Lumacaftor in combination with ivacaftor provides clinically important reductions in the rate of pulmonary exacerbations in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation, new ground-breaking research shows.
The phase 3 randomised double blind placebo controlled TRAFFIC and TRANSPORT trials of 1108 patients who were homozygous for the Phe508del mutation found the combination of drugs produced significant improvements in lung function and weight gain, as well as significant amelioration of respiratory symptoms and pulmonary exacerbations.
“As well as the 30-39 per cent reduction in lung infections, our trial participants reported a decrease in events requiring hospitalisation or use of IV antibiotics,” said lead author Professor Claire Wainwright from the Queensland Children’s Medical Research Institute.
“Results like this mean our novel treatment is a potential game changer for the way we treat CF and other genetic disorders in the future,” she said.
The combination of a CFTR corrector and potentiator represents a treatment milestone for the 45% of patients with cystic fibrosis who are homozygous for the Phe508del, concluded the researchers in their paper which was published online in the NEJM.
Writing in an accompanying editorial Pamela Davis from Case Western Reserve University School of Medicine, Cleveland noted that the extent of improvement was not as great as that produced by ivacaftor alone in the treatment of patients with the Gly551Asp mutation.
The forced expiratory volume in 1 second (FEV1) increased by only about 3 percentage points, as compared with 11 percentage points with ivacaftor alone in patients with the Gly551Asp mutation, she said.
A possible explanation could be drug–drug interactions between lumacaftor and ivacaftor, the former being a strong CYP3A inducer and the latter being a sensitive CYP3A substrate and weak inhibitor.
Nevertheless, the trial results were the beginning of effective therapy for cystic fibrosis associated with the most common mutant form of CFTR, she said.
With further drug development to avoid drug–drug interactions, even the challenging Phe508del CFTR mutation will almost surely come under excellent therapeutic control, she wrote.
The road to success has been long, despite diligence, enthusiasm, and excellent collaborative efforts among academics, industry, and patients.
“The report by Wainwright and colleagues is a celebration of the legions of investigators — involved in clinical and basic research, based in industry and academia — as well as the legions of patients all over the world, who together have paved the way for a new beginning in cystic fibrosis treatment.”
Nine CF centres in Australia participated in the trial. The Food and Drug Administration will make a finl decision on the treatment in July, after which it will be assessed by the TGA.
The trials were sponsored by Vertex, who manufacture lumacaftor and ivacaftor.