Tezacaftor and ivacaftor for the treatment of cystic fibrosis

ABSTRACT

Introduction: Cystic fibrosis (CF) is a complex, multi-system, genetic disease affecting over 70,000 people worldwide. The underlying defect is a mutation in the CFTR gene. Dysfunctional CFTR protein results in abnormal anion movement across epithelial membranes in affected organs. There has been a paradigm shift in CF treatment over the last decade with the advent of CFTR modulation, treatments which target this underlying genetic defect and have the potential to change the course of CF clinical disease.

Areas covered: Available CFTR modulators in current clinical practice are reviewed in this article, with a direct comparison and summary of relevant pivotal clinical trials. The approval of ivacaftor and subsequent development of lumacaftor and tezacaftor dual combinations represents an exciting development in CF management in recent years.

Expert opinion: Tezacaftor/ivacaftor (tez/iva) appears to have a more favorable adverse event and drug–drug interaction profile than lumacaftor/ivacaftor. Tez/iva has been approved, alongside Phe508del, for a large number of ‘residual function’ CFTR mutations, with some based on response to in vitro culture. Dual therapy with tez/iva has paved the way for triple CFTR modulation currently in clinical trials with an ultimate view to provide modulation therapy to the majority of CF genotypes in the future.

KEYWORDS:

• Cystic fibrosis
• CFTR
• Ivacaftor
• Lumacaftor
• tezacaftor

Article highlights

• CFTR modulation is an ever-expanding field within the armamentarium of CF treatment, and has changed the landscape of CF management in the last decade.

• Ivacaftor was the first successful CFTR modulator developed and implemented into clinical practice, approved for Gly551Asp mutations.

• The development of lumacaftor/ivacaftor (lum/iva) demonstrated that patients homozygous for the Phe508del mutation could gain clinical benefit from CFTR modulators. However, issues with tolerability and some important drug–drug interactions (DDI's) are challenges which have encouraged the development of alternative compounds.

• Tezacaftor/ivacaftor (tez/iva) is the most recent CFTR modulator to be approved for clinical use in the EU and US, for Phe508del homozygotes and Phe508del heterozygotes with certain residual function mutations (Table 3).

• Clinical efficacy has been shown in tez/iva phase 3 trials, evidenced by improvements in absolute ppFEV₁, pulmonary exacerbation rates and respiratory symptom scores (CFQ-R). Reductions in sweat chloride have been shown, but to a lesser extent than ivacaftor monotherapy.

• Tez/iva appears to be better tolerated in terms of respiratory adverse events and has less DDI's compared to its predecessor lum/iva.

• Tez/iva has been taken forward into phase 3 trials of triple combination CFTR modulator therapy, alongside next-generation CFTR correctors, showing promising preliminary results.

• Longitudinal patient data will be important to analyse in order to establish evidence of longer-term efficacy of CFTR modulation therapy, particularly dual and triple combinations.

• The development of triple combination CFTR modulators incorporating tezacaftor and ivacaftor will broaden the indications for therapy to the vast majority of the CF population.

Declaration of interest

Both A Horsley and P Barry have been investigators on clinical trials sponsored by Vertex pharmaceuticals involving the use of tezacaftor/ivacaftor, have received speaker/consultancy fees from Vertex pharmaceuticals ltd and are members of the organizing committee of an educational conference which has received sponsorship from Vertex pharmaceuticals amongst others. In addition, A Horsley reports personal fees from Celtaxsys, Chiesi, and Boehringer Ingelheim, grants from NIHR, grants from Cystic Fibrosis Foundation, grants from Cystic Fibrosis Trust. 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

A peer reviewer on this manuscript has disclosed that they are a scientific consultant for Vertex Pharmaceuticals. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded