Vertex Pharmaceuticals recently received a Complete Response Letter from the U.S. Food and Drug Administration (FDA) stating that its supplemental New Drug Application (sNDA) could not be approved in its current form. The application concerns the administration of Vertex’s medicine Kalydeco (ivacaftor) in patients with cystic fibrosis (CF) ages 2 and older who have one of the 23 residual function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
CF is a life-threatening genetic disorder affecting an average 75,000 people in North America, Europe and Australia. It is caused by mutations in the CFTR gene, which is involved in the production of sweat, mucus, and digestive fluids. About 2,000 mutations in the CFTR gene are known to influence the function of CFTR proteins. Dysfunction or deletion of this protein can alter the flow of salt (chloride) and water in the lining of organs, which, in turn, results in the accumulation of thick and sticky mucus that can promote the development of chronic lung infections.
CF has no known cure, but a number of medicines are available to relieve the symptoms. Among them, Kalydeco is an oral drug candidate that treats the underlying cause of CF by improving the transport of salt and water within the cell membrane and hydrates and clears mucus from the airways.
Kalydeco is approved in the U.S., Europe, Canada, Australia, and New Zealand for the treatment of CF patients having specific mutations in the CFTR gene. The medicine was granted an FDA Breakthrough Therapy Designation in 2013 and approved in the U.S. for treatment of CF patients ages 2 and older having one of 10 of the following mutations in their CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or R117H.
In the U.S., more than 1,500 CF individuals age 2 and older have one of the following 23 residual function mutations, which were included in Vertex’ sNDA: 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.
As with the mutations for which Kalydeco was approved, this group of 23 residual function mutations is also associated with some functional CFTR protein at the cell surface, and in vitro (in the lab) results have shown that Kalydeco treatment enhances the chloride transport in cells expressing CFTR.
Vertex’s sNDA was submitted as a result of several encouraging outcomes including the preclinical results for ivacaftor in residual function mutations, the clinical profile of Kalydeco, and data obtained from an exploratory Phase 2a study.
“Our intention with this submission was to rapidly bring KALYDECO to additional people with CF who we believe may benefit,” said Boston-based Vertex Executive Vice President and Chief Medical Officer Dr. Jeffrey Chodakewitz in a company press release. “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.”
Vertex intends to schedule a meeting with the FDA to discuss a proper follow-up and necessary steps that must be taken.