FDA Approves Ivacaftor as First Therapy for Underlying Cause of Cystic Fibrosis in Young Children

The US Food and Drug Administration (FDA) has approved ivacaftor (KALYDECO) as the first and only therapy indicated to treat the underlying cause of cystic fibrosis (CF) in children aged 12 to <24 months with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

The approval is based on data from an ongoing phase 3 open-label safety study (ARRIVAL) of 25 children with CF who have one of 10 mutations in the CFTR gene, in which ivacaftor demonstrated a consistent safety profile to that in previous phase 3 trials involving older children and adults with CF. The therapy was previously approved by the FDA for the treatment of CF in adults aged 2 years and older with 1 of 38 treatment-responsive mutations in the CFTR gene—also based on clinical and/or in vitro assay data.

CF—a rare, genetic disease affecting approximately 75,000 people in North America, Europe and Australia&mdash;is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. The absense of the protein can result in poor water and salt flow into and out of various organ cells, resulting in abrnomally thick, sticky mucus buildup in the lungs. Patients are therefore often exposed to chronic lung infections and progressive lung damage.

There are currently about 2000 known mutations in the CFTR gene, and the median age of death in patients with CF is in the mid-to-late 20s.

In ARRIVAL data presented at the 41^st European Cystic Fibrosis Society (ECFS) Conference in June and published in The Lancet Respiratory Medicine, the most advese events (AEs) were mild or moderate in severity, and none results in patients discontinuing therapy. The most common adverse events (≥30%) were cough (74%), pyrexia (37%), elevated aspartate aminotransferase (37%), elevated alanine aminotransferase (32%) and runny nose (32%). Two patients had reported 4 serious AEs.

The mean sweat chloride for observed children at baseline was 104.1 mmol/L (n= 14). Following 24 weeks of treatment with ivacaftor, patient mean sweat chloride level was 33.8 mmol/L (n= 14). In the 10 subjects with paired sweat chloride samples at baseline and week 24, there was a mean absolute change of -73.5 mmol/L.

Margaret Rosenfeld, MD, MPH, of the Seattle Children’s Research Institute and department of pediatrics at the University of Washington School of Medicine, expressed excitement for the new indication and its implication for the youngest patients with CF.

“The premise of newborn screening for CF is to intervene very early in the course of disease with the goal of improving long term outcomes, so this is a significant milestone for parents and caregivers of young children with CF,” Rosenfeld said.