Orkambi seems to reduce CF lung damage in preschool-age children
Study suggests treatment can modify disease progression in very young patients
by Marisa Wexler, MS | April 3, 2023
In a small clinical trial, Orkambi (lumacaftor/ivacaftor) appeared to reduce structural damage in the lungs, as measured by a chest MRI, for preschool-age children with cystic fibrosis (CF) who are homozygous for the F508del mutation.
“This study suggests that [Orkambi] may modify CF disease progression when administered early in life,” the researchers wrote, noting the findings affirm “the usefulness of chest MRI in evaluating treatment benefit in preschool children with CF and support the potential of chest MRI as an outcome measure in early-intervention clinical trials.”
The study, “Effects of Lumacaftor/Ivacaftor on Cystic Fibrosis Disease Progression in Children 2 through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2 Placebo-controlled Clinical Trial,” was published in the Annals of the American Thoracic Society. The work was funded by Vertex Pharmaceuticals, which markets Orkambi.
CF is caused by mutations in the CFTR gene, which provides instructions for making the CFTR protein. CF-causing mutations lead to the impairment of this protein, ultimately causing thick, sticky mucus to form that drives most CF symptoms.
Orkambi is a combination of two CFTR modulators — molecules that can bind to the CFTR protein and help it function correctly. It’s widely approved for patients who are homozygous for F508del, the most common CF-causing mutation. Homozygous means the mutation is present on both copies of the CFTR gene — one from each parent.
Vertex conducted a Phase 2 clinical trial (NCT03625466) to better characterize how Orkambi affects the progression of CF early in life.
Its main goal was to assess how treatment affects MRI global scores (a measure of lung health based on imaging of the lungs). The researchers noted that lung MRI has been shown to detect improvements in adults and adolescents with CF treated with a CFTR modulator, but its usefulness in young children is less certain.
Orkambi’s effects on young children
The study enrolled 51 children with CF, ages 2-5, at centers in Germany. All were homozygous for F508del. For the first year, 35 participants were treated with Orkambi, while 16 got a placebo.
Two participants left the trial early, but neither was due to issues with the study drug. Some patients had incomplete data because they’d missed planned appointments due to the COVID-19 pandemic, the researchers noted.
MRI global scores improved by an average of 1.7 points after nearly a year in patients given Orkambi, compared to just 0.3 points for those on a placebo, trial results showed. In statistical models, the likelihood that Orkambi was superior to a placebo at improving MRI global scores was 76%.
“These results suggest that chest MRI can be used safely in children 2 through 5 years of age to identify changes or improvements in lung structure and [blood flow], strongly supporting the potential of using chest MRI as an endpoint in pediatric clinical trials of CFTR modulators to assess CF lung disease progression,” the researchers wrote.
Average scores on the lung clearance index, a measure of how well air moves in and out of the lungs, improved by 0.37 points in the Orkambi group, but worsened 0.32 points in the placebo group after a year.
“These results, along with the changes seen in MRI global score, add to the growing body of evidence demonstrating subclinical lung disease develops early in children with CF and that intervention with CFTR modulators in children 2 through 5 years of age may improve lung function and offers the opportunity to slow lung function decline over time,” the researchers wrote.
Measures of weight-for-age and body mass index (a measure of body fat)-for-age on average increased slightly after a year on Orkambi, but decreased slightly for those on a placebo. These findings are “consistent with improvements in nutritional parameters that have previously been reported in open-label studies with [Orkambi] in this age group,” the researchers noted.
Measures of sweat chloride and levels of the enzyme fecal elastase-1 — a biomarker of pancreatic function — in participants’ stool also tended to favor Orkambi over a placebo.
“Taken together, our results support the clinical benefit of early treatment intervention with [Orkambi] in children [at least] 2 years of age with CF” who are homozygous for F508del, the researchers said, adding safety data were consistent with prior studies of Orkambi. A few children saw elevations in liver enzymes or respiratory events, but none of these known medication side effects were considered serious.
The scientists said the study is limited by its small size, which makes it difficult to draw statistically meaningful comparisons between the treatment and placebo groups. They also noted there aren’t many centers that can reliably do chest MRI analyses, which has limited its use in research. “Additional studies with larger numbers of CF treatment centers equipped to perform chest MRI are needed,” they wrote.