A Phase 1 Trial of Tolerability of Enteral N-Acetylcysteine in Infants

Biliary atresia (BA), a neonatal liver disease characterized by impaired bile flow, is the most common indication for pediatric liver transplantation. The only identified treatment option other than liver transplant is a Kasai portoenterostomy (KP). This surgical procedure directly connects the intestines to the liver in an attempt to restore bile flow. By restoring bile flow and decreasing bile retention, the KP's goal is to slow disease progression. Restored bile flow within the first 3-6 months post-operatively is associated with better clinical outcomes. Unfortunately the success of the procedure is quite variable with one-third of KPs never achieving sufficient bile flow to slow disease progression and the remaining one-third never achieving any bile flow. These patients go on to require liver transplantation with 60% of liver transplants in infants <1 year of age and 30% of all pediatric liver transplants being performed for BA. The lack of adjuvant medical therapies for KP is a major gap in the current field of pediatric hepatology.

NAC is an attractive potential therapy for BA, because NAC is the precursor for glutathione. Glutathione in turn addresses much of the problematic pathophysiology in biliary atresia including poor bile flow, oxidative damage, and inflammation. Preclinical studies have demonstrated that glutathione in the form of NAC therapy has been shown to improve liver histology in various rodent models of cholestasis and biliary atresia. In a recent study by Luo et al, rotavirus-induced mouse models of biliary atresia were injected with saline for placebo or 150 mg/kg/day NAC. The mice that received NAC demonstrated better weight gain, decreased hepatic injury, and improved survival when compared to mice that received saline. Liver biopsies demonstrate decreased inflammation, epithelial injury, and portal inflammation in the RRV-induced BA mice that received NAC (RRV+NAC; right two panels) when compared to RRV-induced BA mice that received placebo saline injections (RRV+PBS; middle two panels). These results support the notion that glutathione may reduce inflammation and fibrosis, perhaps by preventing oxidative damage caused by retained bile.

Luo et al also reported clinical data that demonstrated cholestatic infants with upregulation of genes related to regulating glutathione metabolism had improved survival rates at two years of age, lending further support to the hypothesis that glutathione can improve outcomes in cholestatic infants. There is a list of gene groups from livers of patients with biliary atresia at time of diagnosis that were discovered to be upregulated in patients that demonstrated improved survival with their native liver at two years of age. Notably genes for glutathione metabolism, glutathione biosynthesis, and glutathione conjugation were all upregulated in the patients with improved survival with their native liver. This suggests that increased glutathione is associated with improved survival in patients with BA.

An important advantage of NAC therapy is that it is been shown to be safe in both pre-term and term infants with other conditions such as increased risk for chorioamnionitis. Prolonged intravenous (IV) NAC therapy has also been demonstrated to be safe in infants with other liver conditions such as cholestasis secondary to total parental nutrition. Additionally, IV NAC was given to infants and children with non-acetaminophen induced liver failure in similar doses as proposed in this study and there was no significant difference in rates of adverse events between the treatment and control groups.

While NAC is a promising therapeutic agent post-KP that has been demonstrated to be safe in multiple previous studies, the only study to date investigating NAC in BA used an IV formulation (study performed at Texas Children's Hospital, data analysis in process). An IV formulation is the logical choice when infants are on bowel rest immediately post-KP and remain hospitalized with IV access. However, discharging a patient home with indwelling venous access poses a substantial infection risk with up to 30% of peripherally inserted central catheters having at least one complication. Transitioning to oral NAC prior to discharge home would allow for longer duration of therapy without the potential consequences of indwelling venous access, however oral NAC has a sulfuric, unpleasant taste.