Weight-based Uptravi dose for kids with PAH shows promise in trial
Regimen achieves similar drug exposure as standard adult dose
A weight-based dose regimen of Uptravi (selexipag) for children with pulmonary arterial hypertension (PAH) achieves drug exposure similar to that of the standard adult dose regimen, according to results from a Phase 2 clinical trial.
The study also found that the weight-based Uptravi regimen for kids is comparable in safety and efficacy to the standard regimen in adults with PAH.
Findings from the trial were published in Chest, in a paper titled, “A prospective, multicenter, open-label, single-arm Phase 2 study to investigate the pharmacokinetics, safety, tolerability, and exploratory efficacy of selexipag in children with pulmonary arterial hypertension.” The work was funded by Johnson & Johnson, the company that sells Uptravi.
PAH is characterized by elevated pressure in the vessels that carry blood from the heart to the lungs, which strains the heart. Uptravi works by mimicking prostacyclin, a hormone that lowers blood pressure by relaxing and widening blood vessels. The therapy is available in oral and intravenous (into-the-vein) formulations.
Uptravi is approved to treat PAH in the U.S. and Europe. The approvals were based mainly on data from the Phase 3 GRIPHON study (NCT01106014), which tested the oral version of the therapy against a placebo in more than 1,000 adults with PAH. Results showed the therapy significantly reduced the risk of disease progression.
Prescribing for kids can be a challenge
In the U.S., although the risk-benefit ratio of Uptravi in children has not been established, the decision to administer the therapy is at the treating physician’s discretion. A limited number of treatments have been approved for pediatric PAH in the U.S., and the same is true for Europe.
“Given the challenges with conducting pediatric clinical trials, particularly in rare diseases, regulatory bodies now advocate pediatric extrapolation, i.e., using evidence from adults to estimate the efficacy and safety of treatments in pediatric populations more efficiently, provided that disease course and treatment response are sufficiently similar and an effective pediatric dose has been identified,” the investigators wrote.
The Phase 2 study (NCT03492177) aimed to identify a dosing regimen of Uptravi for children that would achieve levels similar to what was seen in adult participants in the GRIPHON study.
The trial enrolled 63 children with PAH, ages 2 to 17. The majority of the participants were girls, and most were white. Most of them had either idiopathic PAH (meaning the underlying cause is not known) or PAH that developed as a complication of congenital heart disease.
All the children were given Uptravi according to a weight-based regimen. Individuals weighing at least 50 kg (about 110 lbs) were started at a dose of 200 mcg twice daily, which was gradually increased to a maximum of 1,600 mcg twice daily based on tolerability — the same regimen recommended for adults. Children weighing at least 25 kg (55 lbs) but less than 50 kg were instead started at a dose of 150 mcg twice daily, increased up to a maximum of 1,200 mcg based on tolerability. For children weighing less than 25 kg, the starting dose was 100 mcg twice daily, increased to a maximum of 800 mcg based on tolerability.
The study met its main goal, showing that the weight-based regimen led to levels of the drug’s active ingredient similar to those seen in adults given the standard dosing regimen.
Safety and efficacy data from the children in the study were also broadly consistent with data from trials in adult patients. Patients on Uptravi tended to report sustained improvements in the distance they could walk in 6 minutes (a common measure of exercise capacity) and reductions in NT-proBNP, a marker of heart damage.
Nearly three-quarters of the children experienced side effects judged to be related to Uptravi. The most common included vomiting, headache, and diarrhea, all of which are well-known side effects of the therapy. Three teenagers experienced serious side effects of Uptravi: one reported severe chest pain, one had abdominal and muscle pain, and one experienced syncope (loss of consciousness upon standing from a seated or lying position). Overall, no unexpected safety issues were reported.
“This phase 2 study achieved its primary objective of confirming a weight-based dosing regimen for [Uptravi] in pediatric patients with PAH that results in similar exposures to that observed in the adult PAH population from the GRIPHON study, assessed across different age groups. No new or unexpected safety findings were reported,” the researchers concluded.
The Phase 2 study is expected to wrap up later this year. In the meantime, a Phase 3 clinical trial called SALTO (NCT04175600) is also ongoing to further evaluate the safety and efficacy of this weight-based Uptravi regimen in children with PAH, aiming to show that Uptravi is superior to placebo at delaying PAH progression when added to standard of care treatment.
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