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Cystic Fibrosis Combo Lumacaftor/Ivacaftor Submitted for FDA Review
A new drug application (NDA) has been submitted to the FDA for a co-formulated combination of lumacaftor (400 mg q12h) and ivacaftor (250 mg q12h) for patients aged 12 years and older with cystic fibrosis (CF) who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
Approximately 22,000 CF patients aged 12 years and older have two copies of the F508del mutation in North America, Europe, and Australia, including approximately 8,500 in the U.S.
The combination of lumacaftor and ivacaftor received a “breakthrough therapy” designation from the FDA in 2012. The U.S. submission includes a request for a priority review, which, if granted, would shorten the FDA’s anticipated review time from approximately 12 months to 8 months. The application seeks approval for a fully co-formulated combination treatment dosed as two tablets every 12 hours (four tablets daily).
The NDA submission was based on previously announced data from two global phase III studies, TRAFFIC and TRANSPORT, and on the first interim data from a subsequent rollover study in CF patients aged 12 years and older who had two copies of the F508del mutation treated with standard-of-care medicines.
The TRAFFIC and TRANSPORT trials showed improvements in lung function and in other measures of disease, such as pulmonary exacerbations, through 24 weeks of treatment with lumacaftor in combination with ivacaftor. Initial interim data from the rollover study showed that the improvements in lung function were sustained during a total of 48 weeks of treatment (24 weeks in the TRAFFIC and TRANSPORT trials plus 24 weeks in the rollover study). In TRAFFIC and TRANSPORT, the most common adverse events included infective pulmonary exacerbation, cough, headache, and increased sputum.
CF is a rare genetic disease for which there is no cure. It is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. The defective or missing protein results in poor flow of salt and water into and out of cells in a number of organs, including the lungs. In people with two copies of the F508del mutation, the CFTR protein is not processed and trafficked normally within the cell, resulting in little-to-no CFTR protein at the cell surface. Lumacaftor, a CFTR corrector, is designed to address the processing and trafficking defect of the F508del CFTR protein, thereby increasing the amount of functional protein at the cell surface, where ivacaftor, a CFTR potentiator, can further enhance its function.
Source: Vertex Pharmaceuticals; November 5, 2014.