Losmapimod的开放标签研究评估FSHD1患者的安全性、耐受性、生物标志物和临床结局评估变化(S23.008)

摘要目的:评价losmapimod治疗FSHD的长期安全性和有效性。

背景:FSHD是由DUX4的异常表达引起的。Losmapimod是一种口服活性、选择性的p38α/β小分子抑制剂。临床前研究表明，losmapimod降低了DUX4在跨多种基因型区分FSHD肌管中的作用

设计/方法:年龄在18 - 65岁、基因上证实FSHD1、临床严重程度评分为2 - 4(范围0-5)、mri符合骨骼肌穿刺活检条件的受试者接受15 mg losmapimod，每天两次，持续52周。主要终点为安全性。通过肌肉活检中dux4驱动基因的表达来评估疗效。定量WB-MSK-MRI评估肌肉健康。临床评估包括RWS, TUG, FSHD-TUG，测力，MFM, 6-MWT和PROs (PGIC, FSHD-HI, FSHD-RODS)。

结果:共纳入14名受试者，平均年龄45.7(+/−11.61)岁，Ricci评分3.5。Losmapimod耐受性良好，无严重药物相关不良事件。未观察到DUX4驱动基因表达较基线的变化。在非终末期肌肉的定量MRI评估中没有或很少观察到变化。RWS在有和没有权重的双边RSA方面都有改善;范围0.03 - -0.04;年化变化率(%)在3.28至5.68之间。按区域评估RSA，表明与基线相比没有进展或改善，特别是象限1和3(肩部以上)和5(后部)。测力评估显示双侧肩外展肌、踝关节背屈肌和握力较基线稳定或改善。在PGIC方面，超过80%的受试者在56周治疗后报告改善或没有变化; no patients reported feeling much worse over 56 weeks. Minimal changes were observed in TUG, FSHD-TUG, MFM, and 6-MWT.

结论:本研究支持losmapimod治疗对结构和FSHD相关临床终点的益处，并支持继续开发。

披露:库尔斯所在的机构得到了福尔库姆治疗公司的研究支持。Voermans夫人的机构作为Dynacure的顾问获得了500- 4,999美元的个人报酬。沃尔曼斯夫人所在的机构因在NIH的科学咨询或数据安全监测委员会任职而获得了0- 499美元的个人报酬。Voermans女士的机构已经获得了500- 4,999美元的个人报酬，作为编辑，副编辑或神经肌肉疾病编辑顾问委员会成员。Karlien Mul没有什么可透露的。他曾因担任Fulcrum Therapeutics的员工而获得个人报酬。Shoskes博士曾作为Fulcrum Therapeutics的员工获得个人报酬。Shoskes博士的直系亲属因担任Exact Science的员工而获得个人补偿。作为福尔库姆的雇员，马歇尔女士获得了个人报酬。他曾因担任X4 Pharma的员工而获得个人报酬。 Dr. Cadavid has received personal compensation for serving as an employee of Fulcrum Therapeutics. Dr. Cadavid has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arvinas. Dr. Cadavid has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abata Therapeutics. Dr. Cadavid has received stock or an ownership interest from X4 Pharma. Dr. Cadavid has received stock or an ownership interest from Fulcrum Therapeutics. Dr. Mellion has received personal compensation for serving as an employee of Fulcrum Therapeutics. Dr. Mellion has received stock or an ownership interest from Fulcrum Therapeutics. The institution of Dr. van Engelen has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Facio. The institution of Dr. van Engelen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum . The institution of Dr. van Engelen has received research support from Stichting Spieren voor Spieren. The institution of Dr. van Engelen has received research support from Prinses Beatrix Fonds. The institution of Dr. van Engelen has received research support from Dutch FSHD society. Dr. van Engelen has received intellectual property interests from a discovery or technology relating to health care.