“This should get them to the starting gate” of drug development, said Robert Beall, president and CEO of CFF. Beall stresses that payments are “all milestone-based,” and expects that within about 18 months Vertex will choose a compound for clinical trials. Vertex said it will retain the rights to any compounds the collaboration identifies.
Cystic fibrosis, which affects about 30,000 people in the United States, is caused by a genetic defect in an ion channel protein called the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). The defective form of CFTR transports chloride ions poorly, and thereby disrupts the water balance in a variety of organs. The accumulation of thick mucus in the lungs causes the most serious and deadly complications of the disease.
The current agreement extends a 2000 drug discovery project between CFF and Aurora Biosciences, San Diego, which Vertex acquired in 2001. Aurora developed automated ways to use fluorescent probes and electrical stimulation to screen ion channel function much more rapidly than traditional patch-clamp techniques. Although some aspects of the high-throughput screening techniques are proprietary, Vertex received a related patent in February.
Beall says the team pursued two strategies to improve ion transport. In one, they looked for small molecules they call “potentiators” to directly increase the gating ability of the defective CFTR. In the other, they looked for compounds they call “correctors” to increase the amount of CFTR in the cell membrane. Much of the defective CFTR is destroyed in the cell before it can be incorporated into cell membranes, which aggravates the disruption caused by its degraded function.
The collaborators first developed a high-throughput assay for both types of activity. They then screened a library of compounds and found “scaffolds,” or families of compounds, that served both as "potentiators" and as “correctors,” but not both. Vertex says that both classes of compounds improved CFTR activity in lung cells from CF patients. Some of the results were presented at CFFT's annual conference in Williamsburg, Va., in early June.
The single recessive gene responsible for defective CFTR was identified in 1989. Since any increase in functional CFTR will be helpful, genetic approaches are also promising. “We are still pursuing the gene therapy,” Beall said, adding that the foundation has “nearly two dozen drugs in the pipeline.”
Michael Partridge, director of corporate communications for Vertex, says that the rapid ion-channel screening techniques were a “tremendous advantage” in the CF progress. But he adds “we're also seeing progress more broadly in the ion-channel area,” as part of the company's strategy of evaluating of drug candidates on proteins coded by families of related genes. For example, ion channels are the targets for current treatments of pain, hypertension, and epilepsy.