On July 2, 2015 the FDA announced its approval for the potent duo of Lumacaftor and Ivacaftor to treat patients suffering from Cystic Fibrosis (CF). Coined Orkambi, which is marketed by Vertex Pharmaceuticals, this effectual treatment is specifically approved for patients ages 12 and older who have the homozygous F508 mutation of the CF transmembrane conductance regulator, or CFTR gene. Orkambi has also already attained breakthrough therapy and Orphan Drug status in the United States and it is currently awaiting an EMA review. While both Lumacaftor and Ivacaftor have not proven to be efficacious for patients with CF as monotherapy, a Phase 2 study of the combination proved these two drugs greatly improve clinical outcomes in patients who are homozygous for the Phe508del CFTR mutation.
Two successful Phase 3 studies led the FDA to their positive opinion of Lumacaftor and Ivacaftor. Coined TRAFFIC and TRANSPORT these trials were comprehensive and multinational. As double-blind, placebo-controlled, randomized and parallel-group studies, both Lumacaftor and Ivacaftor proved to be effectual, tolerable and safe. The studies were designed to evaluate primarily the efficacy of Lumacaftor and Ivacaftor in combination for patients with the homozygous Phe508del CFTR mutation form of CF. Safety was a secondary objective of the study. The patients in these studies were assigned to one of three random groups and given one of the following doses:
- 600 milligrams of Lumacaftor once a day in combination with 250 milligrams of Ivacaftor every 12 hours for 24 weeks.
- 400 milligrams of Lumacaftor every 12 hours in combination with 250 milligrams of Ivacaftor every 12 hours for 24 weeks.
- A Lumacaftor-matched placebo every 12 hours in combination with an Ivacaftor-matched placebo every 12 hours for 24 weeks.
There were a total of 1,122 patients who underwent randomization, specifically 559 in the TRAFFIC study and 563 in the TRANSPORT study. At least one dose of the study drug or the placebo drug was dispensed to 1,108 patients. Both studies of the Lumacaftor/Ivacaftor combination elicited viable clinical changes as early as 15 days into the studies, and showed a sustained efficacy through the 24 week mark. In both studies the percentage of patients who had a relative improvement in the percentage of predicted FEV1 of 5% or higher was demonstrative in the patients who received Lumacaftor and Ivacaftor, as compared to the patients who received the placebo. Additionally, clinically significant reductions of protocol-defined pulmonary exacerbations were found in the patients who were dosed in both Lumacaftor–Ivacaftor trial groups. The reporting of adverse events was similar in both the Lumacaftor/Ivacaftor and placebo groups, with common complaints being a higher than normal creatine kinase level, rash and bronchospasms.
As a genetic disease associated with high rates of early-onset mortality Cystic Fibrosis affects roughly 30,000 patients in the United States. Of these patients almost 30 percent are homozygous for the F508 mutation. The recent approval of Lumacaftor and Ivacaftor as Orkambi is an encouraging development which is greatly needed for this patient population.
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