SUMMARY

• While the risk-benefit ratio relating to the use of UPTRAVI in pediatric patients has not been established, the decision to administer UPTRAVI is at the discretion of the treating physician.
• A phase 2 clinical trial is currently ongoing to investigate the safety, tolerability, and pharmacokinetics (PK) of selexipag in children with pulmonary arterial hypertension (PAH). The study is estimated to be completed in 2026.¹
  • A study reported the PK results, interim safety profile, and exploratory efficacy data.²
• A phase 3 clinical trial is currently ongoing to investigate UPTRAVI as an add-on therapy to standard of care in children with PAH. The study is estimated to be completed in 2027.³
• A phase 2, multicenter, noncomparative, open-label study evaluated the dosage, efficacy, and safety of UPTRAVI in Japanese pediatric patients with PAH. Findings are summarized below.⁴ 
• Additional literature relating to the efficacy and safety of UPTRAVI has been identified and summarized below.^5-18
• Additional citations are included in the REFERENCES section.^19-21

CLINICAL DATA

Information From Ongoing Clinical Trials

Phase 2 Study

A Clinical Study to Confirm the Doses of Selexipag in Children With Pulmonary Arterial Hypertension is a prospective, multicenter, open-label, single-arm, phase 2 study to investigate the safety, tolerability, and PK of selexipag in children with PAH.¹ UPTRAVI will be up titrated to the individual maximum tolerated dose (iMTD) during the first 12 weeks from a starting dose based on the PK extrapolation from adults, while also taking into account the children’s body weight category.

This trial enrolled 63 patients in 3 different age cohorts to obtain at least 45 patients with evaluable PK profiles: cohort 1: ≥12 to <18 years of age, cohort 2: ≥6 to <12 years of age, cohort 3: ≥2 to <6 years of age. Enrollment started with both cohort 1 and cohort 2. Enrollment of cohort 3 (children ≥2 to <6 years of age) started once the appropriate doses were confirmed in a second interim analysis of PK data from cohorts 1 and 2, and if there was no safety concern based on the review by an Independent Data Monitoring Committee.

The study has an estimated completion date of 2026. For additional information, including inclusion and exclusion criteria, please visit http://clinicaltrials.gov (identifier NCT03492177).

Beghetti et al (2023)² reported the PK results, the interim safety profile, and the exploratory efficacy data of selexipag in children with PAH aged ≥2 to <18 years. The primary objective was to confirm the starting doses of UPTRAVI by investigating the PK of selexipag and its active metabolite, ACT-333679. The secondary objective was to evaluate the safety and tolerability of UPTRAVI. Exploratory objectives were to explore the relationship between selexipag exposure and efficacy variables (6-minute walk distance [6MWD], N-terminal pro-B-type natriuretic peptide [NT-proBNP], and echo measures), explore time to clinical worsening, and assess acceptability and palatability of the formulation.

Of the 63 children enrolled in the study, 59 completed ≥16 weeks of treatment and contributed to the primary PK analysis. The median treatment duration was 144.4 weeks. Baseline characteristics are presented in Table: Baseline Characteristics.

The dosing regimen ensured the children had similar selexipag exposure as that of adults; the difference in area under the plasma concentration-time curve over a dose interval at steady state (AUC_{τ,combined,ss}) from that expected (based on the adult-extrapolated data) was <25% (the prespecified criteria for similar exposure was ±30% of that observed in adults) for all weight groups (≥9-<25 kg, ≥25-<50 kg, and ≥50 kg) and age cohorts (≥2-<6 years, ≥6-<12 years, and ≥12-<18 years). PK results are summarized in Table: Primary Endpoint: PK Results.

Safety results are summarized in Table: Secondary Endpoints: Safety.

Exploratory efficacy results are summarized in Table: Exploratory Efficacy and Acceptability.

Phase 3 Study

A Study of UPTRAVI as Add-On Treatment to Standard of Care in Children With Pulmonary Arterial Hypertension is a randomized, multicenter, double-blind, placebo-controlled, parallel-group, event-driven, group-sequential study with an open-label extension period to assess the efficacy and safety of UPTRAVI in children aged 2 to 17 years with PAH.³ Patients will receive UPTRAVI based on the body weight on day 1 and will continue thereafter with twice daily (BID) dosing. UPTRAVI will be uptitrated during the first 12 weeks until patients reach the iMTD or until a maximum dose corresponding to their baseline body weight category is achieved. Up titration is followed by a maintenance period after week 12 until end of treatment, at the maximum tolerated dose.

A total of 138 patients were enrolled. The primary outcome measure is time to disease progression from randomization up to 7 days after study treatment discontinuation. Disease progression is defined as the first occurrence of the following: death (all causes), atrial septostomy or Potts’ anastomosis or registration on lung transplant list, hospitalization due to worsening PAH, and clinical worsening of PAH.

The study has an estimated completion date of 2027. For additional information, including inclusion and exclusion criteria, please visit http://clinicaltrials.gov (identifier NCT04175600).

Phase 2 Study

Iwasa et al (2025)⁴ conducted a phase 2, multicenter, noncomparative, open-label study that evaluated the dosage, efficacy, and safety of UPTRAVI in Japanese pediatric patients with PAH.

The primary efficacy endpoint was the resting pulmonary vascular resistance index (PVRI) after week 16. Secondary efficacy endpoints were pulmonary hemodynamics (listed in Table: Changes in Pulmonary Hemodynamic Variables at Week 16) after week 16 and 6MWD, World Health Organization (WHO) functional class (FC), and NT-proBNP concentration until data cutoff (52 weeks after the last patient was enrolled). Safety endpoints were adverse drug reactions (ADRs), side effects, vital signs, height, weight, laboratory values (blood and urine), and electrocardiographic findings.

UPTRAVI was initiated BID, titrated as per individual tolerance, and uptitrated once the dose was well tolerated for ≥7 days (14 administrations). Dose reduction and re-uptitration were permitted during the titration period (12 weeks). Changes in weight category due to weight gain or loss were allowed. Information regarding the duration and dosage of UPTRAVI for each patient is presented in Table: UPTRAVI Duration and Dosage.

Overall, 6 pediatric patients (3 males and 3 females) with PAH were enrolled. At data cut-off, 5 patients continued UPTRAVI treatment; 1 patient was noncompliant, thus, discontinued the study treatment. The mean age, mean body weight, and mean PAH duration were 9.2 years, 35.25 kg, and 0.99 years, respectively. Five patients had idiopathic pulmonary arterial hypertension (IPAH), and 1 patient had pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). The mean PVRI at baseline was 17.96 Wood units (WU)·m²; 5 patients were WHO FC II and 1 was WHO FC III; 3 patients were on concomitant pulmonary vasodilators, including an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE-5i) and the remaining 3 were not on concomitant pulmonary vasodilators.

The mean (±standard deviation [SD]) change in PVRI at rest from baseline to week 16 was -5.55 (±6.88) WU·m² (95% confidence interval [CI], -12.76 to 1.67); the geometric mean of the after/before ratio (16 weeks/baseline) was 69.4% (95% CI, 46.4-103.8). The change in PVRI at rest from baseline to week 16 in individual patients ranged from -16.61 to 2.58 WU·m²; 5 of 6 patients showed an improvement of ≥1 WU·m². See Table: Changes in Pulmonary Hemodynamic Variables at Week 16 and Table: Changes in 6MWD, NT-proBNP, and WHO FC Until Week 64 for efficacy endpoints.

ADRs with UPTRAVI that occurred up to week 64 are summarized in Table: Safety Results. The incidence of ADRs (vomiting, headache, and nausea) was high in the early treatment period, with no increase in the incidence during the treatment period. No serious adverse events (AEs) or AEs leading to treatment discontinuation were reported.

Slight variations were noted in the blood pressure and pulse rate; no abnormalities were detected in laboratory test values. One patient exhibited electrocardiographic changes during the treatment period and reported an AE (right bundle branch block) not related to UPTRAVI use.

Information From the Literature

Grossman et al (2024)⁵ conducted a retrospective cohort study with the primary objective of assessing UPTRAVI dosing patterns and changes in concomitant PAH agents during the UPTRAVI titration period and a secondary objective of evaluating UPTRAVI efficacy and safety in pediatric patients with PAH.

Of the 27 patients receiving UPTRAVI treatment from September 20, 2020, to October 21, 2022, 15 (56%) were female, and the majority (8 of 27 patients; 30%) had IPAH. The median (interquartile range [IQR]) age, weight, and height at UPTRAVI initiation were 9 (4.5-15) years, 25 (19-50) kg, and 129 (107-161) cm, respectively. Additional baseline demographics are summarized in Table: Select Baseline Characteristics.

See Table: UPTRAVI Dosing Strategies and Table: UPTRAVI Titration Details for information on dosing and titration, respectively.

At UPTRAVI initiation, 24 of 27 patients were receiving treprostinil (subcutaneous [SC], n=20; oral, n=4), which was tapered off based on the iMTD of UPTRAVI for each patient. ERA or PDE-5i doses did not change during the UPTRAVI titration period.

Clinically significant improvements were noted in the severity and functionality markers of pulmonary hypertension (PH; see Table: Efficacy Results).

No patients discontinued UPTRAVI during the study period; 4 patients received reduced doses due to flushing (n=1), drug interactions (n=2), and an increased frequency of nose bleeds (n=1).

Frank et al (2024)⁶ conducted a multicenter, retrospective, cohort study to describe the safety and effectiveness of UPTRAVI in pediatric patients (aged <18 years) with group 1 and 3 PAH. A total of 87 patients were enrolled in the study, of which 32 patients received UPTRAVI as an add-on therapy with no prior prostacyclin agonist exposure and 55 patients transitioned from different prostacyclin agonist to UPTRAVI. The median starting dose of UPTRAVI was 4.7 mcg/kg/dose BID which was up titrated to a median final dose of
28.5 mcg/kg/dose BID. Baseline characteristics are summarized in Table: Select Baseline Characteristics.

No changes were observed between the pre UPTRAVI and immediate post UPTRAVI periods. Following >1 year of add-on UPTRAVI therapy, there was an increase in maximal oxygen consumption during cardiopulmonary exercise testing (VO₂ max) from 27.8 to 30.9 mL/kg/min and 6MWD from 503 to 513 m. In transition patients, no changes in functional testing were observed within the first year on UPTRAVI, however the VO₂ max levels decreased from the last follow-up (26 mL/kg/min vs 19.5 mL/kg/min). In both add-on and transition group, self-reported WHO FC did not differ significantly. The echocardiographic measures showed no change among the time points and right ventricular (RV) fractional area change remained stable in the add-on and transition groups throughout the immediate and most recent follow-ups. A greater frequency of improved RV function was observed in the add-on group, with 69% showing normal function before UPTRAVI, 77% after UPTRAVI, and 80% at follow-up. Catheterization outcomes pre and post UPTRAVI treatment in the add-on and transition groups are presented in Table: Catheterization Outcomes Before and After UPTRAVI Treatment.

Side effects were noted in 41% of patients that initiated UPTRAVI at 200 mcg and 38% that initiated UPTRAVI at 100 mcg. At the last follow-up, 17 patients discontinued UPTRAVI at a median of 623 days (IQR, 393-1041) after initiation. Of which, 2 patients discontinued early (<30 days after initiation) due to AEs and the other 15 patients discontinued due to escalation of care in the context of clinical worsening.

Takatsuki et al (2023)⁷ conducted a single center, retrospective cohort study to evaluate the efficacy, safety, and tolerability of UPTRAVI in 11 patients with PAH. Of the 11 patients, 5 were children with a median (range) age of 9 (3-11) years and 6 were young adults with a median (range) age of 24.5 (19-28) years. Overall, 4 patients initiated UPTRAVI as an initial prostacyclin therapy and 7 were transitioned from beraprost sodium (n=6) or epoprostenol (n=1).

Children weighing more than 40 kg were administered an adult dose of UPTRAVI and those weighing less than 40 kg were treated at 80 mcg/kg; dose was increased every 2 or 4 weeks to the maintenance dose. In 3 children who initiated UPTRAVI as an upfront therapy, the initial doses/day were 100 mcg, 200 mcg, and 300 mcg, each, and the corresponding maintenance doses/day were 1200 mcg, 2000 mcg, and 2400 mcg, each. In 2 children who were transitioned, the initial doses/day were 400 mcg, each, and the corresponding maintenance doses/day were 1000 mcg and 2800 mcg, each.

The median (range) follow-up period after UPTRAVI initiation was 2 (1-3) years. Disease severity was assessed in 10 patients, and none of them showed any improvement or deterioration in New York Heart Association (NYHA) FC. There were no significant differences in brain natriuretic peptide (BNP) levels before and after UPTRAVI initiation (P=0.23); however, 6MWD showed significant improvement (P=0.03). Nine of 11 patients underwent 1-year follow-up catheterization and showed statistically significant improvements in mean pulmonary artery pressure (mPAP; P<0.01), PVRI (P<0.05), and cardiac index (P<0.01). AEs reported in ≥50% of young adults were headache (n=5; 83%) and nausea (n=3; 50%). Among children, 1 (20%) had headache and 1 (20%) had nausea. One young adult discontinued UPTRAVI owing to severe headache, and the overall discontinuation rate was 9%.

Youssef et al (2023)⁸ conducted a multicenter, retrospective study to evaluate the clinical outcomes of UPTRAVI in addition to the standard pulmonary vasodilator therapy in 24 pediatric patients with PH. The median (range) age at UPTRAVI initiation was 9.7 (2-15.5) years. Efficacy data at UPTRAVI initiation, 6 months, and 12 months are summarized in Table: Clinical and Echocardiographic Outcomes and WHO FC With UPTRAVI.

Despite initial improvements, 3 patients died, 1 of whom belonged to group 2 with a background of critical aortic stenosis. The number of patients on prostacyclin therapy as a third agent at baseline and 12 months were 11 (45.8%) and 3 (12.5%), respectively. Patients who failed were put back on intravenous (IV)/SC treprostinil. Oral and inhaled prostacyclins were not used in this population. Gastrointestinal disturbances, cardiovascular adverse effects, and dry lips or rashes were reported in 10 (41.7%), 3 (12.5%), and 2 (8.3%) patients, respectively. Two (8.3%) patients experienced neurological symptoms, including headache and mood alteration; 1 patient who was delisted from a lung transplant owing to disease progression and was kept on triple therapy survived.

Colglazier et al (2022)⁹ conducted a retrospective study to evaluate the hemodynamic changes associated with transitioning from parenteral prostacyclins (SC treprostinil, n=7; IV treprostinil, n=1; inhaled treprostinil, n=3) to UPTRAVI in 11 pediatric patients with PAH. The mean age at presentation with PAH was 8 years. Before transitioning, the mean durations of continuous SC/IV treprostinil and inhaled treprostinil therapies were 20 and 51 months, respectively. The mean duration of UPTRAVI therapy at evaluation was 9 months.

In 9 of 11 patients, transition from treprostinil to UPTRAVI was per outpatient protocol with weekly increases in UPTRAVI doses ranging from 50 to 200 mcg BID while inhaled or parenteral treprostinil doses were simultaneously decreased. Of the remaining patients, 1 underwent a similar protocol as an inpatient and 1 underwent a rapid transition from IV treprostinil to UPTRAVI over 5-7 days while in the hospital.

In 10 of 11 patients, hemodynamic data after transitioning from parenteral to enteral therapy were available. After the transition, PVRI increased (P=0.07). On an average, mPAP (P=0.50) and transpulmonary pressure gradient (TPG; P=0.17), were noted to have increased, with no changes in cardiac index. Overall, 6, 5, and 7 patients had an increase in PVRI, mPAP, and TPG, respectively, whereas 6 had a decrease in cardiac index. BNP level was increased (P=0.44), FC remained I-II in most of the cohort, and in 3 patients who had 6MWD before and after the transition, the values remained unchanged. In 3 of 11 patients, transition failure was reported and reinitiation of parenteral therapy was required; 2 patients had been on inhaled treprostinil therapy before the transition to UPTRAVI and 1 on SC treprostinil therapy. Among the 3 patients who failed the transition, 2 had worsening PAH and 1 had acute RV failure in the setting of an intercurrent viral illness 1 month after the transition. After reinitiation of parenteral therapy, 2 patients reported improvements, whereas the third patient, after a transient improvement, died owing to progression of his complex arterial and venous disease. No AEs were reported during the transition. All patients and/or their families reported a quality-of-life preference for oral UPTRAVI therapy over their previous prostacyclin delivery.

The European Pediatric Pulmonary Vascular Disease Network (EPPVDN) investigated the safety and efficacy of add-on UPTRAVI in a prospective, observational study of 15 pediatric patients with PH.¹⁰ Eight patients had IPAH, 1 patient had heritable PAH, and 3 patients had PAH-CHD. Most patients underwent right heart catheterization at baseline and at a median of 8 months.

In 12 of 15 patients, UPTRAVI treatment was associated with the improvement of stabilization of mean right atrial pressure (mRAP), mPAP/mean systemic artery pressure, mean transpulmonary pressure gradient, diastolic transpulmonary pressure gradient, tricuspid annular plane systolic excursion, and FC at a median follow-up time of 8 months.¹⁰

Case Series

Merrill et al (2023)¹¹ presented data on 7 pediatric patients with PAH that transitioned directly between prostacyclins with no overlapping doses. Transitions took place at the cardiac intensive care unit (CICU), cardiology clinic, or at home. Patients who transitioned in the CICU were observed for 12-48 hours.

All patients remained on their respective transition doses for at least 1 week. After establishing an initial transition dose, UPTRAVI was uptitrated at home in most cases. An equation that reflected a transition dose between treprostinil and UPTRAVI was established in patients less than the adult size (treprostinil dose [ng/min]=UPTRAVI [mcg/dose]). Data regarding direct prostacyclin transition is summarized in Table: Summary of Direct Prostacyclin Transition in Pediatric Patients With PAH.

Other case series and case reports identified are presented in Table: Summary of Case Series and Table: Summary of Case Reports, respectively.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 04 March 2025.