Diroximel fumarate
(Synonyms: 2-(2,5-二氧代吡咯烷-1-基)乙基甲基富马酸酯,ALKS 8700; BIIB098) 目录号 : GC35871A prodrug form of monomethyl fumarate
Cas No.:1577222-14-0
Sample solution is provided at 25 µL, 10mM.
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Diroximel fumarate is a prodrug form of monomethyl fumarate .1 It undergoes esterase cleavage in the gut to release monomethyl fumarate. Formulations containing diroximel fumarate have been used in the treatment of relapsing-remitting multiple sclerosis.
1.Naismith, R.T., Wolinsky, J.S., Wundes, A., et al.Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 studyMult. Scler.(2019)
Cas No. | 1577222-14-0 | SDF | |
别名 | 2-(2,5-二氧代吡咯烷-1-基)乙基甲基富马酸酯,ALKS 8700; BIIB098 | ||
Canonical SMILES | O=C(OCCN1C(CCC1=O)=O)/C=C/C(OC)=O | ||
分子式 | C11H13NO6 | 分子量 | 255.22 |
溶解度 | DMSO: 125 mg/mL (489.77 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.9182 mL | 19.5909 mL | 39.1819 mL |
5 mM | 0.7836 mL | 3.9182 mL | 7.8364 mL |
10 mM | 0.3918 mL | 1.9591 mL | 3.9182 mL |
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Diroximel fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study
CNS Drugs 2020 Feb;34(2):185-196.PMID:31953790DOI:10.1007/s40263-020-00700-0.
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).
Diroximel fumarate to treat multiple sclerosis
Drugs Today (Barc) 2020 Jul;56(7):431-437.PMID:32648853DOI:10.1358/dot.2020.56.7.3151521.
On October 29, 2019, the Food and Drug Administration (FDA) of the United States approved Diroximel fumarate (DRF) as an oral fumarate for the treatment of relapsing forms of multiple sclerosis. Another oral fumarate, dimethyl fumarate (DMF), was approved for the same indication on March 27, 2013. Prior to its approval, DRF did not undergo rigorous testing to determine its efficacy, as its active metabolite, monomethyl fumarate, is the same as that of DMF (bioequivalency). The efficacy, safety and tolerability of DMF have previously been demonstrated in a number of clinical trials and real-world studies. For DRF, one phase III study has been completed, and another is in progress to determine its safety, tolerability and efficacy. In this paper, we review the pharmacology, pharmacokinetics, metabolism, clinical studies and drug safety of DRF.
Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study
Mult Scler 2020 Nov;26(13):1729-1739.PMID:31680631DOI:10.1177/1352458519881761.
Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20). Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.
Diroximel fumarate in Relapsing Forms of Multiple Sclerosis: A Profile of Its Use
CNS Drugs 2021 Jun;35(6):691-700.PMID:34057708DOI:10.1007/s40263-021-00830-z.
Diroximel fumarate (Vumerity®), an orally administered disease-modifying drug (DMD), expands the available treatment options for adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS (RRMS), and active secondary progressive MS. It demonstrates bioequivalence to dimethyl fumarate and was developed to provide similar clinical benefits, but with an improved gastrointestinal (GI) tolerability profile. In RRMS patients who are treatment-naïve or were previously treated with interferon-β or glatiramer acetate, Diroximel fumarate reduces annualized relapse rates, with most patients experiencing no relapses during treatment, and reduces the formation of new MS-associated brain lesions. Diroximel fumarate has an acceptable tolerability profile that is consistent with that of dimethyl fumarate, albeit with a significantly lower rate of GI adverse events.
Efficacy and Safety Outcomes with Diroximel fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study
Adv Ther 2022 Apr;39(4):1810-1831.PMID:35211872DOI:10.1007/s12325-022-02068-7.
Introduction: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated. Methods: EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1. Results: As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was < 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%). Conclusion: After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs. Trial registration: ClinicalTrials.gov (NCT02634307). INFOGRAPHIC.