Lumacaftor/ivacaftor

Lumacaftor/ivacaftor (brand name Orkambi) is a combination drug available a single pill that is used for the treatment of cystic fibrosis in people who have the F508del mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is a combination drug that consists of lumacaftor and ivacaftor. Ivacaftor increases the activity of the CFTR protein at the surface of epithelial cell, while lumacaftor acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. It was approved by the US FDA in July 2015.

Medical use

The combination of lumacaftor/ivacaftor is used to treat people with cystic fibrosis who have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease. The combination treatment improves lung function about 3% in such people and reduced hospitalization events by about 34%.

Precautions, side effects and interactions

Some people taking the combination drug had elevated transaminases; the combination drug should be used with caution for people with advanced liver disease and liver function should be measured for the first three months for all people starting the combination drug.

People starting the combination have respiratory discomfort, and some children taking the combination drug developed cataracts.

Lumacaftor/ivacaftor may interfere with hormonal contraceptives. Dosage of the combination drug should be reduced if the person is taking a drug that inhibits CYP3A, and inducers of CYP3A should not be used concomitantly.

Mechanism of action

F508del is a mutation that causes the CFTR protein to misfold and cells destroy such proteins soon after they are made; lumacaftor acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. Ivacaftor is a potentiator of CFTR that is already at the cell surface, increasing the probability that the defective channel will be open and allow chloride ions pass through the channel pore. The two drugs have synergistic effects.

Physical properties

Each of lumacaftor and ivacaftor is a white to off-white powder that is practically insoluble in water. The combination drug is a single pill containing 200 mg of lumacaftor and 125 mg of ivacaftor.

History

Lumacaftor/ivacaftor was approved by the FDA in July 2015 under breakthrough therapy status and under a priority review.

Society and culture

As of March 2016 the combination drug cost $259,000 a year in the United States.

In Denmark, it was estimated in August 2015 that if the drug were introduced, the cost would amount to 2 million Danish krones (approximately 270,000 euro) each year per person.