FDA Approves First Medicine to Treat Underlying Cause of Cystic Fibrosis in Children with Most Commo

The US Food and Drug Administration (FDA) has approved lumacaftor/ivacaftor (ORKAMBI) to include use in children ages 2 through 5 years with cystic fibrosis who have 2 copies of the F508del-CFTR mutation; it is the first medicine approved to treat the underlying cause of cystic fibrosis in this population.

“For the first time, children ages 2 through 5 who have the most common form of cystic fibrosis have a treatment for the underlying cause of their disease,” said Reshma Kewalramani, MD, executive vice president and chief medical officer at Vertex, in a recent statement. “We believe it is important to treat the underlying cause of the disease as early as possible and this approval is another significant milestone in our journey to bring effective medicines to all people living with cystic fibrosis.”

The treatment is a combination of lumacaftor—which is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein—and ivacaftor—which is designed to enhance the function of the CFTR protein once it reaches the cell surface. Lumacaftor/ivacaftor oral granules are available in 2 dosage strengths (lumacaftor 100mg/ivacaftor 125mg and lumacaftor 150mg/ivacaftor 188mg) for weight-based dosing and should be available for fulfillment within 2 to 4 weeks.

A phase 3 open-label safety trial served as the basis for the approval. A total of 60 patients were enrolled in the trial, and treatment with lumacaftor/ivacaftor for 24 weeks was found to be generally safe and well tolerated; the drug's safety profile was found to be similar to that seen in patients ages 6 years of age and older. Notably, improvements in sweat chloride at week 24 (mean decrease in sweat chloride from baseline of 31.7 mmol/L; 95% CI: -35.7, -27.6, n=49), and changes in key growth parameters were observed, both of which were secondary endpoints in the phase 3 trial.

While most adverse events ranged from mild to moderate in severity, the most common adverse event (≥30%) was a cough (63%). Serious adverse events (2 pulmonary exacerbations, 1 gastroenteritis, 1 constipation) were experienced by 4 patients but only 3 patients discontinued treatment due to treatment-emergent adverse events or elevated liver function tests.

These positive findings were presented at the 41st European Cystic Fibrosis Society Conference in June 2018.

“Cystic fibrosis is a systemic, multi-organ, progressive disease that is present from birth,” added John McNamara, MD, medical director of the cystic fibrosis program at Children’s Minnesota hospital and lead study researcher. “Research suggests lumacaftor/ivacaftor could impact cystic fibrosis outcomes in patients as young as two years old. This approval is a significant development that enables physicians to begin treating the underlying cause of the disease in this population earlier than ever before.”

Previously, lumacaftor/ivacaftor was approved in the United States for the treatment of cystic fibrosis in patients aged 6 years and older who have 2 copies of the F508del-CFTR mutation. A Marketing Authorization Application (MAA) line extension for lumacaftor/ivacaftor in children aged 2 years through 5 years has been submitted to the European Medicines Agency (EMA) with a decision expected in the first half of 2019.