Toward inclusive therapy with CFTR modulators: Progress and challenges

Abstract

Cystic fibrosis is caused by gene mutations that result in an abnormal Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein on the surface of cells. CFTR modulators are a novel class of drugs that directly target the molecular defect. CFTR modulators include potentiators that result in improved activity of the channel; correctors that help the protein traffic to the cell surface properly; and readthrough agents that restore full-length CFTR by suppression of premature termination codons, among other novel classes more recently established. While some of these drugs, CFTR potentiators in particular, have provided remarkable improvements for CF patients, others have yet to achieve profoundly improved outcomes, and many CF patients are not yet impacted by CFTR modulators due to lack of knowledge regarding susceptibility of their mutations to treatment. One limitation to expanding these types of therapies to the maximum number of patients with CF is the lack of rigorously validated clinical biomarkers that can determine efficacy on an individual basis, as well as few pre-clinical tools that can predict whether an individual with a rare combination of mutant alleles will respond to a particular CFTR modulator regimen. In this review, we discuss the various groups of CFTR modulators and their status in clinical development, as well as address the current literature on biomarkers, pre-clinical cell-based tools, and the role of pharmacometrics in creating therapeutic strategies to improve the lives of all patients with cystic fibrosis, regardless of their specific mutation.

Keywords: biomarkers; clinical trials; cystic fibrosis (CF); pharmacology.

FIGURE 1

Relationship between CFTR activity measured in vitro with spirometry improvement assessed in clinical trials. Lum = lumacaftor; Iva = ivacaftor; VX-661 = tezacaftor; F508del = homozygous for F508del CFTR unless otherwise noted. Derived from N Engl J Med. 2011;365:1663–72;365:1663–72; N Engl J Med. 2015;373:220–31; Chest 2012; PNAS 2009; PNAS 2011; Lancet Respir Med 2 2014; 527–538; Donaldson et al., NACFC 2015; Fidler et al., NACFC 2015