Vertex Pharmaceuticals has submitted a new drug application (NDA) to the US Food and Drug Administration and a marketing authorization application (MAA) to the European Medicines Agency (EMA) for a fully co-formulated combination of lumacaftor (400 mg q 12h) and ivacaftor (250 mg q 12h) 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 and 12,000 in Europe.

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 EMA’s 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).

Cystic fibrosis is a rare genetic disease that 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 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.

As part of an expanded access program, in recognition of the immediate needs of some people with cystic fibrosis, 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 IIIb study for a limited number of people who have severe lung disease in the first quarter of 2015, followed by an expanded access program 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 programs for eligible patients in the second quarter of 2015.

Vertex initiated its CF research program in 1998 as part of a collaboration with CFFT, the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. This collaboration was expanded to support the accelerated discovery and development of Vertex’s CFTR modulators.

Source: Vertex Pharmaceuticals