In children 2 years of age or older with cystic fibrosis (CF), treatment with lumacaftor/ivacaftor (LUM/IVA) early in the disease course may modify disease progression, according to findings from a phase 2, placebo-controlled trial published in Annals of the American Thoracic Society.

Among individuals with CF, mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) are observed, with F508del-CFTR the most common CFTR mutation reported. In fact, around 40% of patients with CF are homozygous for F508del—the F/F genotype. CFTR correctors, including lumacaftor, tezacaftor, and elexacaftor, help to “improve the processing and trafficking of CFTR protein to cell surfaces.” In contrast, CFTR potentiators such as ivacaftor “increase the open probability of CFTR channels on cell surfaces.”

Currently, LUM/IVA is the only CFTR modulator regimen that has been approved for the treatment of children ≥2 years of age with CF and the F/F genotype. The investigators sought to evaluate the effects of LUM/IVA on progression of CF in children between 2 and 5 years of age with the use of magnetic resonance imaging (MRI). All of the pediatric participants exhibited the F/F genotype, which was confirmed at screening.

The study was performed in 2 parts. The first part comprised a 48-week, multicenter, randomized, placebo-controlled, double-blind period in which children aged 2 to 5 years with CF homozygous for the F/F genotype were treated with LUM/IVA or placebo. The second part of the study included an open-label period in which all of the participants were treated with LUM/IVA for 48 additional weeks. The results of Part 1 of the study have been described herein.

The primary study endpoint was “absolute change from baseline in MRI global score at [w]eek 48.” Secondary study endpoints were absolute change in lung clearance index2.5 (LCI2.5) through week 48, along with absolute changes in body-mass-index-for-age, weight-for-age, and stature-for-age z-scores at week 48. Other endpoints included absolute changes from baseline through week 48 in the following parameters:

  • Sweat chloride concentration
  • Fecal elastase-1 concentration
  • Serum immunoreactive trypsinogen concentration
  • Fecal calprotectin concentration
  • LCI5.0.

Fifty-one children were enrolled in Part 1 of the study, with 35 participants treated with LUM/IVA and 16 individuals receiving placebo. The study was conducted at 5 German hospitals between August 10, 2018, and October 9, 2020. The mean drug exposure was 47.0±8.5 weeks in the LUM/IVA arm and 48.7±2.3 weeks in the placebo group. Two treatment discontinuations were reported in the LUM/IVA group.

Read more about cystic fibrosis

LUM/IVA therapy was associated with a mean absolute change in MRI global score of –1.7 vs –0.3 with placebo from baseline to week 48 (treatment difference, –1.5; 95% CI, –5.5 to 2.6). LUM/IVA-treated participants exhibited numerically greater decreases vs placebo in consolidations, mosaic pattern, mucus plugging, and perfusion abnormalities.

Within-group numerical improvements in LCI2.5, growth parameters, and biomarkers of pancreatic function, along with greater decreases in sweat chloride levels, were also linked to LUM/IVA compared with placebo.

The authors concluded, “[T]his study suggests that LUM/IVA may modify CF disease progression when administered early in life.”


Stahl M, Roehmel J, Eichinger M, et al. 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. Ann Am Thorac Soc. Published online March 21, 2023. doi:10.1513/AnnalsATS.202208-684OC