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FDA Panel Recommends Approval of Cystic Fibrosis Drug Orkambi

Unmet need trumps questionable efficacy

The FDA’s Pulmonary–Allergy Drugs Advisory Committee has voted 12 to 1 to recommend approval of the experimental cystic fibrosis (CF) treatment Orkambi (Vertex Pharmaceuticals) despite reservations about its effectiveness.

Orkambi combines ivacaftor (Kalydeco) with a new medication, lumacaftor. Both drugs target the most common genetic mutation responsible for CF.

In a briefing document posted online on May 8, the FDA’s advisors said it was unclear whether lumacaftor “contributes any added benefit over” ivacaftor alone. In the new announcement, the panel noted again that Orkambi had “modest effectiveness,” improving lung function by only about 3% compared with placebo. Still, the advisors ruled that the treatment was safe and effective enough to be approved for use in CF patients –– a population in need of new therapies.

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

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 noted, 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 affect 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.

Sources: Reuters; May 12, 2015; New York Times; May 12, 2015; FDA Briefing Document; May 8, 2015.

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