The Food and Drug Administration (FDA) will be evaluating the new drug application (NDA) for Vertex Pharmaceutical’s Orkambi, indicated to treat cystic fibrosis in patients with the F508del mutation on Tuesday, and will make a final decision for approval/disapproval by July 5. The Pulmonary-Allergy Drugs Advisory Committee (PADAC) will be discussing the results of a portfolio of tests compiled for the combination of lumacaftor and ivacaftor fixed dose combination oral tablets.
“While the discussion will include safety, the main topic at the May 12, 2015, PADAC meeting will be efficacy and whether the submitted data support the efficacy of lumacaftor and ivacaftor fixed dose combination (FDC) tablets for the proposed indication (cystic fibrosis patients 12 years of age and older who are homozygous for the F08del mutation in the CFTR gene),” stated the FDA briefing document, provided in advance of the Tuesday decision.
Vertex Pharmaceuticals already produces ivacaftor under the name Kalydeco. It is indicated to treat patients who have one of ten different mutations in the CFTR gene, not including F508del, which is the most common mutation in patients with cystic fibrosis. In patients with F508del, the CFTR protein is truncated in its synthesis, preventing proper protein folding and transport to the cell surface.
Lumacaftor is thought to aid patients with cystic fibrosis by enabling trafficking of CFTR to the cell surface. However, neither lumacaftor nor ivacaftor alone can substantially benefit cystic fibrosis patients homozygous of F508del. Instead, a combination of the two has been used in clinical trials to identify beneficial effects of lumacaftor and ivacaftor FDC.
Results of these trials have not provided overwhelming evidence that FDC treatment is effective. Patients treated with lumacaftor and ivacaftor FDC for six months showed only a 2.5 to 3% improvement in lung function, results that were much lower than expected based on the dramatic results first reported with Kalydeco treatment (10% improvement). There were no patients receiving either drug alone to determine whether FDC provided the 2.5 to 3% improvement, or if either alone could provide this benefit.
“The contribution of lumacaftor to the efficacy of the proposed combination product has not been shown,” stated the conclusion of documentation for a study determining the added benefit of combination treatment. “Treatment with lumacaftor for four weeks produced a small numerical decrease in sweat chloride that was maintained after an additional four weeks of treatment with lumacaftor/ivacaftor. However, the decreases observed for sweat chloride were small when compared to the sweat chloride response noted for ivacaftor in the G551D and R117H mutations.”
The goal of the meeting is to discuss these data in order to make the most informed decision concerning the efficacy of combination treatment in patients with cystic fibrosis before allowing Orkambi to be marketed. After Tuesday, the FDA will continue its scrutiny of the product and make its final decision within two months.