Development of elexacaftor – tezacaftor – ivacaftor: Highly effective CFTR modulation for the majority of people with Cystic Fibrosis

ABSTRACT

Introduction: Cystic fibrosis (CF), the most common life-shortening inherited disorder in people of European descent, also occurs in other ethnicities. The identification of the disease, the isolation of the causative gene, termed the cystic fibrosis transmembrane conductance regulator (CFTR) and the improved survival from comprehensive multidisciplinary treatment is one of the success stories of modern medicine. Survival has increased dramatically over the last 50 years, from 10 years in the 1960s to 30 years in the 1990s and approximately 50 years currently.

Areas covered: This review will examine the development of highly effective modulators for CF which will revolutionize therapy for more than 90% of the people with CF. This review summarizes the development of triple combination CFTR modulator elexacaftor–tezacaftor–ivacaftor.

Expert opinion: The development of this highly effective CFTR modulator for the majority of people with CF will likely change the landscape of CF care. The challenge is to now find highly effective therapy for the remaining 10% of the people with CF who may need other therapeutic agents to correct their primary defect.

KEYWORDS:

• Cystic fibrosis
• elexacaftor
• tezacaftor
• ivacaftor
• CFTR
• CFTR modulators
• precision medicine

Article highlights

• CF is the commonest life-shortening inherited disorder.

• Thirty years after identification of the causative gene, precision medicine has now developed highly effective drugs to mitigate the primary defect in the vast majority of people with CF.

• Improvements in physiology as measured by sweat Cl⁻ are associated with important changes in lung function, nutrition status, pulmonary exacerbations, and overall quality of life.

Declaration of interest

P Middleton was the lead author on the phase 3 trials of elexacaftor– tezacaftor– ivacaftor and was involved in previous trials of tezacaftor–ivacaftor. He has been also involved in Advisory Boards and meetings with Vertex and other pharmaceutical companies in the last 5 years. J Taylor-Cousar was the lead author on the phase 3 trials of tezacaftor–ivacaftor and was involved in trials of elexacaftor–tezacaftor– ivacaftor. She has been also involved in Advisory Boards and meetings with Vertex and other pharmaceutical companies in the last 5 years. 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Information resources

CFF

UK CF Trust

CFA