UPTRAVI - Treatment of Pediatric Patients With Pulmonary Arterial Hypertension

SUMMARY

• The phase 3 SALTO study (N=138) was a randomized, multicenter, double-blind, placebo-controlled, parallel-group study evaluating the efficacy and safety of selexipag vs placebo as add-on treatment to standard of care in pediatric pulmonary arterial hypertension (PAH) patients. The double-blind treatment period of SALTO has been completed, and a 3-year open-label extension period is ongoing, with completion estimated in October 2027.^1-3
  • The primary endpoint was a descriptive analysis of time to first clinical events committee (CEC) confirmed progression event. There was no significant difference between the selexipag and placebo groups.²
  • Adverse events (AEs) were consistent with the known safety profile of selexipag in adults.²
• A phase 2 pharmacokinetics (PK) study (N=63) achieved its primary objective by confirming that body weight-adjusted starting doses and titration regimens for selexipag in pediatric patients with PAH (≥2 to <18 years of age) resulted in a similar systemic steady-state exposure to selexipag and its active metabolite as previously observed in adult patients with PAH.^4,5
• A phase 2, multicenter, noncomparative, open-label study (N=6) evaluated the dosage, efficacy, and safety of selexipag in Japanese pediatric patients with PAH. Key findings are summarized below.⁶
• Additional literature reporting the use of selexipag in pediatric patients has been identified and summarized below.^7-10
• Additional citations are included in the REFERENCES section.^5,11-25

CLINICAL DATA

Information From Clinical Trials

Phase 3 SALTO Study

The phase 3 SALTO study was a randomized, multicenter, double-blind, placebo-controlled, parallel-group trial designed to assess the efficacy and safety of selexipag vs placebo as add-on treatment to standard of care in pediatric PAH patients.^1-3,26 Selexipag oral tablets or matching placebo were initiated twice daily (BID) at a dose based on the the patient's body weight on day 1.¹  A population PK modeling approach was used to determine the proposed selexipag dose regimen in the pediatric PAH population.⁵ A subsequent phase 2 pediatric PK study confirmed that this weight-based dosing regimen was appropriate for assessment in the phase 3 SALTO trial.⁴ Please see Table: Dosing Regimen, as Reported in SALTO. Selexipag tablets in strengths of 50, 100, 150, and 200 mcg were supplied to the SALTO investigation sites to facilitate starting doses. These tablet strengths were combined as needed to achieve each patient’s incremental titration doses and maximum dose.²⁶ Selexipag was up titrated during the first 12 weeks until patients reached either the individual maximum tolerated dose (iMTD) or the maximum dose corresponding to their baseline body weight category. The uptitration period was followed by a maintenance period until the end of treatment, during which patients continued on their maximum tolerated dose.²

To be eligible for the study, patients (aged ≥2 to <18 years) were required to have right heart catheterization (RHC) confirmed PAH, World Health Organization (WHO) functional class (FC) II-III symptoms, be stable for ≥3 months on background therapy with ≥1 PAH-specific therapy, and have an 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 According to the SALTO protocol, children younger than 2 years were excluded due to a potential increased risk of intestinal intussusception, based on toxicological findings observed in young dogs treated with selexipag and the high background incidence of intussusception in infants.²⁶

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 period 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 disease progression event through the double-blind treatment period end date plus 7 days. Events included death, atrial septostomy, Potts’ anastomosis, registration on lung transplant list, hospitalization due to worsening PAH, and clinical worsening of PAH. There was no statistically significant difference between the selexipag and placebo groups for the primary endpoint (hazard ratio, 1.081; 95% confidence interval [CI], 0.607-1.926). The median observation time was 16.2 months for selexipag and 19.6 months for placebo. The number of patients who experienced the first event was 22 (31.9%) and 25 (36.2%) in the 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.^2,3 KM estimates for patients free from disease progression at 2 and 3 years were 64% and 55% in the selexipag group and 69% and 45% in placebo group, respectively²

Post hoc analysis found that 44 cumulative recurrent disease-progression events were reported in the selexipag group and 64 in the placebo group up to 7 days after the last study dose. The average annualized event rate was 0.37 for selexipag and 0.48 for placebo.^2,3

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. The placebo-adjusted reduction in NT-proBNP for the study population was 7% (geometric mean ratio [GMR], 0.93; 95% CI, 0.71-1.21; P=0.5748). Among patients with baseline NT-proBNP levels ≥300 ng/L (n=51), treatment with selexipag resulted in a placebo-adjusted reduction of 26% (GMR, 0.74; 95% CI, 0.46, 1.21). Among patients with baseline NT-proBNP levels <300 ng/L (n=86), treatment with selexipag resulted in a placebo-adjusted increase of 5% (GMR, 1.05; 95% CI, 0.80-1.37). KM estimate of the event-free rate at 1 year was 89.0% (95% CI, 78.3%-94.6%) for selexipag versus 88.3% (95% CI, 78.0%-94.0%) for placebo.^2,3 There was no statistically significant difference between the treatment groups in either secondary endpoint.²

An exploratory analysis revealed a numerically lower proportion of patients remaining in WHO FC III/IV over time with selexipag compared with placebo.^2,3

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

The double-blind treatment period of SALTO has been completed, and a 3-year open-label extension period is ongoing to collect additional pediatric safety information, with completion estimated in October 2027.

Phase 2 Study AC-065A203

Beghetti et al. (2025)⁴ is a prospective, multicenter, open-label, single-arm, phase 2 study investigating the safety, tolerability, exploratory efficacy, and PK of selexipag in children with PAH aged ≥2 to <18 years. The primary PK endpoint was the model-derived combined steady-state exposure (AUC_{τ,ss,combined}) of selexipag and its active metabolite, adjusted for potency, assessed over the 12-week titration phase.⁴ The starting dose of selexipag was based on PK extrapolation data from adults, while also considering the body weight categories in children.⁴

This trial enrolled 63 patients across 3 age cohorts: cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; and cohort 3, ≥2 to <6 years.⁴

Results for the PK primary endpoint (completed on March 28, 2022) were reported along with interim safety data and exploratory efficacy outcomes (up to the data cutoff date of October 29, 2024). Safety and efficacy continue to be assessed over a maintenance period lasting for up to 5 years after the first visit of the last participant. This ongoing study was initiated on July 25, 2018, and the long-term treatment maintenance period is estimated to end in December 2026.⁴

The aim of the study was to confirm the weight-adjusted starting doses and titration regimens that achieve systemic steady-state exposure in children comparable to that observed in adults by assessing the PK of selexipag and its active metabolite (JNJ-68006861, also known as ACT-333679).^4,5 The secondary objective was to asses safety and tolerability, while the exploratory objectives focused on efficacy. The safety and efficacy outcomes are expected to be completed in December 2026.⁴

Baseline characteristics are presented in Table: Baseline Characteristics.⁴

Ratios of estimated/expected exposure were very similar across the body weight groups and age cohorts, ranging from 1.00-1.23.⁴ In pediatric patients aged 2 to 17 years with PAH, the applied body weight adjusted dosing regimen resulted in a combined exposure of selexipag and its active metabolite that was comparable to that observed in adult PAH patients⁴. PK results are summarized in Table: Primary PK Endpoint: Comparison of Model-Based Exposures Estimated from this Study and Expected from the GRIPHON Study.

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

Changes in NTproBNP were reported using geometric mean ratios (GMRs). The GMR (95% CI) was 0.75 (0.58–0.95) at Week 16 and 0.75 (0.57–1.00) at Week 28 (Month 7). Clinically, a reduction from baseline in NTproBNP (ratio < 1) was considered an improvement. See table: Change from Baseline in NT proBNP Levels.⁴

Changes in 6MWD results are presented in Table: Change in 6MWD from Baseline.

Shift in WHO FC from baseline over time are presented in Table: Shift in WHO FC from Baseline over Time.

Phase 2 Study NS304P-P2-1

Iwasa et al (2025)⁶ conducted a phase 2, multicenter, noncomparative, open-label study evaluating 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 included 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 levels up to the data cutoff (52 weeks after the last patient was enrolled). Safety endpoints included adverse drug reactions (ADRs), side effects, vital signs, height, weight, laboratory values (blood and urine), and electrocardiographic findings.

Selexipag was initiated BID, titrated according to 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 the data cut-off, 5 patients continued selexipag treatment; 1 patient discontinued the study treatment due to noncompliance. 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 IPAH, and 1 patient had 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 receiving 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 demonstrated a trend toward improvement, while SvO₂ and mRAP did not show improvement.

ADRs with selexipag occurring up to week 64 are summarized in Table: Safety Results (Safety Analysis). The incidence of ADRs (vomiting, headache, and nausea) was higher in the early treatment period, with no increase in the incidence during the subsequent 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), which was assessed as not related to selexipag use.

Information From the Literature

Grossman et al (2024)⁷conducted 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 the efficacy and safety of selexipag 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. ERA or PDE-5i doses did not change during the selexipag titration period.

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

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

Frank et al (2024)⁸ conducted a multicenter, retrospective, cohort study to describe the safety and effectiveness of selexipag in pediatric patients (aged <18 years) with group 1 and group 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 another 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. After >1 year of add-on selexipag therapy, maximal oxygen consumption during cardiopulmonary exercise testing (VO₂ max) increased from 27.8 to 30.9 mL/kg/min, and 6MWD increased from 503 to 513 m. In transition patients, no changes in functional testing were observed within the first year on selexipag use; however, the VO₂ max levels decreased from the last follow-up (26 mL/kg/min vs 19.5 mL/kg/min). In both the add-on and transition groups, self-reported WHO FC did not differ significantly. Echocardiographic measures showed no change across the time points, and right ventricular (RV) fractional area change remained stable in both groups throughout the immediate and most recent follow-ups. A higher 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 reported in 41% of patients who initiated selexipag at 200 mcg and 38% of those who initiated therapy at 100 mcg. At the last follow-up, 17 patients discontinued selexipag at a median of 623 days (IQR, 393-1041) after initiation. Of these, 2 patients discontinued early (<30 days after initiation) due to AEs, and the remaining 15 discontinued due to escalation of care in the context of clinical worsening.

Takatsuki et al (2023)⁹ 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 their first prostacyclin therapy, while 7 were transitioned from beraprost sodium (n=6) or epoprostenol (n=1).

Children weighing >40 kg were administered an adult dose of selexipag, while those weighing <40 kg received 80 mcg/kg; doses were increased every 2 or 4 weeks to reach maintenance levels. In 3 children receiving selexipag as upfront therapy, initial doses/day were 100 mcg, 200 mcg, and 300 mcg, with corresponding maintenance doses/day of 1200 mcg, 2000 mcg, and 2400 mcg, respectively. In the 2 children transitioned to selexipag, initial doses/day were 400 mcg, with maintenance doses/day were 1000 mcg and 2800 mcg.

The median (range) follow-up period after selexipag initiation was 2 (1-3) years. Disease severity was assessed in 10 patients, with none showing 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 included 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 due to severe headache, yielding an overall discontinuation rate of 9%.

The European Pediatric Pulmonary Vascular Disease Network (EPPVDN) conducted a prospective, observational study evaluating the safety and efficacy of add-on selexipag in 15 pediatric patients with PH.¹⁰ Of these, 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, selexipag treatment was associated with improvement or stabilization of mRAP, the 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

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 05 February 2026.