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Orkambi yields positive results in younger patients with cystic fibrosis

Orkambi improved lung function in patients 6 to 11 years old with cystic fibrosis within 15 days of treatment, according to phase 3 trial results recently published in The Lancet Respiratory Medicine. The findings were also presented at the European Cystic Fibrosis Society conference.

NIH data suggest that cystic fibrosis occurs in one in 2,500 to 3,500 white newborns and is less common in other ethnic groups, affecting about one in 17,000 blacks and one in 31,000 Asian Americans.

“We designed this phase 3 study to further investigate the efficacy and safety of lumacaftor in combination with ivacaftor in patients aged 6 to 11 years with cystic fibrosis homozygous for the F508del-[cystic fibrosis transmembrane conductance regulator (CFTR)] mutation,” Felix Ratjen, MD, The Hospital for Sick Children, University of Toronto, and colleagues wrote. “[Lung clearance index₂₅ (LCI_2-5)] was chosen as the primary endpoint based on knowledge that it is a sensitive measure of lung function in this younger population.”

Researchers enrolled 206 patients in their trial, then randomly assigned 104 to receive Orkambi (lumacaftor/ivacaftor, Vertex Pharmaceuticals), and 102 to placebo. Three patients, including one from the placebo group, were unable to complete the trial.

Ratjen and colleagues found that the average absolute change in LCI_2-5 from baseline in all study visits up to and including a week 24 visit, least squares mean difference was –1.09 units (95% CI, –1.43 to –0.75) for lumacaftor/ivacaftor vs. placebo. In a secondary endpoint, sweat chloride concentration, the least squares mean difference vs. placebo was –20.8 mmol/L (95% CI, –23.4 to –18.2), average absolute change at day 15 and week 4; P < .0001). The least squares mean difference compared with placebo in absolute change in ppFEV₁ from all on-treatment study visits until week 24 was 2.4 (95% CI, 0.4-4.4, P = .0182).

Researchers also reported that 98 patients had moderate adverse events and 87 patients had mild adverse events. Serious adverse events were reported in 13 patients in the lumacaftor/ivacaftor group and 11 patients in the placebo group. Nasal congestion, oropharyngeal pain, productive cough, rhinorrhea, increased sputum and upper abdominal pain were observed more frequently in the lumacaftor/ivacaftor treatment group than in the placebo group.

“This phase 3 trial provides rigorous evidence for efficacy with lumacaftor and ivacaftor in the pediatric population at the early stages of disease and is among the first to use LCI₂₅ as a primary endpoint,” Ratjen and colleagues wrote.

Researchers stated that previous phase 3 studies of lumacaftor and ivacaftor in patients with cystic fibrosis aged at least 12 years homozygous for F508del-CFTR, treatment with lumacaftor and ivacaftor was generally safe and well tolerated. In a related comment, Carla Colombo, MD, of the Cystic Fibrosis Centre, University of Milan, suggested that more potential exists for CFTR modulators, besides those noted by Ratjen’s team.

“The data obtained on lumacaftor and ivacaftor combination therapy in F508del-homozygous patients with cystic fibrosis older than 6 years suggest that further efforts are needed to maximize the expression of F508del-CFTR,” she wrote. “Several new CFTR modulators are in development, including next generation correctors and CFTR amplifiers designed to target CFTR biosynthesis. These new drugs could represent new pharmacological approaches with even better disease modifying potential and impact on prognosis for an increasing number of children and adults with cystic fibrosis.” – by Janel Miller

Disclosure: Ratjen reports acting as a consultant for, and receiving funding from Vertex Pharmaceuticals Inc. Colombo reports participating in advisory boards for Vertex, Novartis, PTC, Proteostasis and Gilead. Please see the study for list of the other authors relevant financial disclosures.

Reference:

NIH Genetics Home Reference Page on Cystic Fibrosis (accessed 06-09-17)