How does Orkambi work in cystic fibrosis?
Orkambi (lumacaftor/ivacaftor) is used for cystic fibrosis caused by the CFTR “F508del” mutation (people with two copies of that mutation). Its core mechanism is to correct two different problems caused by this mutation: misfolding of the CFTR protein and reduced function of the CFTR chloride channel.
Lumacaftor helps the misfolded CFTR protein fold and reach the cell surface more effectively, which increases the amount of CFTR at the apical membrane. Ivacaftor then increases the activity of the CFTR channel at the cell surface so chloride can move through it more effectively. Together, this improves chloride transport and helps restore more normal ion movement across airway and other epithelial tissues. [1]
What does lumacaftor do at the protein level?
Lumacaftor acts as a CFTR “corrector.” For F508del CFTR, many CFTR proteins are degraded before they reach the membrane because they do not fold properly. Lumacaftor increases the probability that the CFTR protein folds in a way that allows trafficking to the cell surface, increasing functional CFTR availability where it can act as a chloride channel. [1]
What does ivacaftor do in the pathway?
Ivacaftor is a CFTR “potentiator.” After CFTR reaches the cell surface, ivacaftor increases how well the channel opens and conducts chloride ions. In other words, it boosts function of the CFTR protein that is already present at the membrane, rather than primarily fixing folding/trafficking. [1]
Why does Orkambi require both drugs?
Using both medicines targets both bottlenecks in F508del CFTR:
- Lumacaftor increases how much CFTR gets to the cell surface.
- Ivacaftor increases chloride channel activity of CFTR that reaches the surface.
This dual approach is why the product is a combination rather than ivacaftor alone or lumacaftor alone. [1]
What is Orkambi expected to change clinically?
By improving CFTR-mediated chloride transport, Orkambi is intended to reduce airway mucus dehydration and improve mucociliary clearance. Clinically, that can translate into fewer respiratory exacerbations and improvements in lung function for eligible people with the specified CFTR mutation pattern. [1]
Are there limitations to the mechanism?
Orkambi’s design is most relevant to the F508del mechanism of CFTR dysfunction. People with different CFTR mutations (not F508del homozygous or not meeting the labeling criteria) may not see the same benefit because the underlying defect and the portion of the CFTR pathway that needs targeting can differ. [1]
Sources:
1. Vertex Pharmaceuticals - ORKAMBI (lumacaftor/ivacaftor) prescribing information / mechanism of action description