Triple therapy shows safety, tolerability for young children with cystic fibrosis
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Key takeaways:
- Children aged 2 to 5 years receiving cystic fibrosis triple therapy tolerated the treatment well.
- Safety in this age group was comparable to that of older children treated with this therapy.
Elexacaftor/tezacaftor/ivacaftor appeared safe and well tolerated for up to 24 weeks in kids aged 2 to 5 years with one or more F508del allele, according to results published in American Journal of Respiratory and Critical Care Medicine.
This study assessed the youngest cohort of children treated with this triple therapy and showed that safety in this group was comparable to that found for older children, according to researchers.
“Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA; Trikafta, Vertex Pharmaceuticals) may be approved by the FDA for children 2 to 5 years of age with CF and at least one F508del mutation in the future,” Margaret Rosenfeld, MD, MPH, professor of pediatrics at University of Washington School of Medicine and co-director of the Center for Clinical and Translational Research at Seattle Children’s Research Institute, told Healio. “This study provides evidence regarding its safety and efficacy and can be used by providers and families to discuss the risks and benefits of initiating ELX/TEZ/IVA therapy.”
As Healio previously reported, this triple therapy improved lung function and respiratory symptoms in children aged 6 to 11 years with the F508del/minimal function genotypes of CF.
In this phase 3, open-label, multicenter study, lead investigators Jennifer L. Goralski, MD, assistant professor of medicine and associate director of the adult cystic fibrosis center at UNC School of Medicine, Felix Ratjen, MD, PhD, pediatric respirologist at The Hospital for Sick Children in Canada, Rosenfeld and colleagues analyzed 93 children aged 2 to 5 years with CF treated with ELX/TEZ/IVA to determine the safety, pharmacokinetics, pharmacodynamics and efficacy of the triple therapy.
Researchers divided their study into two parts. Part A evaluated pharmacokinetics, safety and tolerability over 15 days among 18 children with either F508del/minimal function (F/MF) or F508del/F508del (F/F) genotypes. Part B evaluated safety and tolerability over 24 weeks among 75 children (mean age, 4.1 years; 54.7% girls) with one or more F508del mutation or an ELX/TEZ/IVA-responsive CFTR mutation, which was the researchers’ primary endpoint.
Additionally, researchers evaluated pharmacokinetics and absolute change in sweat chloride concentration and lung clearance index2.5 (LCI2.5, a sensitive lung function test) from baseline to the end of the study period to understand how the triple therapy worked in young children. Pharmacokinetic data from part A validated the dose regimen in the second part.
Researchers determined the dosing of the triple therapy based on whether the child weighed less than 14 kg (80 mg ELX/40 mg TEZ once a day, 60 mg IVA in the morning and 59.5 mg IVA at night) or 14 kg or more (100 mg ELX/50 mg TEZ once a day, 75 mg IVA every 12 hours) on day 1.
Primary endpoint
Of the part B cohort, 52 children had F/MF genotypes and 23 had the F/F genotype. Adverse events occurred in 74 (98.7%) children; however, more than half of these events were classified as mild (62.7%), 36% were moderate and all were “consistent with common CF disease manifestations or childhood infections,” the researchers wrote.
Cough (61.3%) was the most frequent adverse event, followed by fever (34.7%), rhinorrhea (33.3%) and vomiting (28%). Serious adverse events occurred in two children (2.7%), and one child ended up stopping treatment because the event was of “abnormal behavior,” according to researchers. Rosenfeld and colleagues noted that this result may be linked to the triple therapy; however, the other child’s unfavorable event was not linked to the treatment.
Additionally, rash events were found in 15 children (20%), but none were identified as serious or made a child stop the therapy. Researchers further observed that 12 children (16%) had a pulmonary exacerbation.
Secondary endpoints
When evaluating the absolute change in sweat chloride concentration from baseline to week 24, researchers found that reductions at week 4 lasted until the end of the study. By week 24, they found a mean change of –57.9 mmol/L (95% CI, –61.3 to –54.6).
Researchers also found that the triple therapy led to lower LCI2.5 by the conclusion of the study (mean absolute change, –0.83 units; 95% CI, –1.01 to –0.66).
At week 24, mean BMI continued to be in the normal range that was observed at baseline. Rosenfeld and colleagues further observed normal growth parameters both at baseline and throughout the 24 weeks for BMI-for-age z score (mean absolute change, 0.1; 95% CI, 0-0.2), weight-for-age z score (mean absolute change, 0.02; 95% CI, –0.04 to 0.09) and height-for-age z score (mean absolute change, –0.06; 95% CI, –0.11 to 0).
At week 24, researchers additionally reported an increase, though not statistically significant, in fecal elastase-1 (mean absolute change, 39.5 µg/g), a decrease in immunoreactive trypsinogen (mean absolute change, –166.6 µg/L) and a decrease in fecal calprotectin (mean absolute change, –289.66 mg/kg), which 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, previously told Healio are important when considering patients that will benefit from the treatment.
“Future studies may evaluate ELX/TEZ/IVA in younger populations or evaluate longer-term outcomes,” Rosenfeld told Healio.
For more information:
Margaret Rosenfeld, MD, MPH, can be reached at margaret.rosenfeld@seattlechildrens.org.