Abstract
Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV1% predicted (ppFEV1). Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV1 favouring treatment was observed for ivacaftor (IVA) in G551D individuals (≥6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV1 in a sub-group of individuals ≥18 years old with an R117H mutation. No significant improvements in ppFEV1 were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV1 and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.
Highlights
With advances in our understanding of CFTR biology, a new class of small molecule therapies, referred to as CFTR modulators, have been identified using high-throughput small molecule screening; these drugs are unique as they directly target molecular defects in the CFTR protein to increase CFTR activity7–11
Other CFTR modulators, including CFTR “amplifiers” and “translational read-through” agents increase the amount of CFTR protein produced, the latter being specific to mutations leading to a premature termination codon12,13
Several placebo-controlled clinical trials have been conducted investigating the efficacy and safety of CFTR modulators but the results have varied depending on the specific Cystic fibrosis (CF) genotype and therapy under investigation8
Summary
With advances in our understanding of CFTR biology, a new class of small molecule therapies, referred to as CFTR modulators, have been identified using high-throughput small molecule screening; these drugs are unique as they directly target molecular defects in the CFTR protein to increase CFTR activity. CFTR “potentiators” are small molecules capable of increasing the amount of time the CFTR channel is spent in the open position and targets CFTR mutations with defective “gating”. CFTR “correctors” are small molecules that can target mutations such as F508del as they can improve CFTR trafficking or transport to the cell surface www.nature.com/scientificreports/. Www.nature.com/scientificreports by stabilizing the 3D conformation of the protein, even if misfolded. Other CFTR modulators, including CFTR “amplifiers” and “translational read-through” agents increase the amount of CFTR protein produced, the latter being specific to mutations leading to a premature termination codon. Several placebo-controlled clinical trials have been conducted investigating the efficacy and safety of CFTR modulators but the results have varied depending on the specific CF genotype and therapy under investigation. The primary objective of this systematic review was to evaluate the impact of CFTR modulators on lung function and other clinically important outcomes including pulmonary exacerbations, hospitalizations, respiratory symptoms, nutritional status, and adverse events in individuals with CF
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