News
The fixed-dose combination of ivacaftor and lumacaftor has been approved by the Food and Drug Administration for the treatment of cystic fibrosis in people aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. This is the first drug treatment approved for people who have two copies of this mutation, the most common type of cystic fibrosis.
“Today’s approval significantly broadens the availability of targeted treatments for the specific defects that cause cystic fibrosis,” Dr. John Jenkins, director of the Office of New Drugs in the FDA Center for Drug Evaluation and Research, said in a statement. About half of the approximately 30,000 people in the United States who have cystic fibrosis are homozygous for the F508del, the most common CF mutation, according to the FDA.
The combination contains 200 mg of lumacaftor and 125 mg of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator; it is taken twice a day. It will be marketed as Orkambi by Vertex Pharmaceuticals. Ivacaftor, marketed as Kalydeco by Vertex, was approved in January 2012 for treating patients with the G551D mutation (about 4% of patients with CF), and its indications have been expanded since that time to include other CFTR gene mutations.
Dr. Robert Giusti, director of the pediatric cystic fibrosis center at New York University Langone Medical Center, said in an interview that although new treatments have improved survival and patients with CF are now living longer, “we haven’t been able to reverse the downward trend in pulmonary function,” which is about 1%-2% a year in patients with CF. For a significant number of patients with CF, treatment with Orkambi “will reverse that trend and will allow them to maintain their lung function,” he added. Referring to the discovery of the CF gene in 1989, he pointed out that the availability of this treatment for half of all patients with CF is the culmination of more than 25 years of research,.
The approval is “very, very exciting,” said Dr. Susan Millard, director for clinical research for the pediatric cystic fibrosis care center at Helen DeVos Children’s Hospital, Grand Rapids, Mich. Ivacaftor alone was not effective in patients with two copies of the F08del mutation, and both drugs are needed for the beneficial effects, she said in an interview.
Lumacaftor “is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein, and ivacaftor... is designed to enhance the function of the CFTR protein once it reaches the cell surface,” according to a statement from Vertex.
According to the prescribing information for ivacaftor/lumacaftor, “if the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.” The indications and usage section also states that efficacy and safety “have not been established in patients with CF other than those homozygous for the F508del mutation.”
Approval was based on two double-blind, placebo-controlled studies of 1,108 patients with CF with the F508del mutation aged 12 years and older. In the studies, improvements in lung function among those treated with the combination drug were greater than those on placebo.
At 24 weeks, the absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) over placebo, the primary efficacy endpoint, was a mean of 2.6% and 3.0% among those treated with the 400 mg/250 mg fixed dose (two pills) every 12 hours, which were statistically significant changes. In an extension study, the effect was sustained through 48 weeks. There also were reductions in pulmonary exacerbations, improvements in body mass index, and Cystic Fibrosis Questionnaire-Revised improvements – secondary endpoints that favored the treatment arms, according to company presentations at the FDA panel meeting where the drug was reviewed in May.
One of the issues raised by FDA advisers then was that there was no substantial evidence that the efficacy of the combination was greater than with ivacaftor alone. But despite the lack of monotherapy arms and the inability to determine the contribution of the individual components to the treatment effects, the panel agreed that the drug combination had been shown to be efficacious and voted 12-1 that the available safety and efficacy data supported approval for the proposed indication.
Dr. Millard said that one theory that may explain why BMI improves with treatment is that reduced bicarbonate production in CF patients increases the degradation of the pancreatic enzymes they take, and that the drug may result in more appropriate bicarbonate secretion. This possibility is being evaluated in studies comparing bicarbonate secretion in patients on and off the drug, she said.