Combination therapy shows safety, tolerability for young children with cystic fibrosis

Lumacaftor/ivacaftor appeared safe and well tolerated for up to 24 weeks in children aged 1 year to younger than 2 years homozygous for F508del-CFTR, according to a study in American Journal of Respiratory and Critical Care Medicine.

“There were no significant or new safety findings, and the drug combination [of lumacaftor/ivacaftor (Orkambi, Vertex Pharmaceuticals)] was well tolerated,” Susanna A. McColley, MD, scientific director for interdisciplinary research partnerships at Stanley Manne Children’s Research Institute and attending physician in pulmonary medicine at Ann & Robert H. Lurie Children’s Hospital of Chicago, told Healio. “We also saw improvement in markers of pancreatic and intestinal inflammation, good growth and a decrease in sweat chloride. The sweat chloride decrease means that the drug is working to improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.”

As Healio previously reported, combination therapy of lumacaftor/ivacaftor was found to be safe and well tolerated among children aged 6 to 11 years with the F508del mutation in CFTR (F/F genotype) for up to 120 weeks.

This combination therapy also showed similar results in children aged 2 to 5 years with the mutation for over 24 weeks.

In an open-label, phase 3 study, McColley and colleagues analyzed 60 children aged 1 year to younger than 2 years with the F/F genotype to determine the safety, pharmacokinetics and pharmacodynamics of lumacaftor/ivacaftor for this younger population over 24 weeks.

Researchers divided their study into two parts. Part A assessed pharmacokinetics and safety of the therapy over 15 days among 14 children (including one child who discontinued the therapy due to a rash). During this part, the weight of the child determined their dose of the treatment.

For part B, the researchers’ primary endpoint was safety and tolerability of the therapy over 24 weeks among 46 children. Additionally, researchers assessed absolute change in pharmacokinetics and sweat chloride concentration from baseline to the end of the study period. Pharmacokinetic data from part A informed the dose-based weight boundaries for treatment.

Both parts of the study included two age-based cohorts, including one group of children aged 12 months to 18 months, and another of children aged 18 months to 24 months.

Safety, pharmacokinetic data

One child from part B discontinued the therapy due to increased alanine and aspartate concentrations. Of the other 45 children, 44 (95.7%) experienced an adverse event; however, a majority of these events were classified as mild (52.2%) or moderate (39.1%) and were “consistent with manifestations of cystic fibrosis,” the researchers wrote.

Adverse events that occurred among 15% or more children included cough (34.8%), infective pulmonary exacerbation of cystic fibrosis (21.7%), pyrexia (21.7%) and vomiting (17.4%). Serious adverse events occurred in five children (10.9%), but researchers classified these events as mild or moderate in terms of severity.

Regarding pharmacokinetic data, researchers found that the median area under the curve was close to the adult median for lumacaftor and modestly higher than adults, but comparable with other pediatric age groups, for ivacaftor.

Secondary endpoints

When evaluating the absolute change in sweat chloride concentration from baseline to week 24, researchers observed reductions at week 4 that lasted until the final week. By week 24, they found a mean change of –29.1 mmol/L (95% CI, –34.8 mmol/L to –23.4 mmol/L) from baseline.

McColley and colleagues also observed normal growth parameters both at baseline and throughout the 24 weeks for BMI-for-age z score (mean absolute change, 0.04; 95% CI, –0.14 to 0.22), weight-for-length z score (mean absolute change, 0.04; 95% CI, –0.13 to 0.22), weight-for-age z score (mean absolute change, 0.06; 95% CI, –0.05 to 0.17) and length-for-age z score (mean absolute change, 0.07; 95% CI, –0.11 to 0.24).

Researchers additionally reported that they saw improving trends in pancreatic function and intestinal inflammation biomarkers, including an increase in fecal elastase-1 (mean absolute change, 73.1 g/g; 95% CI, 29.4 g/g-116.8 g/g), a decrease in serum immunoreactive trypsinogen (mean absolute change, –295.5 g/L; 95% CI, –416.6 g/L to –174.50 g/L) and a decrease in fecal calprotectin (mean absolute change, –106.63 mg/kg; 95% CI, –180.6 mg/kg to –32.66 mg/kg).

These findings are significant when thinking about who would benefit from the therapy, McColley told Healio.

“We have had good evidence that good nutrition (height and weight) improves life expectancy in cystic fibrosis since the 1980s,” McColley told Healio. “We’ve also known that early life growth — that seen in preschool years — has a profound impact on later lung function and survival for 20 years. Thus, improvement in the pancreas and intestine, along with good growth, are important findings in consideration of recommending this therapy.”

Looking ahead

Future cystic fibrosis research efforts may focus on pulmonary function tests and structure, McColley said.

“Standard spirometry, the pulmonary function test used in older children and adults, can’t be performed in this age group,” she said. “Studies have used chest CT scans to look at structure, but radiation (even though low dose) is a concern. There are newer pulmonary function tests and imaging techniques that may be useful.

“I also want to acknowledge that families make a significant commitment of time and effort for clinical trials in infants and children, and their efforts are greatly appreciated,” McColley added.

This study by McColley and colleagues adds to the literature indicating that CFTR modulator therapy in infants is going to lead to new developments in clinical care, according to an accompanying editorial by Claire E. Wainwright, MBBS, MRCP, MD, professor in the Child Health Research Centre at The University of Queensland, Australia.

“As CFTR modulation becomes established clinically, the window for randomized placebo-controlled trials that provide the best quality evidence has almost closed,” Wainwright wrote. “Consumers, clinicians, and researchers need to rapidly determine how we move forward in developing new CFTR modulator therapy for infants and decide whether infants are indeed ‘little adults’ and benefits can effectively be inferred or whether they deserve the same degree of evidence that older people expect?”

For more information:

Susanna A. McColley, can be reached at smccolley@luriechildrens.org.

Reference:

Wainwright CE. Am J Respir Crit Care Med. 2022;doi:10.1164/rccm.202207-1356ED.