The US Food and Drug Administration (FDA) has accepted for review Vertex Pharmaceuticals Incorporated's supplemental New Drug Application (sNDA) for the use of Kalydeco (ivacaftor) in people with cystic fibrosis (CF) aged 2 years and older who have one of 23 residual function mutations.

The FDA granted Vertex's request for Priority Review of this sNDA, and a target review date of February 6, 2016 was set under the Prescription Drug User Fee Act (PDUFA) for the FDA's decision on the sNDA. The submission was based on preclinical and clinical data showing the effect of ivacaftor on CFTR function in certain residual function mutations.

"Given the severity of cystic fibrosis, we are committed to getting Kalydeco to more people as quickly as possible," said Jeffrey Chodakewitz, M.D., executive vice president and chief medical officer at Vertex.

"Based on the established safety profile of Kalydeco and our increasing understanding of the biology of these specific residual function mutations and their response to ivacaftor, we believe that people with these mutations would benefit from treatment with this medicine."

The sNDA was based on preclinical data for ivacaftor in the 23 residual function mutations, the established clinical profile of Kalydeco and on previously reported data from an exploratory phase 2a study in 24 people with residual function mutations. In 19 of the 24 patients enrolled in this study, 8 of the 23 mutations proposed in the sNDA were represented.

CF is caused by defective or missing cystic fibrosis transmembrane conductance regulator (CFTR) proteins resulting from mutations in the CFTR gene. The defective or missing proteins result in poor flow of salt (chloride) and water into and out of the cell in a number of organs, including the lungs. Chloride transport is a marker of the function of the CFTR protein at the cell surface. Kalydeco is currently approved to treat people with CF aged 2 years and older who have one of 10 mutations in the CFTR gene (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or R117H). As with the mutations for which Kalydeco is currently approved, the 23 residual function mutations in the sNDA are known to have some CFTR protein at the cell surface and have shown in vitro increases in chloride transport in response to ivacaftor in cells expressing the CFTR form produced by each mutation, characteristics associated with clinical response to Kalydeco. Similar to the R117H mutation for which Kalydeco was previously approved, these 23 mutations result in a moderate loss of CFTR chloride transport, and people with these mutations generally have progressive lung function decline and other complications of CF.

There are more than 1,500 people aged 2 and older with CF in the United States who have one of the 23 residual function mutations included in the sNDA. The 23 residual function mutations included in the sNDA are: 2789+5G- > A, 3849+10kbC- > T, 3272-26A- > G, 711+3A- > G, E56K, P67L, R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, and D1270N.

Kalydeco is the first medicine to treat the underlying cause of CF in people with specific mutations in the CFTR gene. Known as a CFTR potentiator, Kalydeco is an oral medicine designed to keep CFTR proteins at the cell surface open longer to improve the transport of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.

Kalydeco is approved in the US, Europe, Canada, Australia and New Zealand to treat people with CF who have specific genetic mutations in the CFTR gene.

Vertex retains worldwide rights to develop and commercialise Kalydeco.

Cystic fibrosis is a rare, life-threatening genetic disease affecting approximately 75,000 people in North America, Europe and Australia. CF is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. Children must inherit two defective CFTR genes — one from each parent — to have CF. There are approximately 2,000 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic test, lead to CF by creating defective or too few CFTR proteins at the cell surface. The defective or missing CFTR protein results in poor flow of salt and water into or out of the cell in a number of organs, including the lungs. This leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median predicted age of survival for a person born today with CF is 41 years, but the median age of death is 27 years.

Vertex initiated its CF research programme in 1998 as part of a collaboration with  Cystic Fibrosis Foundation Therapeutics, Inc, the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. Kalydeco and Orkambi (lumacaftor/ivacaftor) were discovered by Vertex as part of this collaboration.