Lumacaftor (VX-809) is an investigational treatment, being developed by Vertex, for patients with cystic fibrosis (CF). Currently, lumacaftor is only approved with ivacaftor as a combination therapy commercialized by Vertex under the brand name Orkambi. 

How lumacaftor works

CF is a hereditary condition caused by mutations in the CFTR gene, which provides instructions for the production of an ion channel protein called CF transmembrane conductance regulator (CFTR). These mutations cause defects in the CFTR protein, which disrupts the normal salt-water transport across the cell membrane and results in the production of a thick, sticky mucus that may accumulate in different organs including the lungs.

One of the common mutations in the CFTR gene is the so-called F508del mutation, which results in a defective misfolded CFTR protein. The misfolded protein is degraded by the cell before it can reach the cell membrane. Even if some of the defective protein reaches the cell membrane, it is unable to open correctly to allow the passage of chloride ions. 

Lumacaftor and ivacaftor work together to restore the function of the CFTR protein at the cell membrane. Lumacaftor works by increasing the stability of defective CFTR proteins, thereby helping them reach the cell membrane and stay there longer. But because it does not address the problem with the opening of the channel, lumacaftor is generally used in combination with ivacaftor, which acts on the defective proteins, helping them to open more often so that the salt-water balance across the cell surface is restored.

Lumacaftor in clinical trials

Vertex conducted two randomized, double-blind, placebo-controlled 24-week clinical trials called TRAFFIC (NCT01807923) and TRANSPORT (NCT01807949) in 1,108 CF patients, 12 years and older, with two copies of the F508del mutation to evaluate the effect of lumacaftor and ivacaftor. Both trials demonstrated that lumacaftor (400 or 600 mg) taken in combination with ivacaftor (250 mg) every morning, and 250 mg of ivacaftor taken alone at night for six months improved lung function. The combo therapy, called Orkambi, was able to improve patients’ mucus clearance, which reduces the risk of inflammation in the lungs. However, despite the ability of lumacaftor to improve lung function in combination with ivacaftor, the same was not verified in patients given lumacaftor alone.

A Phase 2 clinical trial (NCT01225211) showed that the lumacaftor/ivacaftor combination did not improve lung function in CF patients with one copy of the F508del mutation.

An open-label Phase 3 study (NCT03601637) is currently recruiting in the U.S. and Canada about 40 CF patients, 12 to 23 months old, who carry two copies of the F508del mutation to evaluate the safety of the lumacaftor-ivacaftor combination therapy, and the body’s response to it.

Another Phase 3 rollover study (NCT03125395) is ongoing that aims to evaluate the long-term safety of lumacaftor/ivacaftor treatment in children, 2 and older, who have two copies of the F508del mutation in the CFTR gene.

Other information

Lumacaftor (in Orkambi treatment) is available in three dosages (100 mg, 150 mg, and 200 mg) as tablets or oral granules.

It should be used with caution in patients with advanced liver disease, respiratory problems, or blood pressure problems.

Common side effects of Orkambi include difficulty breathing, nausea, diarrhea, fatigue, rash, flatulence, and flu-like symptoms.

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