Mutation Specific CF Therapies: A Small Lesson

In a previous article I referenced the first portion of the Nature Review, “cystic fibrosis genetics: from molecular understanding to clinical application,” written by Dr. Garry Cutting, to provide a basic understanding of the function of the CFTR protein and its role in the development of cystic fibrosis, which is important to understand novel molecular therapies that are being developed for CF.

Cystic fibrosis results from one of nearly 2000 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene codes for a protein that functions in the apical membrane of epithelial cells as a chloride ion channel. However, CFTR mutations affect the protein by either decreasing its function as a chloride channel in the cell membrane, or by decreasing the amount of the protein that is able to traffic to and insert into the membrane.

The G551D and F508del are two mutations that illustrate the variable effect mutations can have in the CFTR gene. The G551D mutation produces a sufficient amount of the CFTR protein, which properly inserts  into the membrane, but the mutation creates a ‘gating defect’ that prevents the channel from opening properly and decreases the flow of chloride ions. However, the more common F508del creates a mis-folded protein and without its proper shape fails to insert into the cell membrane and as a result its absence leads to a decreased flow of chloride ions across epithelial membranes.

The past few years in CF treatment have created a stir of excitement within the CF community because for the first time molecular therapies are being developed to address the dysfunctional CFTR protein that is the specific cause of the disease. For the 50 years prior to these mutation specific therapies CF treatments were only directed toward the symptoms of the disease, leaving patients in a steady, continual decline in health. However, with funding from the Cystic Fibrosis Foundation through its non-profit drug discovery and development affiliate Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) an increasing number of therapies are being developed in the drug development pipeline to address the underlying cause of the disease with the hope that patients in coming years may soon begin to stabilize in their health.

The first of the mutation specific therapies to be released was Kayldeco (VX-770; ivacaftor) developed by Vertex Pharmaceuticals and released in 2012 for use in patients with the G551D mutation. Since its release the drug is available to ten other mutations which produce a similar ‘gating defect’ as the G551D mutation. Additionally, Vertex announced yesterday, on Wednesday, March 18, that the access to Kayldeco would be extended to patients between the ages of 2 to 5, which increases the total number eligible to take the drug to 1,950 in the United States.

As mentioned previously, the G551D mutation treated by Kayldeco results in a CFTR protein that in large part is able to insert into the membrane but fails to open and allow transport of chloride ions across epithelial cells. Kayldeco serves to fix this defect by functioning as a ‘potentiator,’ which interacts with the protein in such a way as to allow it to open normally. The initial findings of the drug were quite promising and “phase III clinical trials over 4-week and 48-week intervals demonstrated that ivacaftor (Kayldeco) improved lung function (by 10% on average),” Dr. Cutting noted in his review, “and reduced sweat chloride concentration (to an average concentration below the diagnostic threshold of 60 mM).”

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Following the initial success found in Kayldeco, molecular therapies began to be developed to the F508del mutation. This mutation is an attractive target for CF therapy because nearly 50 percent of patients have two copies of F508del with an additional 40 percent with one copy of the mutation. The F508del is different from that of G551D and a bit more complex because the mutation results in a mis-folded protein that is unable to properly place itself into the membranes of epithelial cells. The therapy then requires an additional step to find a way to get the protein to enter the cell membrane.

Since the mutation for F508del is different than that of G551D it requires a different approach in the creation of its molecular therapy. The approach used to correct the F508del is a combination therapy which implements two drugs, ivacaftor (Kayldeco; VX-770) and lumacaftor (VX-809). The goal is that lumacaftor will function as a ‘corrector’ to change the mis-folded CFTR protein to its proper shape which will allow it to correctly insert into the cell membrane. Once lumacaftor has aided the CFTR protein to correctly incorporate itself into the cell membrane, ivacaftor serves as a ‘potentiator’ to enable the channel to open and allow chloride ions to flow across the epithelial membrane.

The results of the phase III clinical trials for the homozygous (two copies) F508del treated with lumacaftor and ivacaftor combination were modest in comparison to the results for the treatment of G551D by ivacaftor alone. The combination therapies in two 24 week trials showed an approximate increase in lung function (FEV1) of 4%, with a decrease in pulmonary exacerbations of 30 to 39 percent.

In the Nature Review originally cited, Dr. Cutting explains that, “two groups have recently reported that ivacaftor exposure for 48 hours diminishes the correction of F508del-CFTR conferred by lumacaftor in primary and immortalized cells.” Therefore, he notes that the, “reduction in the quantity of ‘corrected’ F508del-CFTR due to ivacaftor may explain the modest response observed in clinical trials.”

In January, the Federal Drug Administration (FDA) granted priority review of the combination of lumacaftor and ivacaftor in CF patients homozygous for F508del 12 years of age and older. The FDA decision on the combination therapy is set for July 5. Although the initial results were lower than expected there is great reason for eligible CF patients to be excited as it is the first time they will have access to a drug that addresses their specific mutation.

I will be one of the patients set to take the new combination if it is approved this summer. Despite the fact that the drug is not the final step in my healing, my hope is that it will be the first turn in the trajectory of my health. In the results of the clinical trials I hold onto the finding of a reduction of pulmonary exacerbation by 30 to 39 percent. This could mean that I will be hospitalized only three times in the next year, rather than four or five. That would be the first sign for me personally that the direction of CF healthcare is changing and that my health just might stabilize or even increase over the next ten years.