Uptravi (selexipag), an approved oral therapy for adults with pulmonary arterial hypertension (PAH), appears to also be safe and effective as an add-on treatment for children and adolescents, improving several relevant markers of the disease, a small study found.
Its researchers recommended larger studies in this patient group “to elucidate its broader applicability and usefulness in clinical care.”
The study, “Selexipag for the treatment of children with pulmonary arterial hypertension: First multicenter experience in drug safety and efficacy,” was published in the Journal of Heart and Lung Transplantation.
Children and adults with PAH are living longer, likely due to greater awareness, more accurate diagnosis, better stratification based on risk factors, and an earlier initiation of PAH therapies in recent decades.
Most therapies approved in recent years, and being used in combinations, are for adults. These same treatments are being given off-label to children, but such use is hampered by a lack of testing and data, especially regarding the use of newer oral therapies in triple combination treatments.
Uptravi, sold by Actelion, is a selective agonist of the prostacyclin receptor, or a molecule that works like prostacyclin, a naturally occurring hormone that regulates blood pressure by attaching to receptors found on the cells of the blood vessel walls, causing the vessels to relax and dilate.
It was the first prostacyclin receptor agonist approved by regulatory agencies as an oral treatment, after it significantly lowered by 40% the risk of complications or death in adult PAH patients enrolled in the Phase 3 GRIPHON trial (NCT01106014).
But its use in children with PAH had not been properly evaluated, although the first such use was documented in 2017, about a year after its EU approval, the study noted.
An oral treatment could be of particular importance with young patients, it added, as “a substantial number of children, adolescents, and young adults with PAH may not tolerate parenteral prostacyclin analog therapy (IV administration …) from a compliance or hemodynamic [blood flow] standpoint.”
Researchers in Europe, working with the nonprofit European Pediatric Pulmonary Vascular Disease Network (EPPVDN), set out to explore Uptravi as an add-on treatment for children and adolescents with PAH.
Their study included 15 patients, ages 7 months to 17 years (median 7.4 years), with pre-capillary pulmonary hypertension (PH) whose clinical, heart, and blood markers were not improving after at least six months on a dual oral combination therapy.
Patients were given Uptravi for a median of eight months, starting at doses that largely depended on their weight: a 50−100 microgram (mcg) dose for those weighing less than 10 kg (about 22 lbs); a 100−200 mcg dose for those 10−20 kg; and 200 mcg for patients whose weight was over 20 kg (46 or more lbs).
Doses were then increased every two to three days by increments of 50−100 mcg in the smallest children, and of 100−200 mg in larger children. The target dose was the maximally tolerated dose in regard to side effects. In most cases, the final Uptravi dose was reached after four to eight weeks.
Two years later (a median follow-up of 24.5 months), no one had died due to Uptravi treatment, the researchers wrote. One patient — with genetic, rapid progressive PAH — initially improved on Uptravi, but died 18 months later of right ventricular failure while off the medication. Two children received a lung transplant.
Responses to Uptravi were variable, and tended to be better in less sick patients. Still, Uptravi as an add-on therapy reduced the mean right atrial pressure (blood pressure in the right atrium of the heart) by 2 mm Hg.
“Overall, approximately 50% of our pediatric patients with PAH improved with add-on selexipag, 25% were stabilized, and 20% of the patients deteriorated during the observation period,” the researchers wrote.
The ratios of mean pulmonary arterial pressure to mean systemic artery pressure (mPAP/mSAP), and diastolic pulmonary arterial pressure to diastolic pulmonary arterial pressure, both measures of pulmonary hypertension, were lessened by 17%.
Patients also showed a 17% reduction in mean transpulmonary pressure gradient (mTPG), and a 5.8 mm Hg decrease in mean diastolic transpulmonary pressure gradient (dTPG). These are both measures pulmonary vascular disease.
The add-on treatment also improved a measure of heart function, decreased PH severity in six patients, and lowered a marker of heart strain (NT-proBNP) in half of these children. This marker, however, was nearly unchanged or worsened in the other half.
Researchers also evaluated Uptravi’s using the EPPVDN pediatric PH risk score, which combines a series of blood, heart, and clinical measures, but had not been evaluated in published patient groups. Improvements were seen in seven patients and four other showed disease stabilization. Three patients progressed with Uptravi.
Importantly, the new EPPVDN risk score significantly correlated with other measures of disease, including blood NT-proBNP levels and mean transpulmonary pressure gradient, suggesting it can “reliably indicate a change of clinical status with medication,” the researchers wrote.
No patients stopped Uptravi because of adverse events. Side effects reported were mainly transient, occurred at the start of treatment, and included mostly nausea, headaches, and vomiting.
Overall, “oral add-on therapy with selexipag in children with PAH, although not approved in this age group to date, is well tolerated and appears to be safe when closely monitored,” the researchers wrote.
“In children who underwent invasive cardiac catheterization at baseline [study start] and follow-up, selexipag treatment was associated with the improvement or stabilization of several outcome relevant variables,” they concluded.
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