Vertex Pharmaceuticals Incorporated, a global biotechnology company, announced that it received a Complete Response Letter from the US Food and Drug Administration (FDA) for its supplemental New Drug Application (sNDA) for the use of Kalydeco (ivacaftor) in people with cystic fibrosis (CF) aged 2 and older who have one of 23 residual function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The FDA determined that it cannot approve the application in its present form. Vertex plans to meet with the FDA to determine an appropriate path forward.

"Our intention with this submission was to rapidly bring Kalydeco to additional people with CF who we believe may benefit," said Vertex executive vice president and chief medical officer, Jeffrey Chodakewitz, M.D. "We chose to pursue this approach given our strong belief in the science of CF and in the well-established safety of Kalydeco across many different groups of people with CF. We are disappointed by this decision and look forward to discussing with the FDA the next steps to bring Kalydeco to people with CF who have these residual function mutations."

The sNDA is based on preclinical data for ivacaftor in residual function mutations, the established clinical profile of Kalydeco and on previously reported data from an exploratory phase 2a study. In 19 of the 24 patients enrolled in this study, eight 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, which received the FDA's Breakthrough Therapy designation in 2013, is currently approved in the US to treat people with CF aged 2 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 approved, this group of 23 residual function mutations is known to have some functional CFTR protein at the cell surface. This submission was also based on observed in vitro increases in chloride transport in response to ivacaftor in cells expressing CFTR. The presence of CFTR protein at the cell surface and increases in chloride transport are characteristics associated with clinical response to Kalydeco.

There are more than 1,500 people aged two 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.