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.
• The phase 3 SALTO study was a pivotal, randomized, multicenter, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of selexipag versus placebo as add-on treatment to standard of care in pediatric PAH patients. The study is estimated to be completed in 2027.^1,2 
  • The primary endpoint was the descriptive analysis of time to first clinical events committee (CEC) confirmed progression event. There was no significant difference between selexipag and placebo groups.² 
  • Adverse events (AEs) were consistent with the known safety profile of UPTRAVI in adults.² 
• A phase 2 clinical trial is currently ongoing to investigate the safety, tolerability, and pharmacokinetics (PK) of selexipag in children with PAH. The study is estimated to be completed in 2026.³
  • A study reported the PK results, interim safety profile, and exploratory efficacy data.⁴
• A phase 2, multicenter, noncomparative, open-label study evaluated the dosage, efficacy, and safety of selexipag in Japanese pediatric patients with PAH. Findings are summarized below.⁵ 
• Additional literature relating to the efficacy and safety of selexipag has been identified and summarized below.^6-9
• Additional citations are included in the REFERENCES section.^10-22

CLINICAL DATA

Information From Ongoing Clinical Trials

SALTO Study

The phase 3 SALTO study was a pivotal, randomized, multicenter, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of selexipag versus placebo as add-on treatment to standard of care in pediatric PAH patients. Selexipag or matching placebo was initiated twice daily (BID) at a dose based on the body weight on day 1. Please see Table: Dosing Regimen, as Reported in SALTO. Selexipag was uptitrated during the first 12 weeks until patients reached the individualized maximum tolerated dose (iMTD) or until a maximum dose corresponding to their baseline body weight category was achieved. Uptitration period was followed by a maintenance period until end of treatment, at the maximum tolerated dose.² 

To be eligible for the study, patients (aged ≥2 to <18 years) must have a right heart catheterization (RHC) confirmed PAH, World Health Organization (WHO) Functional Class (FC) II-III symptoms, stable (≥3 months) on background therapy with ≥1 PAH-specific therapy, and have etiology of idiopathic PAH (IPAH), heritable PAH (HPAH), PAH associated with congenital heart disease (PAH-CHD), drug/toxin induced PAH, or PAH associated with human immunodeficiency virus (PAH-HIV).²

A total of 138 patients were enrolled and randomized 1:1 to receive either selexipag (n=69) or placebo (n=69). Of the 138 patients, 43 and 44 completed the double-blind treatment in the selexipag group and placebo group, respectively. Baseline characteristics are presented in Table: Baseline Characteristics, as Reported in SALTO.² 

The primary endpoint was the descriptive analysis of time to first CEC confirmed progression event through double-blind end date plus 7 days, which included death, atrial septostomy or Potts’ anastomosis or registration on lung transplant list, hospitalization due to worsening PAH, and clinical worsening of PAH. There was no difference between selexipag and placebo groups regarding the primary endpoint (hazard ratio, 1.081, 95% Confidence Interval [CI], 0.607-1.926). The number of patients who experienced an event was 22 (31.9%) and 25 (36.2%) for selexipag and placebo groups, respectively. The Kaplan-Meier (KM) estimates of event-free rates at 1 year were 82.1% (95% CI, 70.7-89.4) for selexipag and 82.6% (95% CI, 71.4-89.7) for placebo.² 

The secondary endpoints included powered analysis of change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to week 24 and descriptive analysis of time to first CEC-confirmed hospitalization for PAH or death due to PAH. There was no difference between treatment groups in either secondary endpoint.² 

An exploratory assessment of WHO FC change from baseline demonstrated a lower proportion of patients in WHO FC III/IV over time with selexipag versus placebo.² 

Adverse events were consistent with the known safety profile of UPTRAVI in adults. The most common AEs were well known prostacyclin-related AEs. The most frequent treatment-emergent adverse effect (TEAE) in the selexipag group was headache (55.1%). Please see Table: Safety and Tolerability, as Reported in SALTO.² 

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.³ Selexipag was titrated to the 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).³ 

Beghetti et al (2023)⁴ 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 selexipag by investigating the PK of selexipag and its active metabolite, ACT-333679. The secondary objective was to evaluate the safety and tolerability of selexipag. Exploratory objectives were to explore the relationship between selexipag exposure and efficacy variables (6-minute walk distance [6MWD], 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 2 Study

Iwasa et al (2025)⁵ conducted a phase 2, multicenter, noncomparative, open-label study that evaluated the dosage, efficacy, and safety of selexipag 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 after week 16 (pulmonary vascular resistance index [PVR], mean pulmonary artery pressure [mPAP], cardiac index, total pulmonary resistance [TPR], mixed venous oxygen saturation [SvO₂], and mean right atrial pressure [mRAP]), 6MWD, WHO 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.

Selexipag 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 selexipag for each patient is presented in Table: Selexipag Duration and Dosage.

Overall, 6 pediatric patients (3 males and 3 females) with PAH were enrolled. At data cut-off, 5 patients continued selexipag 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 type 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% 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. PVR, mPAP, cardiac index and TPR showed a trend toward improvement while SvO₂ and mRAP did not demonstrate any improvement.

ADRs with selexipag 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 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 selexipag use.

Information From the Literature

Grossman et al (2024)⁶ conducted a retrospective cohort study with the primary objective of assessing selexipag dosing patterns and changes in concomitant PAH agents during the selexipag titration period and a secondary objective of evaluating selexipag efficacy and safety in pediatric patients with PAH.

Of the 27 patients receiving selexipag treatment from September 20, 2020, to October 21, 2022, 15 (56%) were female, and 8 of 27 (30%) patients had IPAH. The median (interquartile range [IQR]) age, weight, and height at selexipag 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: Selexipag Dosing Strategies and Table: Selexipag Titration Details for information on dosing and titration, respectively.

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

Patients saw improvement in septal position (2 out of 18 patients), right ventricular fractional area change (1 out of 11), tricuspid annular plane systolic excursion (10 out of 18), and 6MWD (1 out of 6). No patients had decrease in right ventricular pressure.

No patients discontinued selexipag 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)⁷ conducted a multicenter, retrospective, cohort study to describe the safety and effectiveness of selexipag 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 selexipag as an add-on therapy with no prior prostacyclin agonist exposure and 55 patients transitioned from different prostacyclin agonist to selexipag. The median starting dose of selexipag 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 selexipag and immediate post selexipag periods. Following >1 year of add-on selexipag 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 selexipag, 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 selexipag, 77% after selexipag, and 80% at follow-up.

A subset of the patients underwent serial invasive monitoring with cardiac catheterization. The ratio of indexed pulmonary vascular resistance to systemic vascular resistance (PVRi/SVRi) improved in the entire cohort (n=34, 0.7 vs 0.55, P=0.011), the add-on cohort (n=16, 0.62 vs 0.53, P=0.034), and the transition cohort (n=19, 0.72 vs 0.58, P=0.181).

Side effects were noted in 41% of patients that initiated selexipag at 200 mcg and 38% that initiated selexipag at 100 mcg. At the last follow-up, 17 patients discontinued selexipag 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)⁸ conducted a single center, retrospective cohort study to evaluate the efficacy, safety, and tolerability of selexipag 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 selexipag 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 selexipag 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 selexipag 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 selexipag 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 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 selexipag owing to severe headache, and the overall discontinuation rate was 9%.

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.⁹ 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 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.⁹

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.