Skip to main content

Johns Hopkins

Johns Hopkins Pediatric

Modifying Disease for CF Patients

June 13, 2013

Michael Boyle, M.D.

Disease modifying compounds, says pulmonologist Michael Boyle, bind with the CFTR protein on the cell membrane, open it up and release chloride to restore normal salt and water balance.

The way pulmonologist Michael Boyle frames the therapeutic picture for cystic fibrosis, great advances have been made in reducing the risk of mucus buildup and potentially lethal lung infections, improving survival that is now approaching 40 years. But to actually prevent such symptoms and raise the survival ceiling significantly higher, stresses Boyle, researchers need to develop therapies that alter the pathogenesis of the disease at its very beginnings.

“In order to make a more significant change, we’re going to have to treat the underlying causes of cystic fibrosis,” Boyle says. “The next generation of medicines is going to do exactly that.”

These so-called “disease-modifying drugs,” Boyle explains, target the defective chloride channel that lines the lungs—defective because CF patients have certain mutations in the CFTR protein, or cystic fibrosis transmembrane conductance regulator, that do not allow it to do its job of balancing salt and water in the channel. The result is too much salt and not enough water passes into the cells, causing the buildup of dry mucus in the lungs that makes CF patients vulnerable to infections. DeltaF508, the most common mutation in CF—affecting 90 percent of patients—prevents the protein from reaching the surface of the channel, where it can activate or fire. But a new Vertex Pharmaceutical compound, VX770, the first FDAapproved disease-modifying medication for CF, says Boyle, has been shown to help propel the CFTR protein to the surface with positive results.

“This corrector compound helps the protein fold right so that it can make it through the quality control mechanism of the cell up to the surface,” Boyle says. “VX770 has been shown in several studies to dramatically improve lung function, prevent people from getting sick as often, and help them gain weight—all the things you want.”

However, Boyle adds, this personalized medicine is based on genotype and only works for about 4 percent of patients. Casting a wider net, Boyle is targeting another mutation, R117H, which allows the protein to make it to the channel surface but, once there, is unable to activate. An answer may come with another Vertex compound under development, VX809, which is designed to open the protein and rev it up so it can fire. Boyle is leading a phase 3 combination therapy trial in which VX809 is being used in combination with VX770 against the mutation.

“The ideal thing is to put those two together to get the protein right where we need it and turn it on to its maximum effect,” says Boyle, citing an earlier phase 2 study in which lung function improved significantly in half the patients.

Next steps, concludes Boyle, include studying other combinations of channel correctors to maximize the effect of VX770.

“It would be a mistake to say VX770 is a cure,” stresses Boyle. “But the way we find a cure is by bunching all these modifiers together to make them work even better and improve their effect on patients.”

© The Johns Hopkins University, The Johns Hopkins Hospital, and Johns Hopkins Health System. All rights reserved.