PDF(Pubmed)
Abstract：
Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017.
摘要：
Risdiplam是每天一次的口服，运动神经元2（SMN2）剪接修饰剂的存活被批准用于治疗脊髓性肌萎缩症（SMA）。JEWELFISH（NCT03032172）调查了安全性，耐受性,药代动力学（PK），非治疗初治SMA患者的利司普坦与PK/药效学（PD）关系。JEWELFISH招募了成人和儿童患者（N=174），确诊为5q-常染色体隐性遗传性SMA，他们以前接受过nusinersen治疗（n=76），前基因abeparvovec(n=14)，奥列肟(n=71)，或参加了剪接修饰剂RG7800（n=13）的MOONFISH研究（NCT02240355）。JEWELFISH是一项开放标签研究，所有参与者都计划接受利司普坦。最常见的不良事件（AE）是发热（42例，24％），最常见的严重AE（SAE）是肺炎（5例，3%)。从治疗的第一年到第二年，AE和SAE的发生率下降了>50%，并且没有导致退出治疗的治疗相关AE。在利沙普坦治疗后观察到血液中SMN蛋白的增加，并且与以前的治疗无关，持续了24个月的治疗。运动功能的探索性疗效评估显示，通过32项运动功能测量评估，平均总分总体稳定。Hammersmith功能电机秤扩展，并修改上肢模块。利司普坦在JEWELFISH中的安全性与利司普坦在未治疗患者中的先前临床试验一致。报告了探索性疗效结果，但应注意，JEWELFISH的主要目的是评估安全性和PK/PD，本研究并非设计用于疗效分析.试验注册：该研究于2017年1月24日在ClinicalTrials.gov上注册（NCT03032172）；首例患者登记时间：2017年3月3日。
