New cystic fibrosis treatment targets underlying cause of the disease

Orkambi (lumacaftor/ivacaftor) targets the F508del mutation in the CFTR gene, the most common causative cystic fibrosis mutation.

Mutations in the gene encoding the CFTR chloride channel lead to the production of abnormally viscous mucus characteristic of cystic fibrosis. | SCIENCE PHOTO LIBRARY
Mutations in the gene encoding the CFTR chloride channel lead to the production of abnormally viscous mucus characteristic of cystic fibrosis. | SCIENCE PHOTO LIBRARY

Orkambi is indicated for the treatment of cystic fibrosis in patients who are homozygous for the F508del mutation in the gene encoding the CFTR channel, which is responsible for chloride transport across the epithelia of many organs.

The F508del mutation reduces the amount of CFTR at cell surfaces and restricts the opening of the channels, impeding chloride transport and contributing to the symptoms of cystic fibrosis.

Further information
View Orkambi drug record
Summary of Product Characteristics
Manufacturer: Vertex Pharmaceuticals
MIMS Respiratory Clinic

Lumacaftor, a CFTR corrector, increases the amount of CFTR at cell surfaces, and ivacaftor, a CFTR potentiator (already available separately as Kalydeco), makes the channels more likely to be open. The exact mechanism by which each drug exerts its effects is unknown.

Clinical evidence

In two randomised, double-blind, placebo-controlled phase III trials, the lumacaftor/ivacaftor combination at a dose of 400mg/250mg twice daily was found to increase the percentage of predicted FEV1 at 24 weeks by an average of 2.8 percentage points (n=369; p<0.001). The rate of pulmonary exacerbations was 39% (95% CI 24—51%) lower in patients taking the combination than in those given placebo.

The incidence of adverse effects was generally similar in the lumacaftor/ivacaftor and placebo groups. The adverse effects most commonly reported with lumacaftor/ivacaftor were dyspnoea, diarrhoea and nausea, which affected 13.0%, 12.2% and 12.5% of patients, respectively (compared with 7.8%, 8.4% and 7.6%, respectively, of those who received placebo).


As a strong inducer of the hepatic enzyme CYP3A, lumacaftor has interactions with commonly used drugs including hormonal contraceptives and anticonvulsants.

Liver function tests are recommended in patients taking Orkambi as elevated transaminases have been reported in studies of the drug.

Draft NICE rejection

In draft guidance due to be finalised in July, NICE noted that the cost of Orkambi was considerably higher than that of the current standard of care and concluded that the drug could not be considered a cost-effective use of NHS resources.

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