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).

中文翻译：

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与富马酸二甲酯相比，富马酸地罗昔梅尔在复发缓解型多发性硬化症患者中表现出更好的胃肠道耐受性：随机、双盲、III 期 EVOLVE-MS-2 研究的结果。


背景富马酸地罗西梅尔（DRF）是一种新型口服富马酸盐，在美国被批准用于治疗复发型多发性硬化症。 DRF 转化为富马酸单甲酯，即富马酸二甲酯 (DMF) 的药理活性代谢物。 DRF 462 mg 和 DMF 240 mg 产生富马酸单甲酯的生物等效暴露，因此预计具有相似的功效/安全性； DRF 独特的化学结构可能有助于其耐受性。目的 本研究的目的是比较复发缓解型多发性硬化症患者 5 周内 DRF 和 DMF 的胃肠道耐受性。方法 EVOLVE-MS-2 是一项 III 期、随机、双盲、头对头、为期 5 周的研究，评估 DRF 462 mg 与 DMF 240 mg（每日两次）在复发缓解型多发性骨髓瘤患者中的胃肠道耐受性硬化症，使用两种自我管理的胃肠道症状量表：个体胃肠道症状和影响量表（IGISIS）和整体胃肠道症状和影响量表（GGISIS）。主要终点是相对于暴露而言 IGISIS 强度评分 ≥ 2 的天数。其他终点包括通过 IGISIS/GGISIS 测量的胃肠道症状严重程度以及安全性/耐受性评估。结果 与 DMF 治疗的患者相比，DRF 治疗的患者 IGISIS 症状强度评分 ≥ 2 的天数显着减少 (46%)（比率比 [95% 置信区间]：0.54 [0.39-0.75]； p = 0.0003）。 DRF 的胃肠道不良事件（包括腹泻、恶心、呕吐和腹痛）发生率低于 DMF（34.8% vs 49.0%）。由于不良事件而停止 DRF 的患者少于 DMF（1.6% vs 5.6%）。6%）和胃肠道不良事件（0.8% vs 4.8%）。结论 与 DMF 相比，DRF 具有改善的胃肠道耐受性，胃肠道事件较轻，自我评估胃肠道症状的天数较少，胃肠道不良事件较少，并且因胃肠道不良事件而停药的比率较低。临床试验注册 ClinicalTrials.gov (NCT03093324)。