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Background Tecfidera ® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy. Objective The objective of this study was to determine whether two Bafiertam™ capsules each containing 95 mg of MMF is bioequivalent to one Tecfidera ® capsule containing 240 mg of DMF, a prodrug of MMF. Methods This was a single-dose, open-label, randomized, two-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Fifty healthy subjects were randomized to receive a single dose of the test drug MMF 190 mg as 2 × 95 mg delayed-release capsules or the reference drug DMF 240 mg as a 1 × 240-mg delayed-release capsule. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. The pharmacokinetic parameters of MMF were calculated including maximum observed concentration, time to reach maximum observed concentration, apparent half-life of the drug in plasma, AUC 0– t which is the area under the plasma concentration–time curve (AUC) from time zero (dosing time) to the last time point, t , with measurable analyte concentration, and AUC 0–inf , which is AUC 0– t plus the extrapolated AUC from time t to infinity. Results The geometric least-squares mean ratios (90% confidence interval) of the test drug MMF vs the reference drug DMF were 96.80% (92.18–101.64), 96.35% (91.81–101.12), and 104.84% (95.54–115.05) for AUC 0– t , AUC 0–inf , and maximum observed concentration, respectively. Two capsules of Bafiertam™ was safe and generally well tolerated. The most common adverse event for both products was flushing, 60% and 51%, for Bafiertam™ and Tecfidera ® , respectively. Conclusions Based on the statistical analysis results of the pharmacokinetic parameters of MMF, a single oral dose of two Bafiertam™ DR 95 mg capsules is bioequivalent to a single oral dose of one Tecfidera ® DR 240 mg capsule. Clinical Trial Registration This study was retrospectively registered with ClinicalTrials.gov (NCT04570670) on 30 September, 2020.

Dimethyl fumarate (Tecfidera ® ) is approved for the treatment of relapsing forms of multiple sclerosis (MS). Based on evidence from the clinical trial and real-world settings, dimethyl fumarate is an effective treatment in this patient population, with benefits maintained over the longer term. In the pivotal, placebo-controlled phase III DEFINE and CONFIRM trials in adults with relapsing-remitting multiple sclerosis (RRMS), twice-daily dimethyl fumarate reduced clinical relapse and MRI measures of disease activity and improved some aspects of health-related quality of life (HR-QoL). Reduced disability progression was also observed with dimethyl fumarate in DEFINE. Results in predominantly East Asian patients (APEX trial) were reflective of those seen in DEFINE and CONFIRM. Dimethyl fumarate had an acceptable tolerability profile. The most common adverse events were flushing and gastrointestinal events, which were of mild or moderate severity and appear to be largely manageable. Thus twice-daily dimethyl fumarate remains an effective treatment option for use in patients with RRMS, with the convenience of oral administration.

Objective Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro‐inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS. Methods Phase‐2, double‐blind, placebo‐controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised (ALSFRS‐R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin‐receptor p75 and quality of life. Results A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS‐R score was not significantly different at week 36 (−1.12 [−3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least‐squares mean: (0.84 [−0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups. Interpretation Dimethyl fumarate, in combination with riluzole, was safe and well‐tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS.

Background and Purpose The first randomized placebo-controlled therapeutic trial in radiologically isolated syndrome (RIS), ARISE, demonstrated that treatment with dimethyl fumarate (DMF) delayed the onset of a first clinical event related to CNS demyelination and was associated with a significant reduction in new and/or newly enlarging T2-weighted hyperintense lesions. The purpose of this study was to explore the effect of DMF on volumetric measures, including whole brain, thalamic, and subcortical gray matter volumes, brainstem and upper cervical spine three-dimensional (3D) volumes, and brainstem and upper cervical spine surface characteristics. Methods Standardized 3T MRIs including 3D isotropic T1-weighted gradient echo images were acquired at baseline and end-of-study according to the ARISE study protocol. The acquired data were analyzed using Structural Image Evaluation Using Normalization of Atrophy (SIENA), FreeSurfer v7.3, and an in-house pipeline for 3D conformational metrics. Multivariate mixed models for repeated measures were used to analyze rates of change in whole brain, thalamic, subcortical gray matter, as well as change in the 3D surface curvature of the dorsal pons and dorsal medulla and 3D volume change at the medulla-upper cervical spinal cord. Results The study population consisted of 64 RIS subjects (DMF:30, placebo:34). No significant difference was seen in whole brain, thalamic, or subcortical gray matter volumes in treated vs. untreated RIS patients. A significant difference was observed in dorsal pons curvature with the DMF group having a lower least squares mean change of − 4.46 (standard estimate (SE): 3.77) when compared to placebo [6.94 (3.71)] ( p  = 0.036). In individuals that experienced a first clinical event, a greater reduction in medulla–upper cervical spinal cord volume ( p  = 0.044) and a decrease in surface curvature was observed at the dorsal medulla ( p  = 0.009) but not at the dorsal pons ( p  = 0.443). Conclusions The benefit of disease-modifying therapy in RIS may extend to CNS structures impacted by neurodegeneration that is below the resolution of conventional volumetric measures.

In a randomized trial, patients who received evobrutinib, an inhibitor of Bruton’s tyrosine kinase, at 75 mg daily had significantly fewer enhancing lesions on MRI during weeks 12 through 24 than those who received placebo. However, there was no significant between-group difference for either a lower or a higher dose of evobrutinib, or in the annualized relapse rate or disability progression at any dose.

In Phase III trials, delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and an acceptable safety profile in patients with relapsing-remitting multiple sclerosis. The purpose of the present study was to examine 2 potential mitigation strategies for flushing and gastrointestinal (GI) events associated with DMF treatment: aspirin (ASA) 325 mg pretreatment for flushing, and slow dose titration of DMF for flushing and GI events. The 8-week study included 173 healthy volunteers randomized to 4 groups; 172 underwent dosing. The placebo group (n = 44) received placebo ASA 30 minutes before placebo DMF (weeks 1−4), then placebo DMF alone (weeks 5−8). The DMF without ASA group (n = 43) and the DMF with ASA group (n = 43) received placebo ASA or ASA, respectively, 30 minutes before DMF (weeks 1−4), then DMF alone (weeks 5−8); in both groups, DMF was dosed at 120 mg BID (week 1) and 240 mg BID (weeks 2−8). The slow dose titration DMF group (n = 42) received DMF 120 mg once daily (week 1), 120 mg BID (week 2), 240 mg in the morning/120 mg in the evening (week 3), and 240 mg BID (weeks 4−8). Subjects recorded information about flushing and GI-related events by using an eDiary and numerical rating scales. Flushing and GI-related events were reported in all groups and were mostly rated as mild or moderate in severity. Flushing events were generally ~1 hour in duration and, for most subjects with flushing, initially occurred the first day of study treatment. The duration of GI-related events and time to first GI-related event varied by event type. ASA reduced the incidence, severity, and number of flushing events without affecting duration or time to first flushing event, and had no adverse effect on GI-related events. Dose titration of DMF had no significant effect on flushing or GI events. No subjects discontinued the study due to flushing events. One subject (2%) in the placebo group, 3 subjects (7%) in the DMF without ASA group, 6 subjects (14%) in the DMF with ASA group, and 2 subjects (5%) in the slow dose titration DMF group discontinued treatment because of GI events. ASA pretreatment may mitigate flushing associated with DMF, with no adverse effect on GI events. Dose titration of DMF did not have a significant effect on flushing or GI events and is being evaluated further in ongoing clinical trials. ClinicalTrials.gov identifier: NCT01568112.

Background Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile. Objectives The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing–remitting multiple sclerosis. Methods EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing–remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability. Results DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39–0.75]; p  = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%). Conclusions DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events. Clinical Trials Registration ClinicalTrials.gov (NCT03093324).

ObjectivesIn a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity.MethodsWe examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF.ResultsNFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001).ConclusionsThis study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.

Dimethyl fumarate (DMF), the first-line oral therapy for relapsing-remitting multiple sclerosis, is rapidly metabolized into monomethyl fumarate. The DMF oral administration provokes gastrointestinal discomfort causing treatment withdrawal. The present study aimed to develop an innovative formulation for DMF nasal administration. Lipid-polymer hybrid nanoparticles (LPNs) were developed to improve DMF stability, limiting gastrointestinal side effects and increasing brain bioavailability by nose-to-brain targeting application. DMF-loaded and unloaded LPNs with or without hyaluronic acid (HA) were prepared using the nanoprecipitation via magnetic/mechanical stirring technique. Particle morphology and surface properties were evaluated; drug content, viscosity, and mucoadhesion were determined. Physico-chemical stability of LPNs and DMF in the LPNs was also explored. In vitro DMF permeation experiments were performed utilizing the PermeaPad . The cytotoxicity and cellular uptake studies were performed using RPMI 2650 and SK-N-BE2 cell lines. DMF nose-to-brain delivery was evaluated by intranasally administering DMF-loaded LPNs to rats. LPNs with average sizes of 120-250 nm and a negative zeta potential -17.3 to -43 mV were obtained, primarily influenced by the presence of HA. HA assured drug stability up to 60 days and promoting the in vitro permeation of DMF compared to the free-DMF. HA greatly improved the viscosity and mucoadhesive properties. LPNs with and without HA did not exhibit any cytotoxicity and showed a rapid cell uptake starting from 15 min to 2 h with a best internalization after 1 h of treatment in both epithelial and neuronal cell lines. Nasal administration of DMF-loaded LPNs allowed to quantify up to about 12 μg/mL of DMF in the rat cerebrospinal fluid. The results highlight the role of HA in improving LPNs properties and performance as carrier of DMF for nasal administration. In particular, LPNs appear able to enter neurons and monolayers of epithelial cells, allowing to promote the nose-to-brain DMF delivery.

The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.