英国伦敦大学学院大奥蒙德街儿童健康研究所Giovanni Baranello团队研究了Risdiplam治疗1型脊髓性肌萎缩症的疗效。2021年2月24日，该研究发表在《新英格兰医学杂志》上。

1型脊髓性肌萎缩症是一种罕见的进行性神经肌肉疾病，由运动神经元（SMN）蛋白功能存活水平低引起。Risdiplam是一种口服给药的小分子，可修饰SMN2前信使RNA剪接，并增加功能性SMN蛋白水平。

研究组报道了一项两部分、临床2-3期、开放标签研究的第一部分结果，招募1-7个月大的患有1型脊髓性肌萎缩症的婴儿，其特征是不能在没有支撑的情况下坐着，采用risdiplam进行治疗。主要结局包括安全性、药代动力学、药效学（包括血液SMN蛋白浓度）以及研究第二部分中risdiplam剂量的选择。探索性结局包括能够在没有支撑的情况下至少坐5秒钟。

共有21名婴儿入组。4名婴儿属于低剂量组，在第12个月时接受0.08 mg/kg/d Risdiplam的最终剂量治疗；17名婴儿属于高剂量组，在第12个月时接受0.2 mg/kg/d Risdiplam的最终剂量治疗。低剂量组和高剂量组的基线SMN蛋白中位值分别为1.31 ng/ml和2.54 ng/ml；在12个月时，中位值分别增加到3.05 ng/ml和5.66 ng/ml，分别是低剂量组和高剂量组基线值的3.0倍和1.9倍。

严重不良事件包括肺炎、呼吸道感染和急性呼吸衰竭。在报告发表时，有4名婴儿死于呼吸系统并发症。高剂量组中有7名婴儿能够在没有支撑的情况下坐至少5秒钟，低剂量组中1例也没有。该研究的第二部分选择了更高剂量的risdiplam（0.2 mg/kg/d）。

研究结果表明，对于患有1型脊髓性肌萎缩症的婴儿，口服Risdiplam治疗可增加血液中功能性SMN蛋白表达。

附：英文原文

Title: Risdiplam in Type 1 Spinal Muscular Atrophy

Author: Giovanni Baranello, M.D., Ph.D.,, Basil T. Darras, M.D.,, John W. Day, M.D., Ph.D.,, Nicolas Deconinck, M.D., Ph.D.,, Andrea Klein, M.D.,, Riccardo Masson, M.D.,, Eugenio Mercuri, M.D., Ph.D.,, Kristy Rose, Ph.D.,, Muna El-Khairi, Ph.D.,, Marianne Gerber, Ph.D.,, Ksenija Gorni, M.D., Ph.D.,, Omar Khwaja, M.D., Ph.D.,, Heidemarie Kletzl, Ph.D.,, Renata S. Scalco, M.D., Ph.D.,, Timothy Seabrook, Ph.D.,, Paulo Fontoura, M.D., Ph.D.,, and Laurent Servais, M.D., Ph.D.

Issue&Volume: 2021-02-24

Abstract:

Background

Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre–messenger RNA splicing and increases levels of functional SMN protein.

Methods

We report the results of part 1 of a two-part, phase 2–3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds.

Results

A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study.

Conclusions

In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood.

DOI: 10.1056/NEJMoa2009965

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2009965