A two-drug combination aimed at improving lung function in people with the most common form of cystic fibrosis won FDA approval Thursday.
The combination of ivacaftor (previously approved as Kalydeco) and lumacaftor, to be marketed as Orkambi, is safe and effective in people 12 and older with cystic fibrosis caused by two copies of a certain mutation, dubbed Phe508del, in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
Ivacaftor/lumacaftor is the first drug to target the root cause of the disease in such people, about 45% of all CF patients, the FDA said.
The CFTR protein is involved in transporting chloride ions across cell membranes and the Phe508del mutation has two effects: it sharply reduces protein levels in the membranes and for channels that reach the cell surface, it disrupts channel opening.
Ivacaftor as a monotherapy was already approved as a drug to increase the "open probability" of CFTR channels -- the fraction of time they are open. Lumacaftor increases the number of CFTR channels on the surface of cells.
Thursday's approval for the drug came after an advisory panel voted 21-1 in favor of it in mid-May.
The combination had been given breakthrough therapy designation because its manufacturer, Vertex Pharmaceuticals of Boston, had demonstrated that it might offer a substantial improvement over available therapies, the FDA said in a statement.
The combination also got a priority review and is designated as an orphan drug.
"Today's approval significantly broadens the availability of targeted treatments for the specific defects that cause cystic fibrosis," commented director of the new drugs office in the FDA's Center for Drug Evaluation and Research.
The approval was based on two phase III, randomized, controlled trials, dubbed TRAFFIC and TRANSPORT, involving 1,108 patients, 12 and older, who were homozygous for the Phe508del mutation.
Patients were randomly assigned either 600 mg of lumacaftor once a day with 250 mg of ivacaftor every 12 hours, 400 mg of lumacaftor every 12 hours with 250 mg of ivacaftor every 12 hours, or placebo.
The primary outcome was improvement in lung function, as measured by the standard one-second forced expiratory volume (FEV1) test, after 24 weeks of treatment. At baseline, the average FEV1 among the patients was 61% of the predicted value.
Compared with placebo, patients getting the combination had an average absolute improvement in the predicted FEV1 ranging from 2.6% to 4.0%, the investigators reported.
At the same time, the proportion of patients reporting adverse events was similar across the groups, with serious adverse events reported by 28.6% of placebo patients and between 17.3% and 22.8% of those getting the combination, depending on dose.
Infective pulmonary exacerbation was the most common serious adverse event, affecting 24.1% of placebo patients and 13% of those getting the combination.