New drug developments in the management of cystic fibrosis lung disease

ABSTRACT

Introduction: Therapies for cystic fibrosis (CF) pulmonary disease have, until recently, all targeted downstream manifestations rather than the root cause of the disease. A step-change in our approach has been achieved in the last few years, with novel small-molecule CFTR modulating drugs entering the clinic.

Areas covered: In this article, we will discuss the field of drug development for CF lung disease. The case will be made for the potential benefits of basic defect-targeted strategies, which will be described in detail. Novel therapies directed at the downstream pulmonary manifestations of CF – infection, inflammation, and mucus impaction – will be reviewed. Finally, we will speculate on future directions and challenges.

Expert opinion: CF drug development is in an exciting phase, catalysed by the impressive results seen in patients with ivacaftor-responsive CFTR mutations. The research field is active with trials of novel therapies targeting the basic defect, alongside drugs targeting downstream effects. In order to detect potentially small improvements due to novel therapies, especially in the context of treating young patients with early disease, sensitive outcome measures and the coordinated efforts of collaborative research networks are crucial.

KEYWORDS:

• Cystic fibrosis
• CFTR modulators
• potentiators
• correctors
• gene therapy
• antibiotics

Article highlights

• Survival for people with cystic fibrosis has improved significantly in recent decades, largely attributable to therapies targeting downstream disease manifestations.

• Therapies directed at the basic CF defect – absent or reduced function of the CFTR protein at the surface of epithelial cells – have recently become a clinical reality.

• Strategies to target the basic defect in CF include gene therapy, ribosomal read-through and small molecules aimed at ‘correcting’ or ‘potentiating’ the mutation-specific CFTR defect. Therapeutic agents in each of these fields have entered clinical trials.

• Ivacaftor, the first CFTR potentiator to demonstrate efficacy in patients with specific CFTR mutations, represents a paradigm-shift in CF therapy. Correcting the more complex processing defect caused by the F508del mutation is a greater challenge, but the results from trials of ivacaftor with lumacaftor provide proof of concept in this field.

• Current treatments of CF pulmonary disease focus on infection, inflammation and airway clearance. New antibiotics and antibiotic preparations, muco-active drugs and anti-inflammatory agents are progressing through clinical trials into the clinic.

• Recognizing the potential benefit of presymptomatic treatment in CF, clinical trials require sensitive measures of early disease, of which lung clearance index shows potential.

This box summarizes key points contained in the article.

Declaration of interest

J.C Davies has been principal investigator on a number of trials for Vertex, PTC, Pharmaxis, Novartis and Forest, all of which produce drugs that were discussed in this review. She has also served on Advisory Boards for several of these companies and has undertaken educational activities for their staff. All fees/ honoraria have been paid to Imperial College, UK, or the Royal Brompton Hospital, UK. She does not hold any shares of relevance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.