Orkambi Benefits CF Patients Across Levels of Lung Health, Study Finds

Orkambi (ivacaftor/lumacaftor) can significantly reduce the number of days people with cystic fibrosis (CF) require intravenous antibiotics for flares and helps with weight gain — independently of a patient’s level of lung function at the start of treatment, a real-world study reported.

While the greatest lung improvements were seen in patients with suboptimal lung function at treatment start, these findings support Orkambi’s use by all eligible patients, regardless of their current lung status, its researchers wrote.

The study, “Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function,” was published in the Journal of Cystic Fibrosis.

Orkambi, marketed by Vertex Pharmaceuticals, is an approved treatment for CF patients who carry two copies of the F508del mutation in the CFTR gene, the most common CF-causing mutation worldwide.

It is approved for patients ages 2 and older, regardless of their lung function at the time of treatment initiation.

Pivotal clinical trials that supported approval, however, demonstrated Orkambi’s safety and efficacy only in patients with a predicted forced expiratory volume in one second (ppFEV1; a standard measure of lung function) ranging between 40% and 90%.

“Reasons for these criteria included the fear of adverse effects in patients with more severe respiratory disease (ppFEV₁<40) and the general belief that, in patients with ppFEV₁≥90, an increase in ppFEV₁ would be very unlikely,” the researchers wrote.

Patients with ppFEV1 outside that middle range were excluded from the trials.

“Reasons for these criteria included the fear of adverse effects in patients with more severe respiratory disease (ppFEV₁<40) and the general belief that, in patients with ppFEV₁≥90 [and high lung function], an increase in ppFEV₁ would be very unlikely,” the study noted.

Researchers in France set out to examine Orkambi’s safety and effectiveness across distinct ppFEV1 levels — including those at baseline [study’s start] outside the pivotal trials’ allowed range.

Their real-world study (NCT03475381) looked at 827 CF patients, ages 12 years and older, who started Orkambi therapy in 2016 and were followed at CF centers across France.

Among these 537 adults and 290 adolescents were 121 patients with low ppFEV1 (less than 40%), 609 with intermediate ppFEV1 (between 40% and 90%), and 97 patients with high ppFEV1 (90% or greater).

Researchers’ goal was to compare over one year of Orkambi’s use the magnitude of improvements in ppFEV₁ and body mass index (a measure of body fat), and changes in exacerbation frequency in patients with higher and lower lung function scores. Changes noted were compared with those seen in study patients with intermediate range baseline ppFEV₁.

Over a first year of treatment, 152 of these patients stopped using Orkambi, and 39 used it intermittently. The remaining 636 patients took Orkambi as prescribed.

Patients with a low ppFEV1 had a nearly two times higher discontinuation rate (28.9%) compared with the others — 16.4% among those with intermediate ppFEV1, and 17.5%, among those with a high ppFEV1.

The main reason given for stopping treatment by low ppFEV1 patients was adverse respiratory adverse events (74%); a similar reason was given by 42% of the intermediate ppFEV1 group, and 29% of  those with a high ppFEV1.

Among continuous Orkambi users over the one-year study, a significant increase in ppFEV1 was seen both in patients with intermediate (by 2.9%) and low (by 0.5%) ppFEV1. Further lung function gains were not evident in those with high ppFEV1 scores at baseline.

A sizable number — 40% — of patients in the intermediate ppFEV1 group also experienced a 5% or greater improvement in lung function scores. Similar gains were seen in 22% of low ppFEV1 patients and in 27% of those with high ppFEV1.

This 5% or greater gain among the midrange patients represented “a proportion that was 1.5 to 2 fold higher than in patients with baseline ppFEV₁ <40 or ppFEV₁≥90,” the researchers wrote.

While Orkambi had the greatest lung functions benefits in the intermediate ppFEV1 group that was its pivotal trials’ focus, the treatment significantly increased body mass index across all patients, regardless of their baseline lung function and age.

Orkambi also significantly reduced exacerbations requiring intravenous (IV) antibiotics in intermediate ppFEV1 patients, and showed a similar trend in the high ppFEV1 group.

The number of days each year with IV antibiotic treatment was significantly lower among all groups, compared with their number over the year prior to starting Orkambi: by six days in the low ppFEV1 group; 6.6 days in the intermediate group; and 4.1 days in the high ppFEV1 group.

These results suggest that adolescents and adults across all ranges of ppFEV1 may benefit from Orkambi, as “BMI increase and reduction in IV antibiotics days/year were observed in all subgroups,” the researchers wrote.

“At the individual level, patients with [low and high ppFEV1] could show a significant improvement in ppFEV1 after initiation of CFTR modulator therapy, which further reinforces the decision from regulatory agencies to grant treatment indication to all patients with eligible CFTR genotypes, regardless of baseline lung function,” they concluded.