Vertex Pharmaceuticals Incorporated, a global biotechnology company, has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for a fully co-formulated combination of lumacaftor (400mg q12h) and ivacaftor (250mg q12h) for people with cystic fibrosis (CF) ages 12 and older who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

There are approximately 22,000 people with CF ages 12 and older who have two copies of the F508del mutation in North America, Europe and Australia, including approximately 8,500 in the United States and 12,000 in Europe.

"The combination of lumacaftor and ivacaftor is the first potential treatment designed to target the underlying cause of cystic fibrosis in people with two copies of the F508del mutation, which is the most common form of the disease," said Jeffrey Chodakewitz, M.D., executive vice president and chief medical officer at Vertex. "Today's submissions represent important progress toward our ongoing efforts to develop new medicines for the vast majority of people with cystic fibrosis, and we look forward to working closely with regulatory agencies to bring this treatment to eligible patients as quickly as possible."

In the US, the combination of lumacaftor and ivacaftor received Breakthrough Therapy Designation in late 2012. The US submission includes a request for Priority Review, which, if granted, would shorten the FDA's anticipated review time from approximately 12 to 8 months. The European Committee for Medicinal Products for Human Use (CHMP) has granted Vertex's request for Accelerated Assessment of the MAA, which is given to new medicines of major public health interest and shortens the review time from approximately 210 to 150 days for the CHMP to give an opinion following the start of the review. The CHMP opinion is then reviewed by the European Commission, which generally issues a final decision within three months. If approved, Vertex would then begin the country-by-country reimbursement approval process. Both applications seek approval for a fully co-formulated combination treatment dosed as two tablets every 12 hours (four tablets daily).

The NDA and MAA submissions are based on previously announced data from two global phase 3 studies, TRAFFIC and TRANSPORT, and the first interim data from the subsequent rollover study in people ages 12 and older who have two copies of the F508del mutation treated with standard-of-care medicines. The TRAFFIC and TRANSPORT studies showed improvements in lung function and 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 lung function improvements were sustained for 48 total weeks of treatment (24 weeks in TRAFFIC/TRANSPORT + 24 weeks in rollover study). The combination was generally well tolerated in all three studies. In TRAFFIC and TRANSPORT, the most common adverse events were infective pulmonary exacerbation, cough, headache and increased sputum.

Cystic fibrosis 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 the cell 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, increasing the amount of functional protein at the cell surface where ivacaftor, a CFTR potentiator, can further enhance its function.

In recognition of the immediate needs of some people with CF, Vertex is working to make the combination of lumacaftor and ivacaftor available to people ages 12 and older who have two copies of the F508del mutation, are in critical medical need and meet additional eligibility criteria. In the US, Vertex plans to begin a phase 3b study for a limited number of people who have severe lung disease in the first quarter of 2015, followed by an expanded access programme in the second quarter of the year, pending discussions with the FDA. Vertex will also work with regulatory authorities outside the United States toward implementing additional expanded access programs in other countries, with a goal of opening programmes for eligible patients in the second quarter of 2015.

The combination of lumacaftor and ivacaftor is the first potential medicine designed to treat the underlying cause of CF in people with two copies of the F508del mutation, the most common form of the disease. In North America, Europe and Australia, there are approximately 22,000 people ages 12 and older who have two copies of the F508del mutation.

Known as a CFTR corrector, lumacaftor aims to address the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein. Ivacaftor is designed to help the CFTR channel at the cell surface open more often to improve the transport of salt and water across the cells. In combination, lumacaftor and ivacaftor are believed to help hydrate and clear mucus from the airways.

Vertex is a global biotechnology company that aims to discover, develop and commercialize innovative medicines so people with serious diseases can lead better lives. In addition to our clinical development programs focused on cystic fibrosis, Vertex has more than a dozen ongoing research programs aimed at other serious and life-threatening diseases.