Lumacaftor-ivacaftor combination improves lung function in cystic fibrosis

Combination therapy with two drugs that target the most common genetic cause of cystic fibrosis (CF) has been found to improve lung function and reduce the rate of pulmonary exacerbations in patients with the disease, according to research published^[1]
in The New England Journal of Medicine on 17 May 2015.

An international team of researchers tested a combination of lumacaftor and ivacaftor in 1,108 patients who had CF and whose disease was caused by the Phe508del CFTR gene mutation, which is responsible for around 45% of cases. The mutation causes a processing defect that drastically reduces levels of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an anion channel that manages the movement of salt and water into and out of cells.

Lumacaftor, a CFTR corrector, enhances the number of CFTR ion channels, whereas ivacaftor, a CFTR potentiator, allows the malfunctioning protein to interact normally with the cell membrane, increasing the time that the channels are open.

The combination is a “major advance” in the treatment and quality of life of people with CF, says lead researcher Stuart Elborn from Queens University Belfast.

Fellow researcher Susanna McColley, professor of paediatrics at Northwestern University Feinberg School of Medicine, points out that significant progress has been made with supportive therapies for cystic fibrosis. “Developing treatments that address the underlying genetic cause has been a challenge,” she adds.

The researchers established two trials that examined different doses of lumacaftor (600mg per day and 400mg every 12 hours) in combination with ivacaftor (250mg every 12 hours) given to patients for 24 weeks. In both studies, participants’ lung function (FEV₁ — forced expiratory volume in one second) was measured. Improvements in FEV₁ were seen after 15 days in both studies and were sustained until the end of the trial.

Nearly twice as many patients in the lumacaftor-ivacaftor groups as in the placebo group had a relative improvement in the percentage of predicted FEV₁ of 5% or higher (39%–46% versus 22%) and 10% or higher (24%–27% versus 13%), the researchers report. There were also “clinically meaningful reductions” in pulmonary exacerbations in both combination dose groups. And the exacerbation rates were lower in the 600mg/day and 400mg/12hr combination dose groups than in the placebo group (30% and 39% lower; P=0.001 and P<0.001, respectively).

“Through 24 weeks, the lumacaftor–ivacaftor groups had reductions in the rate of pulmonary exacerbations, with decreases in the numbers of events leading to hospitalisation or intravenous antibiotic treatment,” the researchers say, adding that FEV₁ and rates of pulmonary exacerbations are strong predictors of survival.

Janet Allen, director of research and care at the Cystic Fibrosis Trust, says the findings “open up a new front in the fight against cystic fibrosis”. The combination therapy “looks set to be an important additional treatment option” that could improve the quality of life of people with the disease, she adds.

Ivacaftor was approved for use in the United States and Europe in 2012. In November 2014, Vertex Pharmaceuticals applied to the US Food and Drug Administration and to the European Medicines Agency for approval of its lumacaftor/ivacaftor combination.