Research Update

By: Rachel Jennifer Fields

Vertex’s Kalydeco approved in eight additional CF mutations

Vertex’s Kalydeco has made a huge impact on the approximately 4% of patients afflicted with the G155D mutation that causes Cystic Fibrosis.  Recently Kalydeco was approved by the U.S. FDA to treat eight additional CF mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D.  There are about 150 additional patients in the U.S. that have one of these mutations.

The CF Community looks forward to Vertex’s Phase III TRAFFIC and TRANSPORT studies

In patients who have the G155D mutation (or any of the other eight mutations listed above) CFTR reaches the cell surface, but is deficient at transporting chloride.  Kalydeco, a CFTR potentiator, works by facilitating chloride transport across the CFTR channel once the CFTR protein is effectively trafficked to the cell membrane. In patients who have the DF508 mutation (which affects approximately 90% of CF patients) CFTR is not properly trafficked to the cell membrane, hence Kalydeco isn’t an effective treatment for patients with DF508.  In order to develop a treatment option for patients with the DF508 mutation Vertex is combining Kalydeco with other small molecule drug candidates that have been pre-clinically shown to act as CFTR correctors and help traffic CFTR to the cell membrane.  An ongoing Phase III clinical trial is pairing Kalydeco with one such molecule called Lumacaftor.  The trial will test whether a combination of these two compounds can improve lung function in patients carrying two copies of the DF508 mutation.   The trials, dubbed TRAFFIC and TRANSPORT, are set to wrap up in the coming months with data expected sometime in the summer of 2014.        

Other Clinical Trial News

With the Success of Kalydeco, other key players are also motivated to develop effective CFTR potentiators and correctors.  In September 2013, Galapagos NV and AbbVie teamed up to just that.  Galapagos has recently selected its first pre-clinical candidate molecule termed GLPG1837, a CFTR potentiator, to begin clinical trials with before the end of 2014.  Ongoing efforts seek to find an effective corrector molecule with which to pair GLPG1837.

When a person with CF inhales irritants or contracts a lung infection, the lung can become inflamed with different immune cells to help ward off the infection.  One such immune cell, called a neutrophil, releases an enzyme called neutrophil elastase in order to break down bacteria or other foreign particles. When left uncontrolled, this enzyme can also damage healthy lung tissue.  Israel-based Kamata Ltd. is developing inhaled Alpha-1 Antitrypsin (AAT), which inhibits neutrophil elastase and reduces destruction of healthy lung tissue, was recently granted Investigational New Drug (IND) approval from the FDA for a Phase II clinical trial of AAT to treat cystic fibrosis in the U.S. The trial is set to begin in the second half of 2014. 

Massachusetts-based biopharmaceutical company Xenetic Biosciences Inc. recently reported promising Phase I data in a Russian clinical trial of PulmoXenTM, a polysialic acid modified, synthetic, recombinant DNase I.  DNase I reduces the viscosity of lung secretions and biofilm formations in CF patients.  Currently there is a DNase I treatment available to CF patients called Pulmozyme that is produced by Genentech, but PulmoXenTM is designed to have a more stable pharmacodynamic profile than Pulmozyme.  This increased stability will allow PulmoXenTM to last longer.  Encouraging data from the Russian trial is leading Xenetic to file an Investigational New Drug (IND) application with the FDA to begin a Phase I trial in the U.S.