Emerging Cystic Fibrosis Transmembrane Conductance Regulator Modulators as New Drugs for Cystic Fibrosis: A Portrait of in Vitro Pharmacology and Clinical Translation

Abstract

Pharmacological correction of the defective ion channel with cystic fibrosis transmembrane conductance regulator (CFTR) has become an attractive approach to therapy directed at the root cause of the life-limiting disease cystic fibrosis (CF). CFTR defects range from absence, misfolding, and resulting degradation to functional defects of the CFTR protein. The discovery and development of the CFTR potentiator ivacaftor was a major break-through in CF therapy and has triggered an enormous incentive for seeking effective modulators such as lumacaftor, tezacaftor or elexacaftor for all patients with CF. A number of emerging CFTR modulators are currently in the development pipeline, and rescue levels of CFTR protein approach a cure for cystic fibrosis. In this review, we identify and characterize all preclinical and clinical emerging CFTR modulators and discuss the in vitro pharmacology, looking at CFTR protein expression and chloride transport and the translation to the clinic. The new emerging CFTR modulators could offer new therapeutic solutions for CF patients.

Figure 1

Disease causing mutation subclasses in cystic fibrosis and different paths to correct CFTR folding. The dysfunctional CFTR mutation at the cell surface does not equate function. Depending on the mutation subclass multiple modes of rescue are possible. Figure adapted with permission from ref (22). Copyright Elsevier 2017.

Figure 2

A schematic of the cystic fibrosis airway epithelial cell with CFTR mutations divided into six categories based on pathogenic mechanism and color-coded treatment options classically categorized based on their molecular action as well as their availability to patients. Green represents preclinical stage, yellow = phase 1 clinical trial, blue = phase 2 clinical trial, red = phase 3 clinical stage, and black represents approval by the FDA and EMEA, respectively.