Preschoolers with Cystic Fibrosis Benefit from Ivacaftor Treatment in UK Trial

The drug ivacaftor appears to be safe for children 2 to 5 years old with specific types of a cystic fibrosis (CF) genetic mutation, according to recent U.K. research. The findings support the drug’s U.S. approval for youngsters in this age group, and also indicate a potential period in early life when organ damage could be lessened.

The study, published in the journal The Lancet Respiratory Medicine, is titled “Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.”

CF is caused by any one of several defects in a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. An estimated 70,000 people worldwide have the disease, for which there is currently no cure.

Ivacaftor (Kalydeco, Vertex), approved for patients with certain CFTR gene mutations, is the first drug that treats the disease’s underlying cause rather than its symptoms. Ivacaftor has been shown to be a safe, effective treatment for CF patients ages 6 years and older with a CFTR gating mutation, and is approved in Europe and Canada for this age group.  (In the U.S., the drug’s FDA approval was extended to the 2–5 age group in March 2015, after its efficacy was confirmed in a Phase 3 trial using a weight-based oral granule formulation of ivacaftor developed specially by the company to mix in soft foods or liquids.)

In the new clinical trial, Jane Davies from the National Heart and Lung Institute, Imperial College London, U.K., and colleagues assessed the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in 34 children ages 2–5 years carrying at least one copy of a mutation in the CFTR gene.

The results revealed that taking the drug orally at one of two doses (50 mg for children with body weight <14 kg, and 75 mg for children with weight equal to or greater than 14 kg), twice daily for six months, improved disease markers including weight gain, sweat chloride levels, and pancreatic function.

The 33 children that completed the six-month treatment protocol had significant decreases in the levels of sweat chloride, indicating an improvement in the body’s capacity to restore salt balance in and out of cells — the biological mechanism that is faulty in CF — and improved weight gain.

The results further showed that more than a quarter of the children rose above the clinical cutoff for pancreatic insufficiency at least once during treatment, indicating “a window in early life where at least partial restoration of pancreatic function might be possible,” the authors suggested, according to a news release.

Results of ivacaftor pharmacokinetics suggested that the safety profile was similar to that reported in adults. Common adverse events included cough and vomiting. Five patients (15 percent) had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had drug treatment interrupted, and one discontinued treatment. Six (18 percent) of the 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor use, and the only adverse event that resulted in study treatment discontinuation.

According to the research team, more studies are needed to confirm  ivacaftor’s safety and its long-term effects in young children. According to Professor Davies, the study’s lead author, “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.”

In a related comment, Sophie Yammine and Philipp Latzin from University Children’s Hospital Bern, Switzerland, and Florian Singer from University Children’s Hospital Zurich, Switzerland, said, “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.”

Vertex reports that in the U.S., Europe and Canada, ivacaftor is indicated for patients with one of the following CFTR gene mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R (as well as for a G970R mutation in Canada, and R117H in the U.S.). The drug, known as a CFTR potentiator, is designed to keep CFTR proteins at the cell surface open longer so as to improve salt and water transport across the cell membrane, helping to hydrate and clear mucus from airways.