Better Outcomes Seen With Lumacaftor-Ivacaftor Treatment in Cystic Fibrosis

By Reuters Staff

October 19, 2019

NEW YORK (Reuters Health) - Lumacaftor-ivacaftor treatment is associated with improved outcomes among adolescents and adults with cystic fibrosis (CF) who tolerate treatment, according to new research.

Lumacaftor-ivacaftor is a CFTR-modulator combination approved by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) for the treatment of patients with CF homozygous for the Phe508del (F508del) mutation. About 40-50% of CF patients are homozygous for Phe508del, and about 70% of CF patients carry at least one Phe508del mutation.

Dr. Pierre-Regis Burgel of Cochin Hospital, APHP, in Paris, and colleagues examined outcomes after the combination's release in France in December 2015 in 292 adolescents and 553 adults who started lumacaftor-ivacaftor treatment in one of the 47 centers participating in the French Cystic Fibrosis Reference Network.

During the first year after treatment initiation, 18.2% of patients (23.5% of adults and 8.2% of adolescents) discontinued treatment, often due to respiratory adverse events (48.1%).

This contrasts sharply with discontinuation rates in the pivotal clinical trials, where less than 5% of patients discontinued lumacaftor-ivacaftor. The researchers speculate that this is related to a higher proportion of patients with severe respiratory disease included in the network.

Besides being higher in adults than in adolescents, discontinuation rates were significantly higher in patients with FEV1 <40% predicted (28.2% vs. 16.3% for those with FEV1 40% predicted or higher) and in patients with repeated intravenous antibiotic courses in the previous year.

FEV1 improved significantly after 12 months in patients with continuous or intermittent lumacaftor-ivacaftor treatment, whereas patients who discontinued treatment experienced nonsignificant decreases in FEV1.

Patients with continuous treatment showed steady weight gains, those with intermittent treatment experienced delayed weight gains, and those who discontinued treatment had no weight gain.

Continuous treatment with lumacaftor-ivacaftor was associated with a 35% reduction in antibiotic courses, whereas patients with intermittent exposure or treatment discontinuation showed no significant changes in the number of antibiotic courses in the 12 months after drug initiation, the researchers report in the American Journal of Respiratory and Critical Care Medicine, online October 11.

More than half of the patients (59.4%) experienced adverse events considered by treating physicians as possibly associated with lumacaftor-ivacaftor, including respiratory adverse events in 38%, digestive adverse events in 21.8%, menstrual abnormalities in 6.4%, fatigue in 4.4%, and headache in 3.3%. Most events occurred in the first months of treatment and decreased gradually over time.

"The present study highlighted the importance of large real-life studies to assess the safety and effectiveness profile of novel therapies because patients treated in post-marketing studies often show reduced lung function and less stable disease characterized by higher rates of exacerbations than those included in clinical trials," the authors conclude. "These data further indicate that the benefits and risks of new therapies cannot be extrapolated to patients who are excluded from clinical trials."

"The anticipated availability of novel combination of CFTR modulators and the extension of indications to younger age groups warrant further real-life study that should be launched as soon as the drugs become available in eligible populations," they add.

The authors note that the study was performed and funded independently from lumacaftor-ivacaftor's manufacturer, Vertex Pharmaceuticals, Inc.

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


Am J Respir Crit Care Med 2019.