title: Advancing clinical development pathways for new CFTR modulators in cystic fibrosis.
abstract: Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70,000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant CFTR genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF.
authors.affiliation: Department of Pediatrics and Biostatistics, University of Washington, Seattle, Washington, USA Seattle Children's Hospital, Seattle, Washington, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Mayer-Hamblett
authors.affiliation: Cystic Fibrosis Foundation, Bethesda, Maryland, USA John Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boyle
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: VanDevanter
mesh_terms: D000627:Aminophenols / Q000627:therapeutic use*; D000631:Aminopyridines / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002986:Clinical Trials as Topic; D019091:Critical Pathways; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000819:agonists / Q000187:drug effects* / Q000235:genetics; D004338:Drug Combinations; D015316:Genetic Therapy; D005838:Genotype; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D011788:Quality of Life; D015363:Quinolones / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; D015415:Biomarkers; C505032:CFTR protein, human; D004338:Drug Combinations; D015363:Quinolones; C000599212:lumacaftor, ivacaftor drug combination; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: Cystic Fibrosis; Rare lung diseases