CFTR modulator therapies in pediatric cystic fibrosis: focus on ivacaftor

ABSTRACT

Introduction: Mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), a disease with life threatening pulmonary and gastrointestinal manifestations. Recent breakthrough therapies restore function to select disease-causing CFTR mutations. Ivacaftor is a small molecule that increases the open channel probability of certain CFTR mutations, producing clear evidence of bioactivity and efficacy in pediatric CF patients. CFTR modulators represent a significant advancement in CF treatment. Extending these therapies to young CF patients is proposed to have the greatest long term impact, potentially preventing later disease.

Areas covered: Here we summarize the research experience of CFTR modulators in pediatrics, focusing on ivacaftor and highlighting challenges in pediatric studies. As a result of these studies, ivacaftor has been approved in CF patients age 2 years and older who have one of ten CFTR mutations.

Expert opinion: Conducting studies in young CF patients presents unique challenges, including small numbers of patients and difficulty selecting sensitive biomarkers and meaningful outcome measures. Adverse events may be more pronounced in children and deserve special attention. Ongoing efforts must focus on expanding and validating new biomarkers, innovative study design, and thorough monitoring of adverse events in children treated with CFTR modulators.

KEYWORDS:

• CFTR
• CFTR modulator
• cystic fibrosis
• ivacaftor
• pediatrics
• VX-770

Article highlights

• CFTR modulators restore function to select disease-causing CFTR mutations

• Ivacaftor is a CFTR modulator that increases the open channel probability of CFTR mutations with gating defects

• Clinical trials of ivacaftor in pediatrics have led to approval in CF patients 2 years of age and older with one of ten specific CFTR mutations

• Selecting relevant biomarkers and sensitive outcome measures is difficult in studies of pediatric CF patients

• Pediatric CF patients may be more sensitive to adverse liver and ocular effects of ivacaftor

• Future efforts should focus on the development and selection of sensitive endpoints, effectively powering studies, and monitoring for adverse events

This box summarizes key points contained in the article.

Declaration of interest

JP Clancy has clinical contracts for trials with Vertex Pharmaceuticals, the manufacturer of ivacaftor. 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.

Additional information

Funding

This work was supported by the National Heart, Lung, and Blood Institute [grant number R01 HL116226-04].