#NACFC2016 – Next-Gen CFTR Correctors Show Improved Activity in Repairing Defects

In a recent talk, researchers showed the enhanced benefits of two next-generation CFTR correctors in cystic fibrosis (CF) patients with specific mutations. The positive results support the clinical evaluation of both drugs in early-stage clinical trials.

The talk, “Discovery and biological profile of next-generation CFTR correctors,” was recently presented at the 30^th Annual North American Cystic Fibrosis Conference (NACFC) Oct. 27-29 in Orlando, Florida.

Cystic fibrosis patients with an F508del mutation in one or two copies of the CFTR gene (the gene which is defective in CF) benefit from a therapeutic strategy based on combining CFTR correctors — drugs that act through several mechanisms to increase the presence of the CFTR protein at the cell surface.

Now, researchers identified “next-generation” CFTR correctors that are not only active by themselves, but can also be added to first-generation correctors such as lumacaftor (VX-809) or VX-661.

Peter Grootenhuis from Vertex Pharmaceuticals presented the pharmacological activity of these new CFTR correctors, called VX-152 and VX-440. They were tested in cultured human bronchial epithelial (HBE) cells derived from CF patients and without a normal production of CFTR protein (specifically, five who were homozygous for F508del, or three patients who were heterozygous for F508del and either G542X or 3905InsT mutations). As controls, researchers used cells from four non-CF donors.

The functional tests confirmed that VX-152 and VX-440 are CFTR correctors, as both drugs enhanced the processing and trafficking of the CFTR protein in the cells of cystic fibrosis patients and increased the amount of CFTR at the cell surface. When combined with a first-generation CFTR corrector, researchers observed an even more pronounced processing and trafficking of CFTR to the cell membrane. Therefore, combining both has an additive effect and more CFTR is shuttled to its proper position (the cell membrane) when compared to either corrector alone.

Also, researchers observed an increase in chloride transport (the natural ion of CFTR channels) from a baseline of 6% normal to 19% and 16% normal with VX-152 and VX-440, respectively. These effects were further enhanced using a triple combination of VX-661, Kalydeco (ivacaftor), and VX-152 or VX-440.

This triple combination with VX-152 or VX-440 also improved fluid transport and ciliary beat frequency when compared to lumacaftor and Kalydeco.

The results support the ongoing clinical evaluation of VX-152 and VX-440 combined with first-generation CFTR correctors and Kalydeco in CF patients who carry the mutation F508del.