Kalydeco (ivacaftor) by Vertex Pharmaceuticals has been approved in the European Union for children ages 1-2 with cystic fibrosis (CF) who carry at least one of nine mutations in the CFTR gene — G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R — that prevent the CFTR chloride channel from working properly.
“For the first time, EU physicians can now treat the underlying cause of CF earlier than ever, helping to improve clinical outcomes in children as young as 12 months,” Reshma Kewalramani, MD, executive vice president and chief medical officer at Vertex, said in a press release.
The approval was based on results from the ongoing Phase 3 ARRIVAL (NCT02725567) trial that enrolled children ages 1-2 with one of 10 CFTR mutations — G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, or R117H.
The trial, conducted in two parts, first treated seven children with 50 mg or 75 mg of Kalydeco, depending on weight, every 12 hours for five days to assess safety. In the second part, nine children received 50 mg of Kalydeco for 24 weeks to evaluate its safety and efficacy.
Results showed that after 24 weeks, the children’s mean sweat chloride levels were about three times lower than those at the trial’s start — dropping from 104.1 mmol/L to a mean value of 33.8 mmol/L.
Measuring the levels of sweat chloride is a tool used to diagnose CF. The higher the values, the more likely a patient is to develop the disease. Levels equal to or higher than 60 mmol/L mean CF is likely; levels lower than 30 mmol/L indicate it is unlikely.
Ten patients showed a decrease of more than than 40 mmol/L in sweat chloride levels by week 24, with four of those achieving levels lower than 30 mmol/L.
Kalydeco also improved the levels of several exocrine pancreatic biomarkers commonly used to determine CF-associated exocrine pancreatic dysfunction.
Researchers also saw that the therapy improved the levels of fecal elastase, serum immunoreactive trypsinogen, and amylase and lipase enzymes important for digestion, supporting Kalydeco’s ability to help prevent digestive complications from progressing at an early age.
Concerning safety, Kalydeco’s profile in younger children was consistent with that observed in prior trials of older children and adults.
The most common adverse effects reported in the trial were cough, fever, elevated liver enzymes, and a runny nose; most were mild or moderate in severity. A serious increase of liver enzyme levels was reported in two patients, who continued treatment after a dose interruption.
“We look forward to supporting additional research on the potential benefit of early intervention with our medicines, with the goal of bringing treatment to all people living with CF,” Kewalramani said.
Results from the ARRIVAL trial were presented in June 2018 at the 41st European Cystic Fibrosis Conference, and published in the journal The Lancet Respiratory Medicine, in the article “Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study.”
Kalydeco is the first medication to treat the underlying cause of CF in people with “gating” mutations — those that result in the production of a faulty CFTR protein that can cause the ion channel’s gate to get stuck closed.
In August 2018, the U.S. Food and Drug Administration (FDA) expanded Kalydeco’s approval to treat CF in 1-year-olds.
In Europe, the therapy was already approved for children age 2 and up who are carrying one of the same nine mutations in the CFTR gene — G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R. Kalydeco is also approved for adult CF patients (age 18 and up), carrying the R117H mutation in the CFTR gene.