Yesterday, the FDA’s Pulmonary-Allergy Drugs Advisory Committee (PADAC) voted 12 to 1 in support of approval for ORKAMBI (lumacaftor/ivacaftor) (Vertex Pharmaceuticals, Inc.), indicated for use in people with cystic fibrosis (CF) ages 12 and older who have two copies of the F508del mutation in the CFTR gene. The meeting materials for this meeting can be found HERE. 

ORKAMBI is a combination of lumacaftor, which is designed to increase the amount of functional protein at the cell surface by addressing the processing and trafficking defect of the protein, and ivacaftor, which is designed to enhance the function of the CFTR protein once it reaches the cell surface. ORKAMBI is an oral medicine that, if approved, would be taken as fully co-formulated tablets that contains both lumacaftor and ivacaftor.

In its pivotal trial, ORKAMBI demonstrated a statistically significant improvement in lung function, a surrogate endpoint for improving CF. Nonetheless, some panel members argued that Vertex never authoritatively proved that lumacaftor made a meaningful contribution to ivacaftor alone.

CF is a rare, life-threatening genetic disease that affects approximately 75,000 people in North America, Europe and Australia. CF is caused by defective or missing CFTR proteins resulting from mutations in the CFTR gene. The defective or missing proteins result 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.

Importantly, ivacaftor (a component of ORAKMBI) was the first drug to treat underlying molecular abnormalities present in certain CF patients. Ivacaftor essentially works by opening up cellular channels that shuttle water and salt across cell membranes, which consequently decreases troublesome buildup of mucus. Prior to the approval of ivacaftor, the only available treatments for CF only managed patients’ symptoms, but didn’t affect the functioning of the faulty channels.

Jeffrey Chodakewitz, M.D., Executive Vice President and Chief Medical Officer at Vertex noted that, “Today’s positive recommendation brings the cystic fibrosis community one step closer to potential approval of the first medicine to treat the underlying cause of this disease for many more people.”

ORKAMBI was granted Breakthrough Therapy designation in 2012 and a New Drug Application (NDA) was submitted to the FDA in November 2014. The FDA is expected to make a final decision by July 5, 2015. The FDA is not bound by the Advisory Committee’s recommendation but often follows their advice.

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