A Review on the Use of Cystic Fibrosis Transmembrane Conductance Regulator Gene Modulators in Pediatric Patients

Abstract

The literature surrounding the use of cystic fibrosis transmembrane conductance regulator-targeted pharmacotherapies in pediatric patients continues to evolve. These therapies represent a departure from symptom management and infection prevention, which have been the mainstay of cystic fibrosis management in pediatrics, to targeting the genetic defect present within these patients. This article reviews the clinical studies evaluating the safety and efficacy of ivacaftor, ivacaftor/lumacaftor, and ivacaftor/tezacaftor. These medications were initially studied in adults and adolescents but have begun to be studied in younger populations. Further investigation into the use of these drugs with different CFTR mutations and in younger age groups will continue to expand the number of patients who can benefit from these therapies. J Pediatr Health Care. (2018) XX, 356−364 KEY WORDS Cystic fibrosis, cystic fibrosis transmembrane conductance regulator, pediatrics OBJECTIVES 1. Describe the six major classes of mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. 2. Review the mechanisms of action of ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor. 3. Compare the indications and efficacy among the three CFTRmodifying drugs. 4. Identify the counseling points for the three CFTR-modifying drugs. EPIDEMIOLOGYCystic fibrosis (CF) is an incurable, autosomal recessive disease affecting over 80,000 people worldwide (Lubamba, Dhooghe, Noel, & Leal, 2012). It involves a defect in a single gene, causing alterations in chloride secretion and sodium transport that ultimately lead to multiorgan complications (Davies, Alton, & Bush, 2007;Pettit & Fellner, 2014). CF often causes symptomatic pulmonary disease, but the pancreas, gastrointestinal tract, liver, and

New drugs in cystic fibrosis: what has changed in the last decade?

“…Although medical advances in recent decades have provided symptomatic treatments that have increased the average life expectancy of these patients, from a median age of death of 25 years in 1985 to 32.4 years in 2017, 49 , 50 the quality of life remains compromised, and the average life expectancy is still lower than that of the general population. 51 However, with novel CFTR modulators, the median predicted survival age for patients born from 2013 to 2017 is now 44 years old. 52…”

“…However, the mutations for which ivacaftor monotherapy is effective correspond to a very small percentage (~5%) of individuals with CF. 51 The most common mutation, F508del, results in a protein with several molecular defects that require a cocktail of modulating drugs, in which each one corrects a portion of the defect with possible synergistic effects on the others.…”