Tmax of CSF MMF peaked only 2 hours later than that of plasma with 11% measured in the CSF so that MMF readily crossed the blood brain barrier allowing potential direct penetration into the brain. NfL CSF levels, and to a lesser extent, GFAP CSF levels, showed correlation to disease activity in pwSPMS . These data suggest that DMF may have some benefit in reducing disease activity in pwSPMS if studied for a longer duration and larger well-controlled studies are warranted. DMF was reasonably well tolerated but 3 of the 16 patients did discontinue DMF at 6 weeks due to persistent side effects. NfL appeared to be more clinically relevant biomarker than brain MRI in this this group during the 28-week study period.

Delayed-Release Dimethyl Fumarate Safety and Efficacy in Pediatric Patients With Relapsing-Remitting Multiple Sclerosis.

Background: Pediatric multiple sclerosis (MS) is rare: only 1.5–5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS.Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13–17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR).Results: Twenty participants [median (range) age, 17 (14–18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16–24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0–6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction (n = 20; 95% confidence interval: 66.8–92.8; p < 0.0001) vs. the year before DMF initiation.Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment.

Medication adherence/persistence among patients with active multiple sclerosis in Finland.

ObjectivesTo explore adherence, persistence, and treatment patterns in patients with multiple sclerosis (MS) in Finland treated with disease‐modifying therapies (DMTs) for active MS in 2005‐2018.Materials and MethodsThe study cohort was identified using the Drug Prescription Register of Social Insurance Institute, Finland. All patients had at least one prescription of glatiramer acetate (GA), beta‐interferons, teriflunomide, or delayed‐release dimethyl fumarate (DMF). Adherence was calculated using proportion of days covered (PDC) (cutoff ≥0.8). Time to non‐persistence was calculated by the number of days on index DMT treatment before the first treatment gap (≥90 days) or switch and analyzed with time‐to‐event methodology.ResultsThe cohort included 7474 MS patients (72.2% female; mean age 38.9 years). Treatment switches were steady over 2005‐2012, peaked in 2015. PDC means (standard deviations) were GA, 0.87 (0.17); beta‐interferons, 0.88 (0.15); DMF, 0.89 (0.14); teriflunomide, 0.93 (0.10). Adherence frequencies were GA, 78.4%; beta‐interferons, 81.3%; DMF, 86.9%; teriflunomide, 91.7%. Logistic regression showed that age group, DMT and the starting year, sex, and hospital district independently affected adherence. Patients receiving teriflunomide and DMF, males, and older patients were more likely to persist on treatment. There was no difference in persistence between patients prescribed teriflunomide and DMF, or between GA and beta‐interferons.ConclusionsOral DMTs had greater adherence and persistence than injectable DMTs.

Dimethyl fumarate treatment shifts the immune environment toward an anti-inflammatory cell profile while maintaining protective humoral immunity

Background: Delayed-release dimethyl fumarate (DMF) demonstrates sustained efficacy and safety for relapsing forms of MS. Absolute lymphocyte count (ALC) is reduced initially, then stabilizes on treatment. Objective: PROCLAIM, a 96-week, prospective, open-label, phase 3b study, assessed lymphocyte subsets and immunoglobulin (Ig) levels during 48 and 96 weeks (W) of DMF treatment. Methods: Patients received 240 mg DMF BID. Endpoints: lymphocyte subset count changes (primary); Ig isotypes and ALC changes (secondary); adverse events and relationship between ALC changes and ARR/EDSS (exploratory); and neurofilament assessment (ad hoc). Results: Of 218 patients enrolled, 158 (72%) completed the study. Median ALC decreased 39% from baseline to W96 (BL–W96), stabilizing above the lower limit of normal (baseline: 1.82 × 109/L; W48: 1.06 × 109/L; W96: 1.05 × 109/L). CD4 + and CD8 + T cells correlated highly with ALC from BL–W96 (p < 0.001). Relative to total T cells, naive CD4 + and CD8 + T cells increased, whereas CD4 + and CD8 + central and effector memory T cells decreased. Total IgA, IgG, IgM, and IgG1–4 subclass levels remained stable. Adverse event rates were similar across ALC subgroups. ARR, EDSS, and neurofilament were not correlated with ALCs. Conclusion: Lymphocyte decreases with DMF were maintained over treatment, yet immunoglobulins remained stable. No increase in infection incidence was observed in patients with or without lymphopenia. Support: Biogen

Absolute Lymphocyte Counts Are Not a Biomarker of Clinical Response in Patients Treated With Delayed-Release Dimethyl Fumarate (830)

Absolute Lymphocyte Counts Are Not a Biomarker of Clinical Response in Patients Treated With Delayed-Release Dimethyl Fumarate (830)

Overall Safety and Efficacy Through 10 Years of Treatment with Delayed-Release Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis (1345)

Overall Safety and Efficacy Through 10 Years of Treatment with Delayed-Release Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis (1345)

Nursing Management of Gastrointestinal Adverse Events Associated With Delayed-Release Dimethyl Fumarate: A Global Delphi Approach

Gastrointestinal (GI) adverse events (AEs) are commonly encountered with delayed-release dimethyl fumarate (DMF), an approved treatment for relapsing multiple sclerosis (MS). Two hundred thirty-nine MS nurses from 7 countries were asked to complete a 2-round Delphi survey developed by a 7-member steering committee. Questions pertained to approaches for mitigating DMF-associated GI AEs. Ninety-six percent of nurses followed the label recommendation for DMF dose titration in round 1, but 77% titrated the DMF dose more slowly than recommended in round 2. Although 86% of nurses advised persons with relapsing forms of MS (PWMS) to take DMF with food, patients were not routinely informed of appropriate types of food to take with DMF. Most nurses recommended both pharmacologic and nonpharmacologic symptomatic therapies for PWMS who experienced GI AEs on DMF. Pharmacologic and nonpharmacologic symptomatic therapies were regarded as equally effective at keeping PWMS on DMF. In round 2, 58% of nurses stated that less than 10% of PWMS who temporarily discontinued DMF went on to permanently discontinue treatment. Sixty-six percent of nurses stated that less than 10% of PWMS permanently discontinued DMF because of GI AEs in the first 6 months of treatment in round 1. Most nurses agreed that patient education on potential DMF-associated GI AEs contributes to adherence. This first real-world nurse-focused assessment of approaches to caring for PWMS with DMF-associated GI AEs suggests that, with implementation of slow dose titration, symptomatic therapies, and educational consultations, most PWMS can remain on DMF and, when necessary after temporary discontinuation, successfully restart DMF.

Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years' follow-up of DEFINE, CONFIRM, and ENDORSE.

Introduction:We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported.Methods:Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0–2 /DMF for years 3–9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed.Results:Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0–2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6–0.8 and 0.9–2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was −1.32% (range −1.60% to −1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 109/L at discontinuation (n = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation.Conclusions:Sustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS.Trial registration:ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).

A Retrospective Analysis of Real-World Discontinuation Rates with Delayed-Release Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis.

IntroductionThe main objective of this study was to examine discontinuation rates associated with delayed-release dimethyl fumarate (DMF) when used for the treatment of relapsing multiple sclerosis (MS) in a real-world, clinical practice setting.MethodsData were collected retrospectively from charts of adult patients with relapsing–remitting MS treated at a single large institution in Australia, who completed at least 6 months of continuous therapy, either with DMF or another MS medication administered following DMF discontinuation. The primary endpoint was overall discontinuation rate. Secondary endpoints included discontinuation rate 6 months after initiation of DMF therapy; incidence of adverse events, particularly gastrointestinal events; discontinuation rate because of adverse events; and use of concomitant medications by patients during administration of DMF.ResultsA total of 100 patients initially prescribed DMF between October 1, 2013 and June 30, 2014 were included in the analysis. The mean age of the patients was 43 years and 80% were female. The overall discontinuation rate was 13%, with 9% discontinuing because of gastrointestinal tolerability issues, within the first 6 months. Dose changes as a result of adverse events occurred in 15% of patients, and none of the adverse events reported were serious. Only one patient discontinued owing to lack of efficacy.ConclusionThis study, conducted shortly after the approval of DMF in Australia when first-hand clinical experience was still limited, demonstrated that DMF has an acceptable tolerability profile in the real-world setting that is similar to that demonstrated in clinical trials.

Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate.

In delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known risk factor for progressive multifocal leukoencephalopathy (PML); DMF-associated PML is very rare. It is unknown whether genetic predictors of SPL secondary to DMF treatment exist. We aimed to identify genetic predictors of reduced white blood cell (WBC) counts in DMF-treated multiple sclerosis (MS) patients. Genotyping (N = 1,258) and blood transcriptional profiling (N = 1,133) were performed on MS patients from DEFINE/CONFIRM. ALCs were categorized as: SPL, < 500 cells/µL for ≥6 months; moderate prolonged lymphopenia (MPL), < 800 cells/µL for ≥6 months, excluding SPL; mildly reduced lymphocytes, < 910 cells/µL at any point, excluding SPL and MPL; no lymphopenia, ≥910 cells/µL. Genome-wide association, HLA, and cross-sectional gene expression studies were performed. No common variants, HLA alleles, or expression profiles clinically useful for predicting SPL or MPL were identified. There was no overlap between genetic peaks and genetic loci known to be associated with WBC. Gene expression profiles were not associated with lymphopenia status. A classification model including gene expression features was not more predictive of lymphopenia status than standard covariates. There were no genetic predictors of SPL (or MPL) secondary to DMF treatment. Our results support ALC monitoring during DMF treatment as the most effective way to identify patients at risk of SPL.

PND11 IMPACT OF A COMMUNITY PHARMACY-BASED INFORMATION PROTOCOL ON MULTIPLE SCLEROSIS PATIENTS' ADHERENCE TO THEIR ORAL TREATMENT WITH DIMETHYL FUMARATE: TECPHIE, A RANDOMIZED STUDY VS USUAL PRACTICE (INTERIM RESULTS)

Delayed-release dimethyl fumarate (DMF) is an oral compound indicated for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). This study aims to assess the impact on adherence of specific advice provided by retail pharmacists. TECPHIE is a randomized, prospective, multicentre study with two groups of pharmacists, one providing 6 motivational interviews in a period of 9 months in addition to the usual drug delivery and one delivering drug in the usual settings. At the end of recruitment, 109 patients were recruited by 190 pharmacists. An interim intent-to-treat analysis has been performed at 6 months with 31 patients: 17 without motivational interviews (control group) and 14 with motivational interviews. Mean age was 42 (range, 18−75) years in both groups and disease anteriority was 6 to 7 years on average, with a sex ratio of 4 women for every 1 man. The DMF pill count in the group without motivational interviews was 94.4% (SD 7.3), whereas it was 98.7% (SD 2.7) in the group with motivational interviews (p<0.05). At 6 months, an interim per-protocol analysis was performed with 28 patients: 15 without and 13 with motivational interviews. The DMF pill count in the group without motivational interviews was 95.5% (SD 4.8), whereas it was 99.1% (SD 2. 6) in the group with motivational interviews (p<0.05). In this interim analysis of RRMS patients treated with DMF, the overall treatment adherence rate at 6 months was high in both groups. However, there was a statistically significant increase in adherence among patients who received motivational interviews by a pharmacist compared with those who did not.

PND24 COST-EFFECTIVENESS ANALYSIS OF DIMETHYL FUMARATE IN THE TREATMENT OF RELAPSING-REMITTING MULTIPLE SCLEROSIS IN ITALY

Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate, DMF) is an oral disease-modifying therapy used for the treatment of relapsing-remitting multiple sclerosis (RRMS). Aim of this economic analysis was to evaluate the cost effectiveness of DMF compared with teriflunomide in first-line treatment of RRMS in Italy, adopting both National Healthcare Service (NHS) and societal perspectives. Cost-effectiveness analysis (CEA) was developed through a Markov model with lifetime horizon. Outcomes were measured in terms of life years (LYs), quality-adjusted life years (QALYs), lifetime costs and incremental cost-effectiveness ratio (ICER). Efficacy of treatments, expressed as reduction of disability progression and relapse rate, were derived from an elaboration of a mixed treatment comparison. Utilities were retrieved from DMF clinical trials and MS survey. Relapses, adverse events, progression to secondary progressive MS were associated with disutilities. Both direct and indirect costs were captured. Unit costs were based on current Italian prices, tariffs, published literature. An annual 3.5% discount rate was applied to costs and outcomes. One-way deterministic and probabilistic sensitivity analyses were conducted, a cost-effectiveness acceptability curve was generated. DMF was more efficacious than teriflunomide for both LYs (19.63 vs. 19.55) and QALYs (6.53 vs. 5.95). From NHS perspective, total costs per patient treated with DMF (€ 348,216) were slightly higher than with teriflunomide (€ 336,896). Resulting ICER was € 19,741 per QALY gained, significantly below the Italian willingness-to-pay threshold (€ 50,000 per QALY). From societal perspective, total costs per patient treated with DMF (€ 1.01 M) were lower than with teriflunomide (€ 1.03 M). DMF was dominant because more effective in terms of QALYs and less costly. Both sensitivity analyses confirmed robustness and reliability of base-case results. Results of this CEA confirm that DMF may be an optimal first-line treatment for RRMS in both Italian NHS and societal perspectives.

Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting: PROTEC.

BackgroundPatient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing–remitting multiple sclerosis (RRMS) disease.ObjectiveThe aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic.MethodsPROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (≤3.5 EDSS and ≤1 relapse in the prior year) patient subgroups were evaluated.ResultsUnadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n = 1105) and 84%, 77%, and 71% lower in newly diagnosed, ≤3.5 EDSS, and ≤1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, ≤3.5 EDSS; 88%, ≤1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline.ConclusionAt 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective.Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708, https://clinicaltrials.gov/ct2/show/NCT01930708.

Gut microbiota composition during a 12-week intervention with delayed-release dimethyl fumarate in multiple sclerosis - a pilot trial.

IntroductionPatients with multiple sclerosis may have a distinct gut microbiota profile. Delayed-release dimethyl fumarate is an orally administered drug for relapsing–remitting multiple sclerosis, which has been associated with gastrointestinal side-effects in some patients.ObjectivesThe purpose of this study was to determine if dimethyl fumarate alters the abundance and diversity of commensal gut bacteria, and if these changes are associated with gastrointestinal side-effects.MethodsThirty-six patients with relapsing–remitting multiple sclerosis received either dimethyl fumarate (n = 27) or an injectable multiple sclerosis disease-modifying therapy (glatiramer acetate or interferons, n = 9) for 12 weeks. Stool samples were collected at baseline, two and 12 weeks. We included 165 healthy individuals as controls.ResultsAt baseline, 16 microbial genera were altered in multiple sclerosis patients compared with healthy controls. In the dimethyl fumarate-treated patients (n = 21) we observed a trend of reduced Actinobacteria (p = 0.03, QFDR = 0.24) at two weeks, mainly driven by Bifidobacterium (p = 0.06, QFDR = 0.69). At 12 weeks, we observed an increased abundance of Firmicutes (p = 0.02, QFDR = 0.09), mostly driven by Faecalibacterium (p = 0.01, QFDR = 0.48).ConclusionsThis pilot study did not detect a major effect of dimethyl fumarate on the gut microbiota composition, but we observed a trend towards normalization of the low abundance of butyrate-producing Faecalibacterium after 12 weeks treatment. The study was underpowered to link microbiota to gastrointestinal symptoms.