The oral drug ivacaftor appears to be safe and could be beneficial to young children between the ages of 2 and 5 with a specific type of cystic fibrosis, according to new research published in The Lancet Respiratory Medicine journal. The findings also suggest a potential window of opportunity in early life when organ damage could be mitigated.
Cystic fibrosis is an inherited disease caused by a defective gene that slowly destroys the lungs and digestive system. The defective gene disrupts the activity of a protein called cystic fibrosis transmembrane conductance regulator (CFTR) which regulates salt transport in the body's cells. This causes thick, sticky mucus to build up in organs, especially the lungs and digestive system, and leads to recurring infections and irreversible lung damage. Around 10000 people are living with cystic fibrosis in the UK and more than 70000 worldwide. Currently, there is no cure.
Ivacaftor targets the basic defect of cystic fibrosis, or CFTR, seen in about 4% of cystic fibrosis patients with at least one mutation in the CFTR gene. Earlier studies confirmed the drug to be a safe and effective treatment in children aged 6 and older, adolescents, and adults with these so called "gating" mutations, and the drug has been approved for use in these groups. But, until now, no studies have examined its effects in younger children.
This trial, involving 34 pre-school children with cystic fibrosis aged between 2 and 5 years with at least one copy of a mutation in the CFTR gene, showed that taking the oral drug at one of two doses (50mg for children with bodyweight <14 kg and 75mg for ?14 kg) twice daily for 6 months improved several markers of disease including sweat chloride levels, weight gain, and pancreatic function .
The 33 participants who completed the 6 month treatment experienced significant reductions in sweat chloride levels suggesting an improvement in the body's ability to restore the balance of salt in and out of cells--the process which when defective leads to cystic fibrosis--and improved weight gain that could provide a "buffer" against the decline in nutritional status and better lung function in later childhood. What is more, over a quarter of the children rose above the clinical cut off for pancreatic insufficiency at least once during treatment, suggesting, say the authors, "a window in early life where at least partial restoration of pancreatic function might be possible."  This is the first time that this has been shown with any drug in cystic fibrosis patients.
Ivacaftor was generally well tolerated with a safety profile similar to that seen in adults (table 2). The most commonly reported adverse events were cough (19 children; 56%) and vomiting (10; 29%). Five children (15%) had liver function tests (LFTs) eight times higher than the upper limit of normal, resulting in one child stopping treatment. All five patients had a history of elevated LFTs at screening and all were reversible. However, given the frequency of LFT elevations, the authors suggest that more frequent monitoring should be considered in younger children, particularly those with a history of elevated LFTs.
The authors caution that more data are needed before these long-term treatment effects and safety can be confirmed. According to study leader Professor Jane Davies from the National Heart and Lung Institute at Imperial College London, London, UK, who led the study from Royal Brompton & Harefield NHS Foundation Trust, London, UK, "This was a small trial, but we are thrilled to see these results. Ivacaftor is a potential new treatment to offer children aged 2 years and older with cystic fibrosis and a CFTR gating mutation. This novel therapy could substantially impact on these children's lives, potentially opening the way to even greater progress in years to come." 
Writing in a linked Comment, Sophie Yammine and Philipp Latzin from University Children's Hospital Bern, Bern, Switzerland, and Florian Singer from University Children's Hospital Zurich, Zurich, Switzerland say, "Davies and colleagues' study is groundbreaking for cystic fibrosis care in children aged 2-5 years. Targeted treatment of this basic defect has potential for both prevention of damage and functional improvement of affected organs. Ivacaftor is safe, and results of secondary outcome measures suggest efficacy in this age group that is similar to that in older patients. Many unknowns remain, however, such as the earliest age of possible application, data for natural fluctuation of new outcome variables, and other points that have been reviewed previously. In any case, the results published by Davies and colleagues are good news for young children with cystic fibrosis and their families, who often have an insufficient amount of advocacy."
NOTES TO EDITORS:
This study was funded by Vertex Pharmaceuticals Incorporated.
 In around 80-90% of patients with cystic fibrosis pancreatic function is irreversibly damaged from early life, which means that the pancreas no longer functions at a level needed to digest food. As a result, children with cystic fibrosis often have problems maintaining or gaining weight.
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