Lumacaftor-Ivacaftor Combination Effective for Some Cystic Fibrosis Patients

By Will Boggs MD

January 04, 2017

NEW YORK (Reuters Health) - The combination of lumacaftor and ivacaftor is effective for the long-term treatment of patients with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation, according to the PROGRESS study.

Ivacaftor, a CFTR potentiator, was previously shown not to be effective in these patients; lumacaftor, a CFTR corrector, improves the processing and trafficking of the F508del-CFTR protein, but it, too, appears to lack efficacy as monotherapy in these patients.

Together, however, lumacaftor with ivacaftor resulted in improved lung function and reduced pulmonary exacerbation rates in patients with CF who were at least 12 years old and homozygous for the F508del-CFTR mutation, supporting the approval of this combination for the treatment of this patient population, researchers note in The Lancet Respiratory Medicine, online December 20.

Dr. Michael W. Konstan from Case Western Reserve University School of Medicine and Rainbow Babies and Children's Hospital in Cleveland, Ohio, and colleagues now report findings of a 96-week extension study of lumacaftor/ivacaftor in 1,030 patients with CF aged at least 12 years and homozygous for this mutation who completed treatment in one of two previous phase 3 trials (TRAFFIC or TRANSPORT).

Among the 513 patients treated with lumacaftor 400 mg once daily/ivacaftor 250 mg every 12 hours, 7% discontinued treatment as the result of an adverse event. The most frequently reported adverse events were infective pulmonary exacerbations of CF (65%), cough (44%), increased sputum (22%), and hemoptysis (20%).

Most adverse events were considered mild or moderate, and there were no deaths related to the study drug.

Patients treated with lumacaftor/ivacaftor experienced sustained improvements in percent predicted FEV1, and patients transitioned from placebo to the combination showed improvements in percent predicted FEV1 that were maintained through extension week 96.

Results were similar for Cystic Fibrosis Questionnaire-Revised respiratory domain scores, and pulmonary exacerbation rates continued at lower levels in the lumacaftor/ivacaftor groups and decreased to similar levels among patients switched from placebo to lumacaftor/ivacaftor.

Propensity score-matched analyses confirmed the significant improvements in lung function decline associated with lumacaftor/ivacaftor treatment. The annualized rate of decline of percent predicted FEV1 was reduced in lumacaftor/ivacaftor-treated patients compared with controls (-1.33 vs. -2.29 percentage points, p<0.001).

Results were generally similar for patients treated with lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 hours.

"These data show that lumacaftor/ivacaftor combination therapy provides short-term multisystem benefits that continue to be observed over a longer term, and suggest that lumacaftor/ivacaftor might be a disease-modifying therapy in cystic fibrosis," the researchers conclude.

Dr. Steven M. Rowe from the University of Alabama at Birmingham, who wrote an accompanying editorial, told Reuters Health by email, "The most interesting aspect was the magnitude of the change in decline compared to controls. I would have expected that the change in decline would have been much less, or difficult to detect, due to the small amount of FEV1 improvement seen in the original studies. This degree of rate of decline change is very impactful, and probably reflects that small amounts of CFTR restoration can have a big impact."

"I think the drug is indicated in most patients homozygous for F508del," he said. "The drug must be used more cautiously in those with lower lung function, particularly below 40% predicted FEV1, as the incidence of chest tightness, which can sometimes impact lung function, is more prominent in this population. For the same reason, I recommend only starting in patients who are stable."

"I think this drug is only the beginning," Dr. Rowe concluded. "As we do even better with CFTR modulators, we can expect even greater benefits."

Dr. Susanna A. McColley from Northwestern University Feinberg School of Medicine in Chicago, who has studied lumacaftor/ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR, said, "Reducing the rate of decline in pulmonary function is an important goal of CF care, and utilizing therapies that have this effect is an important strategy to improve long-term health and well-being. There is increasing evidence that CFTR modulator therapies can modify disease progression and optimism that using these drugs earlier in life may reduce morbidity and mortality from CF."

"As a pediatric pulmonologist, I'm especially excited by the data in 6- to 11-year-old patients (approval by the US FDA for this age group occurred in September 2016), who had higher lung function at enrollment," she told Reuters Health by email.

"There was improvement in pulmonary function as measured by a very sensitive pulmonary test, the lung clearance index, in both an open-label study and in a placebo-controlled study (treated patients had improvement compared to controls)," said Dr. McColley, who was not involved in the new study. "Combined with the 2-year data in older patients, this suggests that giving treatment to patients with very mild lung disease could make a big difference over time."

Vertex Pharmaceuticals, Inc. funded the trial, employed several authors and had various ties to several others. Dr. McColley has also received speaking and consultation fees from the company.

Dr. Konstan did not respond to a request for comments.


Lancet Respir Med 2016.