Pediatric Year in Review

PEDIATRIC YEAR IN REVIEW 2 NEXT GENERATION CYSTIC FIBROSIS CONDUCTANCE REGULATOR (CFTR) COMBINATION THERAPY Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, Plant BJ, Prais D, Ramsey BW, Taylor-Cousar JL, Tullis E, Uluer A, McKee CM, Robertson S, Shilling RA, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Rowe SM; VX16-659-101 Study Group. VX-659–Tezacaftor– Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med 2018; 379:1599-611. Summary The study evaluates the effects of triple combination therapy, VX659-tezacaftor-ivacaftor, on PheF508del CFTR function in subjects who were either homozygous for the mutation or heterozygous for Phe508del with a minimal function CFTR mutation. In this randomized controlled double- blind multicenter trial there was a marked improvement in FEV1, reduction in the sweat chloride concentrations and improvement in the CFQR when subjects received triple therapy. Comments 1. There was a > 9% improvement in FEV1 when on triple therapy. 2. The safety and side effect profiles were acceptable. 3. Sweat chloride concentrations decreased significantly while on triple therapy. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S, Savage J, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Taylor-Cousar JL; VX16- 445-001 Study Group. *, VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl Ltded 2018; 379:1612-20. Summary The study evaluates the effects of triple combination therapy, VX451-tezacaftor-ivacaftor, on PheF508del CFTR function in subjects who were either homozygous for the mutation or heterozygous for Phe508del with a minimal function CFTR mutation. In this randomized controlled double- blind multicenter trial there was a marked improvement in FEV1, reduction in the sweat chloride concentrations and improvement in the CFQR when subjects received triple therapy. Comments 1. There was a > 10% improvement in FEV1 when on triple therapy. 2. The safety and side effect profiles were acceptable. 3. Sweat chloride concentrations decreased significantly while on triple therapy. THE USE OF CYSTIC FIBROSIS CONDUCTANCE REGULATOR (CFTR) MODULATOR THERAPY IN INFANTS Rosenfeld M, Wainwright CE, Higgins M, Wang LT, McKee C, Campbell D, Tian S, Schneider J, Cunningham S, Davies JC; ARRIVAL study group. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med. 2018 Jul;6(7):545- 553PMID:29886024 Summary The study evaluates the effects of ivacaftor therapy, on infants between the age of 12-24 months of age with cystic fibrosis and a CFTR gating mutation. In this trial the safety of ivacaftor was examined in this young age group. In addition, sweat chloride concentration and exocrine pancreatic function were assessed. In this study the drug is well tolerated and treatment with ivacaftor was associated with a significant decrease in sweat chloride concentration. In the majority of infants, treatment with ivacaftor was also associated with improvements in a number of biomarkers of exocrine pancreatic function including fecal elastase -1, immunoreactive trypsinogen, lipase and amylase. TREATMENT OF EARLY PSEUDOMONAS INFECTION IN CYSTIC FIBROSIS Mayer-Hamblett N, Retsch-Bogart G, Kloster M, Accurso F, Rosenfeld M, Albers G, Black P, Brown P, Cairns A, Davis SD, Graff GR, Kerby GS, Orenstein D, Buckingham R, Ramsey BW; OPTIMIZE Study Group. Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial. Am J Respir Crit Care Med. 2018 Nov 1;198(9):1177-1187. PMID:29890086 Summary The study tested the hypothesis that the addition of azithromycin to inhaled tobramycin therapy in children UPDATE IN CYSTIC FIBROSIS MANAGEMENT Marie E. Egan, MD Yale University Pediatrics and Cellular and Molecular Physiology New Haven, CT UPDATE IN CYSTIC FIBROSIS MANAGEMENT