Kalydeco’s Safety and Benefits Maintained Long-term in 2-to-5-year-olds with CF, Phase 3 Trial Shows

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Long-term treatment with Kalydeco (ivacaftor) is well-tolerated and efficient, with improvements in sweat chloride concentration, growth, and pancreas function maintained over 84 weeks in 2-to-5-year-old children with cystic fibrosis (CF), results from the Phase 3 KLIMB extension study show.

Trial findings were published in the study, “An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2–5 years (KLIMB),” in the Journal of Cystic Fibrosis.

Complications due to CF, such as poor nutritional status and lung damage, appear during infancy, so early intervention is very much needed. The disease is caused by mutations in the gene providing instructions for a transporter called the cystic fibrosis transmembrane conductance regulator (CFTR). For this reason, therapies that regulate the defective CFTR transporter are beneficial to CF patients.

Kalydeco, developed by Vertex Pharmaceuticals, is an approved medicine for CF that works by keeping the CFTR gate open longer at the cell surface, making it easier for salts and water to cross the cell membrane, and consequently helping in hydration and mucus clearing.

A previous Phase 3 trial (NCT01705145) called KIWI showed that treatment with Kalydeco was safe and efficient in CF children between the ages of 2 and 5 with specific types of the CFTR genetic mutation.

KIWI results revealed that taking the therapy orally at one of two doses — 50 mg for children weighing less than 14 kilograms (roughly 31 pounds), and 75 mg for children weighing 14 kilograms or more — twice daily for 24 weeks improved disease markers including sweat chloride levels, weight gain, and pancreatic function.

The Phase 3 KLIMB (NCT01946412) study is an open-label extension trial that followed the patients who completed the KIWI study for 84 additional weeks to evaluate Kalydeco’s long-term safety.

Patients enrolled in the first study had a median age of 3 years, weighed at least 8 kilograms (about 18 pounds), had a confirmed CF diagnosis, and carried one of 10 CFTR gene mutations — G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D. There was no treatment interruption between the two studies.

Conducted at several sites in the United States, United Kingdom, and Canada, from December 2013 to December 2015, the trial enrolled a total of 33 patients.

Children received one of two doses of Kalydeco as granules (50 or 75 mg, based on their weight as in the KIWI trial), twice daily. Children who turned 6 years old during the study received 150 mg of Kalydeco twice daily as tablets.

Out of the 33 children enrolled, 28 (84.8%) completed the 84-week treatment. The trial’s main objective was safety.

All children reported at least one adverse effect during the study period, most commonly a cough (72.7%), followed by fever (39.4%), vomiting (39.4%), and pulmonary exacerbation (30.3%). However, researchers noted that these events are common among children with CF.

A total of 21 serious adverse effects were reported in 11 children, and most were linked to liver damage, as shown by increased levels of alanine and aspartate transaminases — two markers of liver damage. In 10 children, levels more than three times higher than normal were detected. Treatment was temporarily stopped for five children who reported levels eight times higher than the upper normal limit, but only one child discontinued Kalydeco completely due to a worse liver function test after restarting Kalydeco.

The reduction in sweat chloride seen in the KIWI trial was also observed in the 84-week KLIMB trial, supporting Kalydeco’s effect on CFTR function. In addition, the children’s nutritional status continued to improve, as shown by the body mass index (BMI) z-score, a measure of body fat.

Regarding pancreatic function, the researchers saw that at the start of the study, one out of 17 children had fecal elastase-1 levels of 200 micrograms per gram (μg/g) or higher (the cutoff value to define pancreatic exocrine insufficiency). After 84 weeks, six of the children (35%) reached this value. Moreover, the blood levels of immunoreactive trypsinogen (a marker of pancreatic function) continued to decrease after 84 weeks. CF patients typically have high levels of trypsinogen.

Increases in fecal elastase-1 and reduction of blood immunoreactive trypsinogen supports Kalydeco’s effects in delaying the deterioration of pancreatic function.

“This is the first study reporting long-term safety and efficacy of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation,” the researchers wrote.

“The reduction in sweat chloride concentration, growth benefits, and improvements in markers of pancreatic exocrine function observed during 24 weeks in KIWI were maintained for an additional 84 weeks in KLIMB,” they concluded.

The U.S. Food and Drug Administration recently approved Kalydeco for the treatment of CF infants 6 to 12 months old, with at least one mutation in the CFTR gene.