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.
