Lumacaftor/ivacaftor therapy beneficial in pediatric cystic fibrosis over 96 weeks
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Key takeaways:
- Kids aged 2 to 5 years receiving cystic fibrosis dual therapy for either 96 weeks or 48 weeks had improved chest MRI global scores.
- With both treatment lengths, lung clearance index improved.
Lumacaftor/ivacaftor showed improvements in several measures in children aged 2 to 5 years homozygous for F508del-CFTR over 96 weeks, according to results published in Annals of the American Thoracic Society.
“These results demonstrate the potential for early initiation of [lumacaftor/ivacaftor] to have a clinically beneficial impact on CF disease progression and support use of chest MRI as diagnostic tool for evaluating CF disease progression and treatment benefit,” Mirjam Stahl, MD, head of the division of cystic fibrosis at Charité – Universitätsmedizin in Berlin, Germany, and colleagues wrote.
In part two of a phase 2 study, Stahl and colleagues evaluated 49 children aged 2 to 5 years with CF who received at least one dose of lumacaftor/ivacaftor (LUM/IVA; Orkambi, Vertex Pharmaceuticals) during a 48-week open-label treatment period (mean duration, 47.1 weeks) to discover how the combination therapy impacts various endpoints over 96 weeks.
Healio previously reported on the first part of this study, which was randomized, double-blind and placebo-controlled. Researchers analyzed the same group of children noted above to determine how treatment with LUM/IVA changes chest MRI global score and other outcomes over a total of 48 weeks compared with a placebo.
Similar to part one, part two looked at absolute changes in chest MRI global score, lung clearance index2.5 (LCI2.5), z scores for weight-for-age, stature-for-age and BMI-for age, sweat chloride concentration, fecal elastase-1, serum immunoreactive trypsinogen and fecal calprotectin from baseline to the end of the study period.
In part one, 33 children received LUM/IVA for 48 weeks. In part two, the same 33 children received the combination therapy for 48 more weeks, totaling 96 weeks. The remaining 16 children who received placebo in part one now received LUM/IVA for 48 weeks.
Efficacy
Adverse events of distal intestinal obstruction syndrome and a rise in alanine aminotransferase, each reported in one child, resulted in LUM/IVA discontinuation, according to researchers.
Since a negative value in terms of MRI global score indicates improvement, researchers found improvement in both those who received LUM/IVA for 96 weeks (mean absolute change, –2.7; 95% CI, –5.2 to –0.1) and those who received LUM/IVA for 48 weeks (–5.6; 95% CI, –9.2 to –1.9).
Researchers further broke down the global score into the two scores that make it up and observed that both the 96-week and 48-week LUM/IVA groups had larger changes in MRI morphology scores (mean absolute change, –1.9; 95% CI, –3.8 to 0.1; –4.8; 95% CI, –7.4 to –2.1) than MRI perfusion scores (–0.8; 95% CI, –1.7 to 0; –0.8; 95% CI, –2.3 to 0.6).
When assessing the mean absolute change in LCI2.5, which was measured with a multiple-breath washout device, reduced LCI2.5 was found among patients receiving the combination therapy for the entire study period (–0.92) and patients receiving the therapy for 48 weeks (–1.26) by the 96-week mark.
By the end of the study period, Stahl and colleagues also observed stable growth parameters with 96-week and 48-week LUM/IVA: weight-for-age z score (mean absolute change, 0.09; 95% CI, –0.03 to 0.22 vs. 0.03; 95% CI, –0.24 to 0.29), stature-for-age z score (mean absolute change, 0.08; 95% CI, –0.09 to 0.24 vs. 0.15; 95% CI, –0.07 to 0.36) and BMI-for-age z score (mean absolute change, 0.14; 95% CI, –0.08 to 0.36 vs. –0.18; 95% CI, –0.64 to 0.28).
Between baseline and week 96, sweat chloride concentration declined in those taking LUM/IVA for 96 weeks (mean absolute change, –26.4 mmol/L) and those taking LUM/IVA for 48 weeks (–30.1 mmol/L).
Researchers additionally reported that both groups had improvements in the studied pancreatic function and intestinal inflammation biomarkers by the end of the study period. Those receiving LUM/IVA for 96 weeks vs. 48 weeks demonstrated a greater increase in fecal elastase-1 (mean absolute change, 81.9 µg/g vs. 47.5 µg/g) and a greater decrease in immunoreactive trypsinogen (mean absolute change, –79.5 ng/mL vs. –75.9 ng/mL), but those receiving LUM/IVA for 48 weeks had a greater decrease in fecal calprotectin (mean absolute change, –140.31 µg/g vs. –103.08 µg/g).
Safety
Adverse events occurred in 44 children (89.8%). When divided by severity, 38.8% of events were classified as mild and 40.8% were classified as moderate, according to researchers.
Nasopharyngitis was the most frequent adverse event (38.8%), followed by infective pulmonary exacerbation of CF (22.4%) and cough (22.4%).
Among all those receiving LUM/IVA, a serious adverse event was reported in 12 children (24.5%).
“Safety data were consistent with the established safety profile of LUM/IVA and no new safety concerns were identified,” Stahl and colleagues wrote.