Merlini G, Lousada I, Ando Y, Dispenzieri A, Gertz M A, Grogan M, Maurer M S, Sanchorawala V, Wechalekar A, Palladini G, Comenzo R L
Amyloid Research and Treatment Center, Department of Molecular Medicine, University of Pavia, IRCCS Policlinico San Matteo, Pavia, Italy.
Amyloidosis Research Consortium, Inc., Boston, MA, USA.
Leukemia. 2016 Oct;30(10):1979-1986. doi: 10.1038/leu.2016.191. Epub 2016 Jul 15.
Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.
淀粉样轻链（LC）淀粉样变性（AL淀粉样变性）是一种罕见的致命疾病，目前尚无获批的治疗方法。在AL淀粉样变性患者中，LC聚集体在器官中逐渐积累，导致器官衰竭，当心脏受累时尤其致命。对于AL淀粉样变性患者以及任何罕见、严重且异质性疾病患者的治疗开发而言，一个重大障碍一直是满足传统临床试验终点（例如总生存期或无进展生存期）。正是出于这个原因，包括美国食品药品监督管理局通过其《安全与创新法案》加速批准途径在内的许多组织，都认识到需要生物标志物作为替代终点。国际AL淀粉样变性专家群体一致认为，脑钠肽前体（NT-proBNP）的N端片段经过分析验证且在临床上符合作为生物标志物的条件，可作为AL淀粉样变性患者生存的替代终点。这一共识的基础在于，尽管患者群体、治疗类型和治疗方案存在差异，但在所有评估NT-proBNP的干预性研究中，它都是心脏反应的指标。此外，NT-proBNP的表达直接受心肌细胞中淀粉样LC引发的信号转导途径调控。NT-proBNP的使用将极大地促进AL淀粉样变性靶向治疗的开发。在此，我们回顾支持将NT-proBNP用作替代生存终点的相关数据，NT-proBNP是一种经过分析验证、临床上符合条件、受LC直接调控且为AL淀粉样变性专家普遍接受的生物标志物。
