Vertex Drug Targets Defect from G551D Mutation

Phase 2a Clinical Results Show Promising Results in CFTR Function

Recently, the pharmaceutical company Vertex released news of exciting progress from the Phase 2a clinical trial for their drug Vx-770. This oral drug may be the first to successfully target the actual genetic defect for patients who carry the G551D mutation. This mutation causes a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) - the ion channel that allows chloride to pass through cells - so that chloride channels are prevented from crossing through the cell membranes.

The preliminary testing on 20 patients with this mutation found the following positive results:

• Lung Function: patients receiving the highest dose of VX-770 had on average a 10% increase in FEV1 over the 14 day trial; while those receiving placebo had no increase
• Nasal Potential Difference (NPD): NPD assesses several aspects of ion channel activity by measuring voltage changes across the nasal epithelia and is used as a direct measure of CFTR activity and chloride ion movement in upper airway epithelial cells. This measurement is used in CF patients who display low ion movement in the upper airways. Patients receiving the highest dose had a significant change in mean NPD while those who received placebo did not see any change.
• Sweat Chloride Levels: The measurement of sweat chloride levels is a standard diagnostic tool for cystic fibrosis patients, who typically have much higher levels (more than 60 mmol/L) of chloride in their sweat than normal (less than 40 mmol/L). Patients who received the highest dose of VX-770 found that sweat chloride decreased from a mean 95.5 mmol/L at baseline to 53.2 mmol/L over the 14-day dosing period. There was no notable change in sweat chloride in patients receiving placebo.

These results are quite exciting because no current therapies can target the actual genetic defect that causes CF. The fact that these results are apparent in different measures of CF indicate that the drug is having a direct effect on the CFTR protein.

It is important to note that these results are preliminary and much longer studies on additional patients need to be done before any definite conclusions can be made. Additionally, the G551D mutation affects just 4% of patients with CF, so this drug would not be beneficial to a majority of CF patients. However, there is some more tentative good news in that Vertex is developing an additional drug specifically for the most common defect, delta F508. This mutation results in a defect in the way the CFTR protein is folded, resulting in the protein getting stuck in the endoplasmic reticulum so that it never even makes it to the cell membrane. The new drug in development, VX-809, may be able to free up the CFTR protein so that the channel can make it to the cell membrane and pass chloride ions. Phase 1a clinical studies have begun on VX-809. Hopefully the results from these studies will be as positive as those from VX-770.

You can read more about these drugs from the Vertex Pharmaceuticals website:
VX-770 Study
VX-809 Study