Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
Office of Rare Disease, Pediatrics, Urologic and Reproductive Medicine, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
J Inherit Metab Dis. 2024 Sep;47(5):1096-1106. doi: 10.1002/jimd.12746. Epub 2024 May 13.
Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are conditions caused by deficiency of one or more key enzymes, cofactors, or transporters involved in a specific metabolic pathway. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme and is one of the most effective treatment options for IEMs. In this paper, we review the first-in-human (FIH) protocols for ERT drug development programs supporting 20 Biologic License Applications (BLA) approved by the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) in the period of May 1994 to September 2023. We surveyed study design elements across these FIH protocols including study population, dosage form, dose selection, treatment duration, immunogenicity, biomarkers, and study follow-up. A total of 18 FIH trials from 20 BLAs were identified and of those, 72% (13/18) used single ascending dose (SAD) and/or multiple ascending dose (MAD) study design, 83% (15/18) had a primary objective of assessing the safety and tolerability, 72% (13/18) included clinical endpoint assessments, and 94% (17/18) included biomarker assessments as secondary or exploratory endpoints. Notably, the majority of ERT products tested the approved route of administration and the approved dose was tested in 83% (15/18) of FIH trials. At last, we offer considerations for the design of FIH studies.
先天性代谢缺陷（IEM），如溶酶体贮积症（LSD），是由特定代谢途径中一种或多种关键酶、辅助因子或转运蛋白缺乏引起的疾病。酶替代疗法（ERT）提供了受影响酶的外源性来源，是 IEM 最有效的治疗选择之一。本文回顾了支持美国食品和药物管理局（FDA）药物评估和研究中心（CDER）在 1994 年 5 月至 2023 年 9 月期间批准的 20 项生物制品许可申请（BLA）的 ERT 药物开发计划的首次人体（FIH）协议。我们调查了这些 FIH 方案中的研究设计要素，包括研究人群、剂型、剂量选择、治疗持续时间、免疫原性、生物标志物和研究随访。确定了来自 20 个 BLA 的 18 个 FIH 试验，其中 72%（13/18）使用单次递增剂量（SAD）和/或多次递增剂量（MAD）设计，83%（15/18）的主要目标是评估安全性和耐受性，72%（13/18）包括临床终点评估，94%（17/18）将生物标志物评估作为次要或探索性终点。值得注意的是，大多数 ERT 产品测试了批准的给药途径，83%（15/18）的 FIH 试验中测试了批准剂量。最后，我们提供了 FIH 研究设计的考虑因素。
