Letairis (ambrisentan), an approved therapy for pulmonary arterial hypertension (PAH) in adults, appears to also be effective and safe in children ages 8 and older, a study based on clinical trial data reports.
All doses tested were well tolerated by children with PAH, and Letairis’ benefit-risk profile was similar to that seen in adults.
The study, “A Randomized Study of Safety and Efficacy of Two Doses of Ambrisentan to Treat Pulmonary Arterial Hypertension in Pediatric Patients,” was published in The Journal of Pediatrics: X and was conducted by an international team of researchers.
The treatment of PAH in children is challenging, and most targeted PAH therapies are used off-label in this patient population — meaning a drug is used to treat a condition for which it has not been officially approved.
Because Letairis “is not associated with liver safety concerns and has a low risk of drug interactions” it is seen as “a promising candidate in children with PAH,” the researchers wrote.
An open-label, Phase 2b study (NCT01332331) was conduced to assess the safety and efficacy of Letairis in pediatric patients with PAH (ages 8 to 18). Of note, Letairis is marketed in the U.S. by Gilead, and in Europe by GlaxoSmithKline under the brand name Volibris.
In total, 41 enrolled children were included in this analysis. Each had been randomized to a high (5, 7.5, or 10 mg) or low (2.5 or 5 mg) dose of oral Letairis, once daily for 24 weeks. Most patients were receiving other PAH medication that could not be changed during the trial.
The study’s primary goal was to evaluate the safety, measured by the occurrence of treatment-emergent adverse events (TEAEs).
Efficacy endpoints served as secondary goal, and included changes in: exercise capacity over 24 weeks, assessed by 6-minute walk distance test (6MWD), the distance walked in six minutes; WHO functional classifications (WHO FC); and in the blood levels of a PAH biomarker called n-terminal pro-b-type natriuretic peptide (NT-proBNP).
Results showed that one or more TEAEs were experienced by most patients (80%). In terms of severity, 22% were mild and 49% were moderate, with no differences observed between dose groups.
Most common TEAEs observed were headache (24%), nausea (17%), abdominal pain (12%), and nasopharyngitis (a cold, 12%). Eight patients had serious TEAEs, and two children died. Neither death was considered by investigators to be related to the treatment.
“Treatment with low or high doses was well tolerated and no new adverse safety findings were identified beyond those previously reported in the adult PAH population,” the researchers wrote.
Contrary to previous studies in adults using Letairis, no relevant changes in blood tests or measures of liver health were observed, supporting the potential safety of the therapy in children.
Improvements were seen on all efficacy measures analyzed at both doses.
An improvement in the 6MWD was observed across the 24 weeks of the study in both dose groups, with patients walking a mean of 40.69 meters more compared to the study’s start.
After 24 weeks, the WHO functional class was maintained in 70% of the patients, and improved in 27% of them.
In both dose groups, a general decrease in NT-proBNP levels was also seen after 12 weeks (minus 14.29 nanogram/L) and at the end of the study (minus 29.63 nanogram/L).
“In children, change in NT-proBNP serum level is predictive of Functional Class, some echocardiogram parameters and survival,” the researchers noted.
An additional efficacy endpoint analyzed was the change in cardiorespiratory hemodynamics — how well the blood flows in the heart and lung vessels — as assessed by right heart catheterization and echocardiogram.
Improvements were observed in the 21 patients given the low dose, as their mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were reduced. No valid hemodynamic assessment was available from the 20 children in the high dose group.
“Overall, efficacy findings were in line with those previously reported in studies evaluating ambrisentan in the adult PAH population, and compared well with those reported for other PAH treatments studied and licensed for use in children,” the researchers wrote.
“There is a persistent need for robust clinical evidence to support treatment selection in children with PAH; our findings support a potentially similar benefit-risk profile in pediatric (8 to <18 years) and adult patients with PAH,” the team concluded.