Ivacaftor for the treatment of cystic fibrosis in children under six years of age

ABSTRACT

Introduction

Cystic fibrosis (CF) results from aberrant ion transport due to abnormalities or absence of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride transporter that resides on the apical surface of epithelial cells. A novel class of medications, known as CFTR modulators, specifically target the abnormal protein.

Areas covered

Ivacaftor increases the open probability of CFTR located on the cell surface, leading to enhanced chloride transport, and has been shown to improve lung function, weight, and quality of life. We reviewed the sentinel studies that lead to the approval of the use of ivacaftor in people with CF age six months and older with at least one CFTR gene mutation that is responsive to ivacaftor based on clinical trial and/or in vitro data. Children with CF have the greatest potential to benefit from CFTR modulator therapy when it is initiated prior to the development of permanent damage; however, challenges remain regarding use of ivacaftor in the youngest pediatric population.

Expert opinion

Ivacaftor is safe and effective CFTR modulator that can be prescribed in children over six months of age with at least one CFTR gene mutation that is responsive to ivacaftor.

KEYWORDS:

• CFTR modulator therapy
• CFTR mutation
• cystic fibrosis
• ivacaftor
• pediatrics
• potentiator

Article highlights

• Cystic fibrosis is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene that encodes CFTR, a protein on the cell surface that is responsible for chloride and bicarbonate transport.

• CFTR mutations are divided into six different classes based on the manner in which the CFTR protein is defective.

• Cystic fibrosis is characterized by progressive obstructive lung disease as well as multisystem involvement including exocrine pancreatic insufficiency leading to nutrient malabsorption and malnutrition, poor growth, sinus and hepatobiliary disease, and male infertility.

• The current mainstay of therapy includes antibiotics, mucus-modulating agents, anti-inflammatory agents, and pancreatic enzyme replacement. However, the newest therapies, known as CFTR modulators, address the underlying defect in the CFTR protein by increasing the presence and effectiveness of the protein at its site of action on the cell surface.

• Ivacaftor increases the open probability of the CFTR protein at the cell surface allowing it to transport ions more effectively. It was one of the first CFTR modulators developed and is currently approved for use in individuals greater than 6 months of age with at least one mutation that has shown to be responsive to ivacaftor through clinical or in-vitro studies.

• In clinical studies, ivacaftor has shown to improve lung function, weight gain, and quality of life in people with CF. Additionally, studies have shown that modulation of CFTR has the potential to alter the microbiome, making people less susceptible to certain infections, and improve or reverse pancreatic insufficiency.

• Ivacaftor is well tolerated with very few reported side effects. Children treated with ivacaftor should have close monitoring of their liver function as well as annual ophthalmologic exams due to the risk for cataracts appreciated in preclinical studies.

• Current studies are examining the possibility of once-daily dosing to improve adherence, expanding the CF population that can be treated with ivacaftor through theratyping, and gaining a more complete understanding of long-term effects of sustained use of CFTR modulators, especially in children.

Declaration of interest

P Mogayzel has received grant funding from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation. 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 review on this manuscript has disclosed that in the last 12 months, they have received grants to their institution for research conduct from Vertex and Proteostasis, received consulting fees for clinical trial design from Vertex, Proteostasis and Santhera and received speaker fees from Vertex. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.