Letermovir Phase I Trial

该项目，第一阶段，适应，升级单剂量和多剂量的药代动力学和安全性 由David领导的莱特莫夫对有症状的先天性巨细胞病毒病婴儿的评估 马里兰州W·金伯林先天性巨细胞病毒(CMV)感染是导致 感音神经性听力损失(SNHL)和已知的最常见的精神发育迟缓的病毒原因，影响 工业化国家活产婴儿的0.5%至0.7%。美国每年的出生人口为380万人， 据估计，每年有19,000名和26,600名婴儿出生时患有先天性巨细胞病毒感染。10%的 先天感染的新生儿在分娩时有症状疾病，其中35%患有SNHL，多达2- 三分之一的人有神经缺陷，4%的人在新生儿时期死亡。SNHL的发生率较低 90%的先天感染新生儿在分娩时没有症状，但因为还有更多 无症状新生儿多于有症状的新生儿。大多数由CMV引起的SNHL病例发生在 无症状组。 具有抗CMV活性的抗病毒药物的数量非常少，只有三个活性部分获得批准 美国食品和药物管理局(FDA)：磷甲酸钠(1991年批准)，更昔洛韦(1994年批准)， 和西多福韦(1996年批准)。伐更昔洛韦，更昔洛韦的L-缬氨酸酯，因此具有相同的 更昔洛韦的部分药物于2001年获得批准。到目前为止，所有关于先天性巨细胞病毒病治疗的研究 曾使用更昔洛韦或伐更昔洛韦，并已证明治疗对听力和 发展成果。此外，我们还发现，有症状的先天性巨细胞病毒病患者 在治疗第14天前将病毒抑制到≤2.5log并在接下来的4个月内保持这种水平的人有 从统计上看，在出生后的头两年，听力更有可能有所改善。 2017年11月，FDA批准来特莫韦用于预防成人CMV感染和疾病- 异基因造血干细胞移植的血清阳性接受者，使其成为全球首个巨细胞病毒新药 二十多年来。莱特莫韦作为一种安全有效的抗病毒药物的可用性 与更昔洛韦不同的作用机制为探索联合治疗提供了机会。第一, 然而，莱特莫韦在新生儿中的药代动力学和安全性必须得到表征。我们建议 对单剂和多剂进行第一阶段适应性、多中心、剂量递增评估 静脉注射来特莫韦治疗婴幼儿有症状的先天性巨细胞病毒病 新生儿和婴幼儿症状性先天性巨细胞病毒病的给药方案。

This project, A Phase I Adaptive, Escalating Single-Dose and Multiple-Dose Pharmacokinetic and Safety Assessment of Letermovir in Infants with Symptomatic Congenital Cytomegalovirus Disease, is led by David W. Kimberlin, MD. Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of sensorineural hearing loss (SNHL) and the most frequent known viral cause of mental retardation, affecting 0.5% to 0.7% of live births in industrialized countries. With a U.S. birth cohort of 3.8 million annually, between 19,000 and 26,600 babies are estimated to be born each year with congenital CMV infection. Ten percent of congenitally infected neonates have symptomatic disease at delivery, of whom 35% have SNHL, up to two- thirds have neurologic deficits, and 4% die in the newborn period. SNHL occurs at a lower rate among the 90% of congenitally infected neonates who are asymptomatic at delivery, but because there are so many more asymptomatic neonates than symptomatic ones the majority of cases of SNHL caused by CMV occurs in this asymptomatic group. The number of antiviral drugs with activity against CMV is very small, with only three active moieties approved by the U.S Food and Drug Administration (FDA): foscarnet (approved in 1991), ganciclovir (approved in 1994), and cidofovir (approved in 1996). Valganciclovir, the L-valine ester of ganciclovir and therefore the same moiety as ganciclovir, was approved in 2001. To date, all studies of the treatment of congenital CMV disease have utilized ganciclovir or valganciclovir, and have documented a modest benefit of treatment on hearing and developmental outcomes. In addition, we have found that patients with symptomatic congenital CMV disease who achieve viral suppression to ≤ 2.5 log by day 14 of therapy and then maintain it over the next 4 months are statistically more likely to have improved hearing across the first two years of life. In November 2017, the FDA approved letermovir for prophylaxis of CMV infection and disease in adult CMV- seropositive recipients of an allogeneic hematopoietic stem cell transplant, making it the first new CMV drug in over two decades. The availability of letermovir as a safe and effective antiviral drug with a completely different mechanism of action from ganciclovir offers the opportunity to explore combination therapy. First, though, the pharmacokinetics and safety of letermovir in neonates must be characterized. We propose to perform a Phase I adaptive, multi-center, dose-escalation evaluation of single-dose and multiple-dose administration of intravenous letermovir in infants with symptomatic congenital CMV disease to develop a safe dosing regimen for neonates and young infants with symptomatic congenital CMV disease.