Todd Matthew, Kang Sanghoon, Wu Shunwen, Adhin Devanand, Yoon Deok Yong, Willcocks Rebecca, Kim Sarah
Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
Department of Physical Therapy, University of Florida, Gainesville, FL, USA.
J Neuromuscul Dis. 2025 Jul 29:22143602251360664. doi: 10.1177/22143602251360664.
Duchenne muscular dystrophy (DMD) is a rare X-linked genetic muscle disorder affecting primarily pediatric males and leading to limited life expectancy. This systematic review of 85 DMD trials and non-interventional studies (2010-2022) evaluated how magnetic resonance imaging biomarkers-particularly fat fraction and T2 relaxation time-are currently being used to quantitatively track disease progression and how their use compares to traditional mobility-based functional endpoints. Imaging biomarker studies lasted on average 4.50 years, approximately 11 months longer than those using only ambulatory functional endpoints. While 93% of biologic intervention trials (n = 28) included ambulatory functional endpoints, only 13.3% (n = 4) incorporated imaging biomarkers. Small molecule trials and natural history studies were the predominant contributors to imaging biomarker use, each comprising 30.4% of such studies. Small molecule trials used imaging biomarkers more frequently than biologic trials, likely because biologics often target dystrophin, an established surrogate biomarker, while small molecules lack regulatory-approved biomarkers. Notably, following the 2018 FDA guidance finalization, we observed a significant decrease in new trials using imaging biomarkers despite earlier regulatory encouragement. This analysis demonstrates that while imaging biomarkers are increasingly used in natural history studies, their integration into interventional trials remains limited. From XGBoost machine learning analysis, trial duration and start year were the strongest predictors of biomarker usage, with a decline observed following the 2018 FDA guidance. Despite their potential to objectively track disease progression, imaging biomarkers have not yet been widely adopted as primary endpoints in therapeutic trials, likely due to regulatory and logistical challenges. Future research should examine whether standardizing imaging protocols or integrating hybrid endpoint models could bridge the regulatory gap currently limiting biomarker adoption in therapeutic trials.
杜氏肌营养不良症（DMD）是一种罕见的X连锁遗传性肌肉疾病，主要影响儿童男性，会导致预期寿命受限。这项对85项DMD试验和非干预性研究（2010 - 2022年）的系统评价评估了磁共振成像生物标志物——特别是脂肪分数和T2弛豫时间——目前是如何被用于定量追踪疾病进展的，以及它们与基于传统活动能力的功能终点相比的使用情况。成像生物标志物研究平均持续4.50年，比仅使用活动功能终点的研究大约长11个月。虽然93%的生物干预试验（n = 28）纳入了活动功能终点，但只有13.3%（n = 4）纳入了成像生物标志物。小分子试验和自然史研究是成像生物标志物使用的主要贡献者，各占此类研究的30.4%。小分子试验比生物试验更频繁地使用成像生物标志物，可能是因为生物制剂通常靶向抗肌萎缩蛋白（一种已确立的替代生物标志物），而小分子缺乏监管批准的生物标志物。值得注意的是，在2018年美国食品药品监督管理局（FDA）指南定稿后，尽管早期有监管方面的鼓励，但我们观察到使用成像生物标志物的新试验显著减少。该分析表明，虽然成像生物标志物在自然史研究中的使用越来越多，但它们在干预试验中的整合仍然有限。通过XGBoost机器学习分析，试验持续时间和起始年份是生物标志物使用的最强预测因素，在2018年FDA指南发布后出现了下降。尽管成像生物标志物有潜力客观地追踪疾病进展，但它们尚未被广泛用作治疗试验的主要终点，可能是由于监管和后勤方面的挑战。未来的研究应探讨标准化成像方案或整合混合终点模型是否可以弥合目前限制生物标志物在治疗试验中应用的监管差距。
