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FDA Advisors Question Benefits of Cystic Fibrosis Drug Orkambi

Treatment combines ivacaftor and lumacaftor

The FDA’s Pulmonary–Allergy Drugs Advisory Committee (PADAC) has questioned the benefits of the experimental cystic fibrosis (CF) drug Orkambi (Vertex Pharmaceuticals), including whether the addition of a second drug ingredient adds to the product’s effectiveness.

Orkambi combines ivacaftor (Kalydeco) with a new medication, lumacaftor. In a briefing document posted online, the FDA panel says it’s unclear whether lumacaftor “contributes any added benefit over” ivacaftor alone.

Orkambi is intended to treat the most common form of CF, which affects approximately 8,500 individuals aged 12 years and older in the U.S. In clinical trials, patients treated with Orkambi for 6 months showed a 2.5% to 3.0% improvement in lung function –– a key measure for CF patients. That improvement was statistically significant, the FDA advisors note, but “the clinical meaningfulness of the magnitude of the improvement remains to be determined.”

CF is a life-threatening autosomal recessive disease that affects approximately 70,000 individuals worldwide (30,000 in the U.S.). It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which result in the lack of or inadequate function of CFTR proteins on the surface of epithelial cells. The CFTR protein is a chloride channel that helps regulate salt and water absorption and secretion across epithelial cells. Approximately 2,000 mutations have been identified in the CFTR gene; since CF is an autosomal recessive disease, patients need mutations in both CFTR alleles to develop the disorder.

Typically, the lungs, the gastrointestinal system (i.e., intestines, pancreas, and liver), and the reproductive system are the predominantly affected organ systems in CF patients. Death is usually due to respiratory failure as a result of obstructive lung disease and chronic pulmonary infection. Ultimately, the severity of the disease depends on the type of mutations present as well as on other modifying factors. Currently, the median age for survival is the mid to late 30s.

Ivacaftor is a small-molecule drug that has been shown to increase chloride ion transport across the CFTR chloride channel in epithelial cell membranes. It is currently approved in tablet and granule formulations in the U.S. for the treatment of patients as young as 2 years of age with CF defined by having one of ten mutations in the CFTR gene (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H). These mutations together encompass relatively few CF patients in the U.S. (about 2,000).

Lumacaftor, another small molecule, was developed by Vertex to promote CFTR intracellular processing and trafficking. While its mechanism of action is not completely understood, it appears to promote the proper folding of the defective F508del-CFTR protein during its processing in the endoplasmic reticulum, thereby allowing it to exit the endoplasmic reticulum and move to the apical surface of the epithelial cell membrane. In vitro data suggest that it does this by inducing a change in F508del-CFTR protein conformation that is more like the normal “wild-type” CFTR, resulting in increased F508del-CFTR maturation.

Given the actions of the individual drug components, Vertex has proposed that the combined effect of ivacaftor and lumacaftor in CF patients homozygous for the F508del mutation would be to both increase the quantity (lumacaftor) and improve the function (ivacaftor) of the F508del-CFTR ion channel at the epithelial cell surface, resulting in improved overall chloride ion transport and clinical benefit.

The FDA is scheduled to make an approval decision for Orkambi on July 5. The agency is not required to follow the recommendations of its advisory committees, but it usually does so.

Sources: Medical Xpress; May 8, 2015; and FDA Briefing Document; May 8, 2015.

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