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.

CFTR rescue with VX-809 and VX-770 favors the repair of primary airway epithelial cell cultures from patients with class II mutations in the presence of Pseudomonas aeruginosa exoproducts

“…However, novel approaches, directly targeting the basic CFTR default with mutation-specific therapies, have recently emerged. A first CFTR potentiator (VX-770, Kalydeco®, enhancing channel activity) has been approved for patients with different class III and IV mutations, characterized by improper channel gating and reduced channel conductance, respectively [13]. In addition, several small molecules called correctors (e.g.…”

Cystic Fibrosis and Genotype-Dependent Therapy: Is There a Need for a Sex-Specific Therapy?

“…Cystic fibrosis transmembrane conductance regulation potentiators are small molecule drugs that increase the gating of CFTR, increasing open probability ( P o ), causing the channel to spend more time in the open configuration and facilitating the movement of anions across the cell membrane. 10,58,59 Potentiators were identified using heterologous gene expression, coupled with HTS approaches. 58 The HTS screening target used was the G551D mutation.…”

Rapid therapeutic advances in CFTR modulator science

“…Potentiators are CFTR modulators which increase the gating of CFTR (Po), leading to more time spent by the channel in the open configuration . This results in increased ion transport across the epithelium, which impacts many of the downstream processes that are defective in CF‐affected tissues.…”

“…Potentiators are CFTR modulators which increase the gating of CFTR (Po), leading to more time spent by the channel in the open configuration. 43,44 This results in increased ion transport across the epithelium, which impacts many of the downstream processes that are defective in CF-affected tissues. Compounds that have been developed into potentiator drugs were identified through high throughput screening (HTS) assays performed in standardized heterologous expression systems.…”