Oregon Health Sciences University Pediatrics, Portland, OR, USA.
University of Florida Health Physical Therapy, Gainesville, FL, USA.
J Neuromuscul Dis. 2019;6(1):43-54. doi: 10.3233/JND-180341.
Edasalonexent is an orally administered small molecule designed to inhibit NF-κB, which is activated from infancy in Duchenne muscular dystrophy and is central to causing muscle damage and preventing muscle regeneration.
Evaluate the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of three doses of edasalonexent in ambulatory males ≥4 to <8 years of age with genetically confirmed Duchenne muscular dystrophy.
This was a 1-week, open-label, multiple-dose study with 3 sequential ascending doses (33, 67 and 100 mg/kg/day) of edasalonexent administered under different dietary conditions to 17 males with a mean age of 5.5 years.
All doses of edasalonexent were well tolerated, with no serious adverse events, no drug discontinuations and no dose reductions. The majority of adverse events were mild, and the most common adverse events were gastrointestinal (primarily diarrhea). Edasalonexent was rapidly absorbed with peak levels observed 2-6 hours after dosing and exposures appeared to increase nearly proportionally to dose for the 2 lower and all 3 doses under low-fat and high-fat meal conditions, respectively. Only minor plasma accumulation of edasalonexent was observed with 7 days of dosing. After treatment with edasalonexent for 7 days, levels of NF-κB-regulated genes and serum proteins were decreased.
This first report of edasalonexent oral administration for one week in male pediatric patients with Duchenne muscular dystrophy showed that treatment was well tolerated and inhibited NF-kB pathways.
Edasalonexent 是一种口服小分子药物，旨在抑制 NF-κB，NF-κB 在杜氏肌营养不良症患者从婴儿期就被激活，是导致肌肉损伤和阻止肌肉再生的关键。
评估 edasalonexent 在 17 名年龄 4 至<8 岁、经基因确诊的杜氏肌营养不良症男性门诊患者中的安全性、耐受性、药代动力学和探索性药效学，这些患者接受了三种递增剂量（33、67 和 100mg/kg/天）的 edasalonexent 治疗，且给药期间有不同的饮食条件。
这是一项为期 1 周、开放性、多剂量研究，17 名平均年龄为 5.5 岁的男性患者接受了三种递增剂量（33、67 和 100mg/kg/天）的 edasalonexent 治疗，且给药期间有不同的饮食条件。
所有剂量的 edasalonexent 均耐受良好，无严重不良事件、药物中断或剂量减少。大多数不良事件为轻度，最常见的不良事件为胃肠道（主要为腹泻）。edasalonexent 吸收迅速，给药后 2-6 小时达到峰值，在低脂和高脂肪餐条件下，分别在较低的 2 个剂量和所有 3 个剂量下，暴露量似乎与剂量成比例增加。连续给药 7 天后，仅观察到 edasalonexent 的轻微血浆蓄积。在 edasalonexent 治疗 7 天后，NF-κB 调节基因和血清蛋白的水平降低。
这是首例报告 edasalonexent 在男性儿科杜氏肌营养不良症患者中口服给药一周的情况，结果表明治疗耐受良好，并抑制了 NF-κB 通路。
