Lumacaftor/Ivacaftor Safe, Effective for Pediatric Cystic Fibrosis

Combination lumacaftor/ivacaftor therapy was found to be safe and effective in patients with cystic fibrosis aged 6 to 11 years.

A study recently published in the Lancet Respiratory Medicine found lumacaftor/ivacaftor combination therapy to be safe and effective in pediatric patients with cystic fibrosis (CF), homozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation.  

“This study for the first time demonstrates the safety and efficacy of CFTR modulator therapy for the largest patient group, those with the most common genetic mutation, if given at a young age,” said Falix Ratjen, MD, PhD, FRCP(C), FERS, head of the Division of Respiratory Medicine, Sellers Chair of Cystic Fibrosis, and professor at the University of Toronto, Hospital for Sick Children, Ontario, Canada, in an email interview with Pulmonology Advisor.

“It also used a novel approach to capture treatment response, which is more sensitive than traditional measures of lung function, such as spirometry, which does not capture the early abnormalities seen in young CF children,” Dr Ratjen added.

The phase 3, randomized, double-blind, placebo-controlled, parallel-group trial ( identifier: NCT02514473) enrolled 206 patients between July 23, 2015, and September 20, 2016, from 54 hospitals and research centers in 9 countries. All patients were between the ages of 6 and 11 years, had a confirmed diagnosis of CF, and were homozygous for the F508del-CFTR mutation. Study participants were randomly assigned 1:1 to 1 of 2 treatment groups: lumacaftor 200 mg/ivacaftor 250 mg every 12 hours or placebo.

“In the past, treatment of CF patients has focused on addressing the downstream effects of the genetic defect; more recently, new treatments addressing the genetic defect have become available,” Dr Ratjen explained.

“This treatment (Orkambi, Vertex Pharmaceuticals) has previously been shown to have some benefits in older patients with established disease; here, we could demonstrate that treating young, school-age children who have mild disease and limited symptoms can improve their lung health,” he added.

The study found significant improvements in lung function in the group of patients treated with lumacaftor/ivacaftor vs placebo, as evidenced by the average absolute change in the lung clearance index from baseline up to and including week 24 of treatment (−1.09 units; 95% CI, −1.43 to −0.75 units; P <.0001). The average absolute change in sweat chloride concentration vs placebo was −20.8 mmol/L (95% CI, −23.4 to −18.2 mmol/L; P <.0001). The most dramatic reduction in sweat chloride concentration in the treatment group was observed on day 15 of lumacaftor/ivacaftor combination treatment (−20.0 mmol/L).

“The important finding is that there were no major safety issues, which is key for a treatment that likely would be needed to be administered over the whole lifetime of a patient,” emphasized Dr Ratjen.

Only 3% (3 of 103) of patients had to discontinue treatment because of adverse events. Although 96% of patients reported adverse events, most of them were mild (43%) or moderate (48%) in nature. Comparable rates of serious adverse events were reported in the lumacaftor/ivacaftor (13%) and placebo (11%) groups.

“Given that clear benefits were seen, the high price of the medication is the major hurdle for bringing this to the patient; the risk-benefit ratio over this 6-month period is certainly very positive,” concluded Dr Ratjen.

Study Limitations

  • To the best of the investigators’ knowledge, average absolute change in the lung clearance index has not previously been used as a primary endpoint.

Disclosures: Dr Ratien reports receiving grant funding from Vertex Pharmaceuticals. Drs. Hug, Marigowda, Tian, Huang, and Waltz are employees of Vertex Pharmaceuticals. Dr Milla reports receiving clinical trial funding from Vertex Pharmaceuticals, Parion Sciences Incorporated, Proteostaisis Therapeutics, and Gilead Sciences Incorporated, as well as the National Institutes of Health. For a full list of investigator disclosures, please see the full study. 

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Ratjen F, Hug C, Marigowda G, et al; on behalf of te VX14-809-109 Investigator Group. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomized, placebo-controlled phase 3 trial [published online June 9, 2017]. Lancet Respir Med. doi: 10.1016/S2213-2600(17)30215-1