Dr. Fiel: The area of great excitement has to do with CFTR modulation, with the approval of ivacaftor, a small-molecular-weight compound developed to treat specifically the G551D mutation. Unfortunately, this drug only treats 4% of cystic fibrosis patients.
Narrator: Ivacaftor, which is an oral drug, is also being evaluated for patients with other mutations, including R117H and F508del.
Dr. Fiel: We're specifically looking at drugs that will improve the gating and conductance function of CFTR, which affects the proteins already at the cell membrane, and those defects that affect the amount or quantity of CFTR that gets to the cell surface. In ΔF508, not a significant amount of protein is getting to the cell surface. And in the G551D [mutation], there is plenty of protein at the apical membrane, but the chloride channel or the protein itself is not functioning properly by either not gating or conducting properly.
So in looking at the class mutations, we have functional abnormalities such as the class 3 and 4 defects, which includes G551D and R117H; and quantitative problems where the corrector drugs hopefully will be of value in the future.
Narrator: Two of these candidate “corrector” molecules that assist with F508del folding and allow F508del CFTR to be transported to the apical surface include lumacaftor, or VX-809, and VX-661, both of which have reached clinical trials.6,7 In a phase 2 trial, adult patients with homozygous F508del mutations were randomized to receive lumacaftor or placebo. Lumacaftor treatment resulted in a small but statistically significant decrease in sweat chloride values in a dose-dependent manner, but no improvements in pulmonary function or nasal potential difference were detected.8 Combination strategies with this agent are being assessed as well.
The F508del mutation manifests both Class II and Class III defects, which means that it may be possible to address both functional defects through combined use of a corrector such as VX-809 or VX-661 and a potentiator such as ivacaftor. A phase 2 trial of combined treatment with lumacaftor and ivacaftor in adult patients with homozygous or heterozygous F508del has evaluated different dose combinations. Available data indicate that the regimen of 600 mg lumacaftor daily combined with ivacaftor at a dose of 250 mg twice daily resulted in an improvement in lung function in homozygous patients compared with those given placebo.9 Among patients in the treatment arm, 19% achieved an absolute improvement in FEV1 of ≥10% compared with no patients in the placebo arm. Additional phase 3 studies are underway to evaluate lumacaftor in combination with ivacaftor.10,11
VX-661 is another small-molecular-weight compound that is being evaluated in combination with ivacaftor.12
Dr. Fiel: The problem in patients—and about 80% of our North American CF population has at least one copy of the ΔF—is in the folding of the protein, such that the protein cannot get to the cell surface. If a corrector can improve the amount of drug that gets to the cell surface, then the combination of a corrector and a promoter may well be the future of CF care.
Looking at all of our CF mutations and their functional defects and classifying each of these into a quantitative or corrector problem and/or a functional problem—we will then be able to treat many more of our patients with CF and hopefully change the way this disease is looked at, and disease-modify CF completely such that survival may improve and this may no longer be the lethal disease that it is today.
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