New treatment for cystic fibrosis


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BigNorseWolf wrote:
Is this thing just better or somehow revolutionary?

Revolutionary.

Prior to this drug treatment meant managing the symptoms. Dealing with numerous infections and many, many hospital visits. One such treatment involves wearing an inflatable vest which oscillates pressure on your chest. The effect pushes excess mucus towards the larger cavities in your lungs where you can now cough it up or have it suctioned out. Patients who need this often need it multiple times a day.

When this drug is effective it basically stops the disease in it's tracks as long as you take it. Your lungs stop deteriorating and you stop producing mucus in your lungs. It changes how your lungs function, not just treating the symptoms after they appear.


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Orkambi (the new Vertex drug) is a combination of ivacaftor (the active principle in the old Vertex drug, Kalydeco) and lumacaftor.

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) protein potentiator that helps the protein in its function to transport chloride ions across cell membranes. This function of the CFTR was lost due to a defect in the CFTR protein (specifically the G551D mutation, which is present in about 4-5% of CF cases).

Lumacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) protein corrector that suppresses misfolding of the CFTR protein. The misfolding problem arises from a different defect in the CFTR protein (specifically the deletion of the phenylalanine amino acid at position 508 (F508del) of the CFTR protein).

Both the old drug Kalydeco (ivacaftor alone) and Orkambi (ivacaftor and lumacaftor together) work at the level of the CFTR protein, and not at the level of symptoms. Orkambi is not revolutionary in the sense of changing the treatment paradigm from symptoms to causes, because Kalydeco already worked at the protein level. Orkambi may be more effective at treating a much broader spectrum of CF patients because only 4-5% of CF patients have the G551D mutation of the CFTR protein, whereas up to 90% of CF patients have the F508del mutation.

Also, the combination of ivacaftor and lumacaftor (Orkambi) has a significant effect in patients who have the F508del mutation of the CFTR gene on both chromosomes (homozygous), but not in patients who have the F508del mutation of the CFTR gene on only one of the chromosomes (heterozygous) (see http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(14)70132-8/a bstract). This will place further limits on the effectiveness of Orkambi across the CF population. It should also be note that while the forced expiratory volume (FEV) results were significant for heterozygous F508del patients, they do not appear to be overly spectacular in comparison to the control group. Orkambi will be a boon to more CF patients than previous treatments, but there is still a ways to go.

While drugs that correct protein function at the level of the protein itself are revolutionary compared to ones that only treat the physiological symptoms, a deeper cause of the problem is genetic mutations on the gene that encodes the CFTR protein. Once gene therapy is developed to the point of being able to correct the genetic disorders at the level of nucleotides on the DNA, another revolution in CF treatment will occur.

Finally, CF can be caused by any one of several different mutations on the CFTR gene. To completely defeat CF, treatments applicable to all of these genetic mutations (or at least the subset of mutations common to all CF patients) will need to be developed.

Orkambi is a step in the right direction, but it is not going to be a panacea for CF.


Thanks for the technical breakdown, Pink Dragon.

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