A combination of two drugs - lumacaftor and ivacaftor - improves lung function in children aged 6-11 with cystic fibrosis within 15 days of treatment, according to a phase 3 trial published in The Lancet Respiratory Medicine journal and presented at the European Cystic Fibrosis Society conference.
Cystic fibrosis is a genetic disease that causes the lungs and digestive system to become clogged with thick mucus. The disease eventually causes respiratory failure and early death. It currently has no treatment that targets the underlying cause of the disease, but there are treatments to reduce symptoms of the disease.
Cystic fibrosis is caused by mutations in the CFTR gene. A mutation called F508del-CFTR is the most common with 38% of patients having two copies of this mutation. The drug combination trialled in the study corrects the errors in the cells caused by this genetic fault.
Lumacaftor and ivacaftor are two of the first medicines developed to target the underlying causes of the disease, and potentially provide a way to slow progression of cystic fibrosis - an important goal in the treatment of children with the disease.
The trial was done in children aged 6-11. Currently, the drugs are approved for patients with cystic fibrosis who have two copies of the F508del-CFTR mutation by the US Food and Drug Administration and Health Canada (for children aged 6 years and older), as well as the European Medicines Agency and Therapeutic Goods Administration of Australia (12 years and older).
In the study, led by researchers from The Hospital for Sick Children, University of Toronto, Canada, 206 children aged 6-11 years old with cystic fibrosis were either given the drug combination or a placebo for 24 weeks. The trial took place across 54 hospitals in nine countries1.
The study found that those taking the drugs showed improved lung function - taking less time to clear air from their lungs. Meanwhile, lung function remained the same for those given the placebo.
As a result of reduction in the amount of chloride in the children's sweat (a sign to diagnose the condition), the research also suggest that the drugs are acting on the errors caused by the gene mutation.
These improvements were apparent in the group given the drug combination within 15 days of treatment and continued to be significantly lower than those given the placebo throughout the 24 weeks of the trial.
The proportion of patients who discontinued the study because of side effects related to their treatment was similar in each group, with three patients discontinuing because of side effects in the drug group, and two in the placebo group.
The study adds to evidence from other trials of the drug combination showing similar results in patients aged 12 and over.
"Our results suggest that this drug combination may help to preserve lung health in children with cystic fibrosis, potentially slowing the progression of the disease and allowing these children better quality, longer lives," says lead author Professor Felix Ratjen, The Hospital for Sick Children, University of Toronto, Canada. "Further research into long-term effects will be needed. If successful, giving the drug treatment soon after diagnosis will be crucial to ensure that the disease is slowed as soon as possible." 2
The authors note some limitations in their study, including that the study was the first to use the lung clearance index as a primary measure of treatment success and experience of using it is still limited. During the study, patients in both groups continued to take other treatments to address the symptoms of their disease.
Writing in a linked Comment, Professor Carla Colombo, University of Milan, Italy, says: "The development of cystic fibrosis transmembrane conductance-regulator (CFTR)-correcting therapies is changing the way we treat cystic fibrosis, shifting therapy from a mostly symptom-based approach addressing downstream complications to a precision medicine approach targeting the underlying cause... 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."
The study was funded by Vertex Pharmaceuticals Incorporated. A full declaration of interests is available in the Article. It was conducted by scientists from The Hospital for Sick Children, University of Toronto, Vertex Pharmaceuticals, Stanford University School of Medicine, The Children's Hospital at Westmead, Imperial College London, and Royal Brompton Hospital.
Article: Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial, Prof Felix Ratjen, MD et al., The Lancet Respiratory Medicine, doi: 10.1016/S2213-2600(17)30215-1, published 9 June 2017.
Comment: Cystic fibrosis transmembrane conductance-regulator modulators for children, Carla Colombo, The Lancet Respiratory Medicine, doi: 10.1016/S2213-2600(17)30208-4, published 9 June 2017.