Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Ann Clin Transl Neurol. 2020 Dec;7(12):2393-2408. doi: 10.1002/acn3.51235. Epub 2020 Dec 7.
The novel morpholino antisense oligonucleotide viltolarsen targets exon 53 of the dystrophin gene, and could be an effective treatment for patients with Duchenne muscular dystrophy (DMD). We investigated viltolarsen's ability to induce dystrophin expression and examined its safety in DMD patients.
In this open-label, multicenter, parallel-group, phase 1/2, exploratory study, 16 ambulant and nonambulant males aged 5-12 years with DMD received viltolarsen 40 or 80 mg/kg/week via intravenous infusion for 24 weeks. Primary endpoints were dystrophin expression and exon 53 skipping levels.
In western blot analysis, mean changes in dystrophin expression (% normal) from baseline to Weeks 12 and 24 were - 1.21 (P = 0.5136) and 1.46 (P = 0.1636), respectively, in the 40 mg/kg group, and 0.76 (P = 0.2367) and 4.81 (P = 0.0536), respectively, in the 80 mg/kg group. The increase in mean dystrophin level at Weeks 12 and 24 was significant in the 80 mg/kg group (2.78%; P = 0.0364). Patients receiving 80 mg/kg showed a higher mean exon 53 skipping level (42.4%) than those receiving 40 mg/kg (21.8%). All adverse events were judged to be mild or moderate in intensity and none led to study discontinuation.
Treatment with viltolarsen 40 or 80 mg/kg elicited an increasing trend in dystrophin expression and exon 53 skipping levels, and was safe and well tolerated. The decline in motor function appeared less marked in patients with higher dystrophin levels; this may warrant further investigation. This study supports the potential clinical benefit of viltolarsen.
新型吗啉代反义寡核苷酸 viltolarsen 针对肌营养不良蛋白基因外显子 53，可能是杜氏肌营养不良症 (DMD) 患者的有效治疗方法。我们研究了 viltolarsen 诱导肌营养不良蛋白表达的能力，并检查了其在 DMD 患者中的安全性。
在这项开放标签、多中心、平行组、1/2 期、探索性研究中，16 名 5-12 岁的可走动和不可走动的男性 DMD 患者接受静脉输注 40 或 80mg/kg/周的 viltolarsen 治疗，共 24 周。主要终点是肌营养不良蛋白表达和外显子 53 跳跃水平。
在 Western blot 分析中，40mg/kg 组从基线到第 12 周和第 24 周的肌营养不良蛋白表达平均变化（%正常）分别为-1.21（P=0.5136）和 1.46（P=0.1636），80mg/kg 组分别为 0.76（P=0.2367）和 4.81（P=0.0536）。第 80mg/kg 组在第 12 周和第 24 周时肌营养不良蛋白水平的增加具有统计学意义（2.78%；P=0.0364）。接受 80mg/kg 治疗的患者外显子 53 跳跃水平（42.4%）高于接受 40mg/kg 治疗的患者（21.8%）。所有不良事件均为轻度或中度，无研究中止。
viltolarsen 40 或 80mg/kg 的治疗引起肌营养不良蛋白表达和外显子 53 跳跃水平的增加趋势，且安全且耐受良好。具有较高肌营养不良蛋白水平的患者的运动功能下降似乎不那么明显；这可能需要进一步研究。本研究支持 viltolarsen 的潜在临床益处。
