Cystic fibrosis treatment: targeting the basic defect

ABSTRACT

Introduction: Cystic Fibrosis (CF) is a disease caused by different class mutations in the CF transmembrane conductance regulator (CFTR) gene. It can therefore benefit from a personalized medicine approach based on the individual genotype of each patient.

Areas covered: This review provides a detailed overview of the current major development of new CF treatments that target the basic CF defect. The review summarizes gene therapy, mRNA repair strategies, read-through agents, and CFTR-modulators (potentiators, correctors, stabilizers, amplifiers and different combination therapies).

Expert opinion: We are currently perhaps at the most exciting stage in the history of CF, with the potential to cure the disease now on the horizon. The good results obtained with ivacaftor in patients with at least one gating mutation have encouraged researchers to develop agents targeting the basic CF defect; such agents are designed for use as monotherapy or combination therapy in patients with other genotypes. However, disease aspects such as pharmacoeconomics, drug–drug interactions, use in infants, or the need for additional endpoints in future clinical trials, may ultimately hinder research and the potential availability of novel drugs for CF patients.

KEYWORDS:

• CFTR
• correctors
• cystic fibrosis
• gene therapy
• ivacaftor
• lumacaftor/ivacaftor
• modulators
• personalized medicine
• potentiators
• read-through

Article highlights

• The characteristic features of cystic fibrosis (CF) are various class mutations in the CF transmembrane conductance regulator (CFTR) gene. Personalized medicine strategies, according to patient genotype, are now being used with new treatments targeting CFTR protein anomalies.

• Basic defect-modifying therapies that have been marketed recently or that are currently being investigated comprise: gene therapies, read throug agents, CFTR potentiators and correctors in monotherapy or in combination, stabilizers and amplifiers.

• The potentiator ivacaftor and the corrector lumacaftor are already marketed in several countries worldwide. The impressive results with ivacaftor in patients with gating mutations clearly indicate that the CFTR protein can be modified. Lumacaftor and ivacaftor in combination have shown efficacy and safety in the most prevalent CF genotype, F508del/F508del, but with more modest results.

• Potential drug interactions, side effects, and poor treatment adherence are important considerations for new CF treatments, although the biggest drawback is the high cost of such treatments. Several patients are not eligible for ivacaftor monotherapy or its combination with lumacaftor. It is therefore essential to find new treatments aimed at patients homozygous or heterozygous for F508del, or with class I–V–VI or non-F508del class II mutations.

• In future, the management of CF will likely involve various drug combinations: eg, gene therapy or mRNA repair with CFTR modulators; various correctors plus a potentiator ± a stabilizer; read-through agents plus potentiators and/or correctors; and targeting each of the two mutations in the genotype with specific agents. The downsides of this are the potential for increased treatment costs, and increased risks of adverse effects and drug interactions.

This box summarizes key points contained in the article.

Declaration of interest

A Escribano has participated in scientific talks and obtained fees from Roche and Gilead. M Sanchez-Solis has received payments for educational activities led by Vertex. P Mondejar-Lopez and M Dolores Pastor-Vivero have obtained fees for Gilead advisory boards and educational talks. Medical writing and editorial assistance was provided by Steve Clissold of Content Ed Net, Madrid, Spain and was funded by Vertex Pharmaceutical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Medical writing and editorial assistance was funded by Vertex Pharmaceuticals Spain.