Safety and Efficacy of Selexipag for Pediatric Pulmonary Arterial Hypertension in Japanese Patients　― An Open-Label Phase 2 Study ―

Abstract

Background: Selexipag, an oral prostacyclin (PGI₂) receptor agonist, is approved for adult patients with pulmonary arterial hypertension (PAH). This study evaluated the efficacy and safety of selexipag for Japanese pediatric patients with PAH.

Methods and Results: The study enrolled 6 patients who received selexipag twice daily at an individualized dose based on body weight; maintenance doses were determined for each patient by 12 weeks after starting administration. Efficacy, including pulmonary hemodynamics, was evaluated after 16 weeks, and efficacy and safety were further evaluated 52 weeks after treatment was initiated in the last enrolled patient. The mean (±SD) change in the pulmonary vascular resistance index from baseline to Week 16 (the primary endpoint of the study) was −5.55±6.88 Wood units·m²; improvements were also seen in other pulmonary hemodynamic parameters. The 6-min walk distance increased and N-terminal pro-B-type natriuretic peptide decreased up to Week 64, but the between-subject variability was large. The World Health Organization functional class was improved in 1 of 6 patients at Week 16 and in 2 of 4 patients at Week 64. No patient worsened. The major side effects of selexipag were those characteristic of PGI₂, and the safety profile of selexipag was similar to that in adult patients.

Conclusions: The efficacy and safety of selexipag in Japanese pediatric patients with PAH were demonstrated.

Pulmonary arterial hypertension (PAH) is a rare and life-threatening pulmonary vascular disease. PAH is caused by elevation of pulmonary arterial pressure and pulmonary vascular resistance (PVR), primarily due to narrowing of the internal lumen of pulmonary resistance arteries. As the disease progresses, dyspnea and decreased exercise capacity due to decreased cardiac output of the right ventricle occur, resulting in right heart failure and death.¹ The histology and pathophysiology of pediatric patients with PAH is quite similar to that of adult patients;² therefore, the diagnostic criteria and clinical classification of pediatric PAH are almost the same as those for adult PAH.^1,3,4 Of the clinical classifications of PAH, idiopathic PAH (IPAH), heritable PAH (HPAH), and PAH associated with congenital heart disease (CHD-PAH) are reported to account for the majority of pediatric patients with PAH.^5–7 The annual incidence of pediatric PAH is approximately 0.5 to 1–2 cases per million of the pediatric population per year,⁵ with a similar incidence in Japan.⁸

The treatment strategy for pediatric PAH is similar to that for adults, consisting of pulmonary vasodilators based on 3 different mechanisms of action: (1) prostacyclin (PGI₂), its derivatives, and prostacyclin receptor (IP receptor) agonists; (2) endothelin receptor agonists (ERAs); and (3) phosphodiesterase (PDE) 5 inhibitors and soluble guanylate cyclase (sGC) stimulators.¹ Currently, only 4 pulmonary vasodilators, namely epoprostenol, bosentan, ambrisentan, and sildenafil, have pediatric PAH indications in Japan, but no oral PGI₂ drug is indicated for children with PAH. Epoprostenol, a prostacyclin, is indicated with a Class I recommendation for high-risk patients with PAH (i.e., World Health Organization [WHO] functional classes III and IV), but continuous intravenous infusion is required, and there are concerns about the decreased quality of life and the risk of catheter-related bacterial infection due to central venous catheter placement.¹ Furthermore, developing orphan drugs for pediatric patients in Japan alone is difficult and time-consuming because of the small number of target patients. Therefore, problems remain in treating pediatric PAH.

Selexipag is an orally administered IP receptor agonist with a non-prostanoid structure. It has been proven to reduce the risk of morbidity/mortality events for adult patients with PAH and has been approved for treating adult PAH in >70 countries.⁹ The histology and pathophysiology of PAH are similar between adult and pediatric patients, so selexipag is expected to be effective in pediatric patients with PAH. However, data on the use of selexipag to treat Japanese pediatric patients with PAH are lacking.

This study investigated the dosage, efficacy, and safety of selexipag in pediatric patients with PAH in Japan. The global Phase 2 study investigating the pharmacokinetics and safety of selexipag in pediatric PAH (ClinicalTrials.gov ID: NCT03492177) and the Phase 3 study examining the efficacy and safety of selexipag in pediatric PAH (ClinicalTrials.gov ID: NCT04175600) are ongoing outside of Japan. The Phase 2 study results are available on ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT03492177?a=49).

Methods

Study Subjects

Eligible participants were Japanese PAH patients aged 2–14 years, weighing ≥9 kg, with IPAH, HPAH, CHD-PAH, PAH associated with drugs and toxins, PAH associated with HIV infection, or PAH associated with connective tissue disease. All WHO functional classes were eligible for inclusion in the study.

The study excluded patients with: PAH with Eisenmenger syndrome in CHD-PAH; CHD-PAH Group 1 in the Nice 2013 classification for pulmonary hypertension;¹⁰ PAH with significant left-to-right shunt; CHD-PAH Group 2 in the Nice 2013 classification; and cyanotic CHD-PAH, such as transposition of the great arteries, truncus arteriosus, single ventricle, or pulmonary atresia with ventricular septal defect, and postoperative state of Fontan palliation.

Patients were required to have a mean pulmonary arterial pressure (mPAP) of ≥25 mmHg, a pulmonary arterial wedge pressure of ≤15 mmHg, and a PVR index (PVRI) of ≥3 Wood units·m² as measured by right heart catheterization within 4 weeks before initiating study treatment. Concomitant use of ERAs, PDE5 inhibitors, sGC stimulators, or calcium channel blockers was allowed if the dosage had been stable for >90 days before baseline pulmonary hemodynamic evaluation. In addition, discontinuation of ERAs, PDE5 inhibitors, sGC stimulators, and PGI₂ and its derivatives before baseline pulmonary hemodynamic evaluation was allowed after a wash-out period of 4 weeks for PGI₂ and its derivatives (except beraprost sodium), ERAs, PDE5 inhibitors, and sGC stimulators, and 1 week for beraprost sodium. Other inclusion/exclusion criteria are listed in the Supplementary Appendix.

The study was conducted under the ethical principles established by the institutional review boards of the participating facilities or regions and the Declaration of Helsinki. The study design was approved by the Institutional Review Board of the National Cerebral and Cardiovascular Center (Reference no. 1135), as well as the institutional review boards of each study site. The parents of all participants provided written informed consent for participation in the study before enrollment, and informed assent was obtained from the participant if the participant could understand the explanation of the study with the assent documents. The planning, case enrollment, and promotion of the study were supported by the clinical trial promotion activities of the Japanese Society of Pediatric Cardiology and Cardiac Surgery.

Study Design

This was a Phase 2 multicenter non-comparative open-label study. An overview of the study design is shown in Figure 1. Participants were administered selexipag orally twice daily, starting with the starting dose specified for each weight category. Doses were uptitrated in the increments specified for each weight category at incremental intervals of at least 7 days (14 administrations), while taking into account the tolerance of the participants. Dose reduction and re-uptitration were allowed during the titration period. The maintenance dose for each participant was determined by Week 12, and the participants then continued treatment at each maintenance dose for 4 weeks. The initial weight category assigned at the start of the study was not to be changed during the efficacy evaluation period (at 16 weeks) even if each participant’s weight category changed due to weight gain or loss.

Figure 1.

Schematic of the study design. Selexipag was initiated twice daily at the dose for each body weight category and titrated according to individual tolerance. If the dose was well tolerated for at least 7 days (14 administrations), it was uptitrated in increments of the dose for each body weight category. Dose reduction and re-uptitration were allowed during the titration period.

Treatment was continued with each maintenance dose during the long-term treatment period, and uptitration, downtitration, and re-uptitration were allowed if deemed appropriate by the investigator. In addition, changes in weight category due to weight gain or loss were permitted. Data were cut off 52 weeks after the last patient had been enrolled.

Based on the population pharmacokinetic analysis in the Phase III study in adult patients with PAH (GRIPHON study),⁹ we estimated the dosage for pediatric patients with PAH as follows:

• body weight ≥50 kg: initial dose of 0.2 mg/dose, increment of 0.2 mg/dose, maximum dose of 1.6 mg/dose

• body weight ≥25 and <50 kg: initial dose of 0.15 mg/dose, increment of 0.15 mg/dose, maximum dose of 1.2 mg/dose

• body weight ≥9 and <25 kg: initial dose of 0.1 mg/dose, increment of 0.1 mg/dose, maximum dose of 0.8 mg/dose.

In the study, participants took the same formulation as Uptravi tablets 0.2 mg (Nippon Shinyaku Co., Ltd.) and a newly developed 0.05-mg tablet for pediatric patients. The pediatric 0.05-mg tablets could be dispersed in water.

Assessment of Outcomes

Resting PVRI after 16 weeks was assessed as the primary evaluation point of efficacy. Secondary endpoints were pulmonary hemodynamics after 16 weeks (resting mean right atrial pressure [mRAP], mPAP, cardiac index, PVR, total pulmonary resistance [TPR], and mixed venous oxygen saturation [SvO₂]), 6-min walk distance (6MWD), WHO functional class, and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations, until data cut-off. Pulmonary hemodynamics were measured by right heart catheterization. Cardiac output was measured at least 3 times by the thermodilution method and the mean value was calculated; however, if the investigator judged the use of the thermodilution method to be inappropriate, the indirect Fick method was permitted. The method chosen was used for measurement at both baseline and 16 weeks of evaluation. The pharmacokinetics endpoints were plasma concentration trends and pharmacokinetic parameters of selexipag and its active metabolite following multiple doses of selexipag for 7 days. The safety endpoints were adverse drug reactions (ADRs), side effects, vital signs, height, weight, laboratory values (blood and urine), and electrocardiogram.

Statistical Analysis

The success criterion of this study was set as an improvement in the mean change in PVRI of ≥1 Wood units·m² based on the results of the Phase 2 study of adult Japanese patients with PAH (AC-065A201 study).¹¹ Exploratory analysis was conducted on the patient population of the AC-065A201 study (IPAH/HPAH or CHD-PAH with at least one PAH drug). Patients were categorized into 2 subgroups with changes in PVRI from baseline to 16 weeks of treatment with selexipag of ≥1 and <1 Wood units·m², and all efficacy endpoints other than PVRI improved more in the subgroup with changes of ≥1 Wood units·m² than in the subgroup with changes of <1 Wood units·m². We considered that an improvement in PVRI by ≥1 Wood units·m² is clinically significant, and so specified the success criterion in the study as an improvement in the mean change in PVRI of ≥1 Wood units·m² based on the results of the exploratory analysis.

The mean (±SD) change in PVRI from baseline to 16 weeks of selexipag treatment in the specific patient population of the AC-065A201 study (IPAH/HPAH or CHD-PAH with at least one PAH drug) was −2.15±2.29 Wood units·m². The results of a Japanese Phase 2 study (AC-065B201) of selexipag in Japanese adult patients with chronic thromboembolic pulmonary hypertension,¹² which has pathological similarities to PAH, were also used for analysis (mean [±SD] change in PVRI −2.1±4.09 Wood units·m²). Hence, the mean (±SD) change in PVRI for the participants in this study was assumed to be −2±4.3 Wood units·m². Under this assumption, the sample size required for a 70% or greater probability of the mean being less than the success criterion −1 was calculated to be 6.

The primary endpoint, PVRI, and, among the secondary endpoints, other pulmonary hemodynamic measurements (mRAP, mPAP, cardiac index, PVR, TPR, and SvO₂), 6MWD, and NT-proBNP were calculated as changes from baseline (with 95% confidence intervals [CIs] in the full analysis set). The geometric mean (with 95% CIs) was also calculated for the after/before ratios (end of efficacy evaluation period/baseline) for PVRI and NT-proBNP. Regarding WHO functional class, “improved” was defined as an improvement from baseline by ≥1 class and “worsened” as a worsening from baseline by ≥1 class. The pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2 (Cetara, Princeton, NJ, USA). All other analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Patients

Seven patients for whom parental consent was provided were initially enrolled in 2020–2022; of these, 6 (3 males, 3 females) were finally enrolled and received selexipag. One of the original 7 patients did not meet the selection criteria during the screening period and was not treated with selexipag. All 6 participants who received selexipag completed the efficacy evaluation period and proceeded to the long-term treatment period. At data cut-off (52 weeks for the last participant), 5 participants were continuing selexipag treatment, 4 of whom had reached 64 weeks of treatment. One participant discontinued the study treatment because of non-compliance with the protocol, which made it difficult to continue the treatment.

The baseline demographic characteristics of the patients are presented in Table 1 and Supplementary Table 1. The mean age of patients was 9.2 years (minimum 3–maximum 13 years). The mean body weight was 35.25 kg (minimum 12.8–maximum 53.8 kg), and 2 patients were enrolled in each body weight category (i.e., ≥9–25, ≥25–50, and ≥50 kg). The mean duration of PAH was 0.99 years. The PAH classification was IPAH in 5 (83.3%) patients and CHD-PAH (postoperative PAH) in 1 (16.7%) patients. Three (50.0%) patients were concomitantly taking pulmonary vasodilators, and all patients were taking ERAs and PDE5 inhibitors. None of the patients received concomitant oxygen therapy. The mean PVRI at baseline was 17.96 Wood units·m². The WHO functional class at baseline was II or III, with no patients in WHO Class I or IV.

Table 1.

Patient Characteristics at Baseline (Full Analysis Set; n=6)

Age (years)
Mean±SD	9.2±4.0
Median (range)	10.0 (3–13)
Age group
2 to <6 years	1 (16.7)
6 to <12 years	3 (50.0)
12 to <15 years	2 (33.3)
Sex
Male	3 (50.0)
Female	3 (50.0)
Height (cm)
Mean±SD	134.58±25.72
Median (range)	137.35 (94.6–162.0)
Body weight (kg)
Mean±SD	35.25±18.01
Median (range)	38.00 (12.8–53.8)
Body weight group
9 to <25 kg	2 (33.3)
25 to <50 kg	2 (33.3)
≥50 kg	2 (33.3)
BMI (kg/m2)
Mean±SD	18.02±4.56
Median (range)	16.98 (13.6–25.0)
Time since diagnosis of PAHA (years)
Mean±SD	0.99±1.24
Median (range)	0.64 (0.0–3.1)
PAH classification
IPAH	5 (83.3)
CHD-PAH	1 (16.7)
Persisting/recurring/progressive ≥6 months after repair of CHD	1 (16.7)
PVRI (Wood units·m2)
Mean±SD	17.96±9.97
Median (range)	15.40 (9.52–37.50)
WHO functional class
II	5 (83.3)
III	1 (16.7)
Concomitant use of pulmonary vasodilators
Used	3 (50.0)
ERA+PDE5 inhibitor	3 (50.0)
None	3 (50.0)
Concomitant use of oxygen therapy
Used	0 (0.0)
None	6 (100.0)

Unless indicated otherwise, data are given as n (%). ^AThe time since the diagnosis of pulmonary arterial hypertension (PAH) was calculated as: (date of starting selexipag – date of diagnosis as PAH + 1) / 365.25. BMI, body mass index; CHD-PAH, pulmonary arterial hypertension associated with congenital heart disease; ERA, endothelin receptor agonist; IPAH, idiopathic pulmonary arterial hypertension; PDE5, phosphodiesterase 5; WHO, World Health Organization.

The treatment period and maintenance dose for individual patients are presented in Table 2. The maintenance dose reached the maximum dose for each body weight category in 3 of 6 patients. The other 3 patients could not be titrated to the maximum dose because of adverse events.

Table 2.

Selexipag Duration and Dosage for Each Subject

	Body weight (kg)
	9–25		≥25–50		≥50
Patient no.	1	2	3	4	5	6
Administration period (days)	930	512	365	783	780	316
Initial dose (mg/dose)	0.1	0.1	0.15	0.15	0.2	0.2
Maintenance doseA (mg/dose)	0.8	0.8	0.75	1.2	0.2	1.0

^ADose at the start of the maintenance period (12 weeks after administration).

Efficacy

Figure 2 shows changes in PVRI from baseline to 16 weeks, Table 3 presents changes in PVRI for each patient, and Table 4 presents a summary of changes in pulmonary hemodynamic variables. The mean (±SD) change in PVRI at rest from baseline to 16 weeks after selexipag administration was −5.55±6.88 Wood units·m² (95% CI −12.76, 1.67 Wood units·m²), achieving the success criterion in this study, namely an improvement in the mean change in PVRI by ≥1 Wood units·m². 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 up to 16 weeks after selexipag administration in individual patients ranged from −16.61 to 2.58 Wood units·m², and 5 of 6 patients demonstrated an improvement of ≥1 Wood units·m². Regarding variations in other pulmonary hemodynamic parameters, the mean (±SD) change from baseline to 16 weeks was −6.24±6.54 Wood units (95% CI −13.10, 0.63 Wood units) for PVR, −5.7±15.6 mmHg (95% CI −22.0, 10.7 mmHg) for mPAP, 0.46±0.47 L/min/m² (95% CI −0.03, 0.96 L/min/m²) for cardiac index, and −5.82±6.59 Wood units (95% CI −12.74, 1.10 Wood units) for TPR, indicating a trend towards improvement. In contrast, SvO₂ and mRAP did not demonstrate any improvement.

Figure 2.

Changes in the pulmonary vascular resistance index (PVRI) from baseline to 16 weeks. (A) Mean (±SD) PVRI at baseline and 16 weeks. (B) Geometric mean of PVRI at 16 weeks, expressed as a percentage of baseline. Error bars indicate 95% confidence intervals.

Table 3.

Change in the PVRI From Baseline to Week 16 for Each Subject

	Body weight (kg)
	9–25		≥25–50		≥50
Patient no.	1	2	3	4	5	6
PVRI (Wood units·m2)
Baseline	16.79	14.00	17.05	37.50	9.52	12.90
Endpoint	7.19	7.67	16.01	20.89	7.23	15.48
Change from baseline	−9.6	−6.33	−1.04	−16.61	−2.29	2.58

PVRI, pulmonary vascular resistance index.

Table 4.

Changes in Pulmonary Hemodynamic Variables (n=6; Full Analysis Set)

	Baseline	Endpoint	Change
PVRI (Wood units·m2)	17.96±9.97	12.41±5.85	−5.55±6.88 (−12.76, 1.67)
			69.4% (46.4%, 103.8%)A
PVR (Wood units)	17.52±8.78	11.29±4.30	−6.24±6.54 (−13.10, 0.63)
mPAP (mmHg)	55.2±18.6	49.5±18.0	−5.7±15.6 (−22.0, 10.7)
Cardiac index (L/min/m2)	2.90±0.75	3.36±0.68	0.46±0.47 (−0.03, 0.96)
TPR (Wood units)	19.77±9.39	13.95±4.68	−5.82±6.59 (−12.74, 1.10)
SvO2 (%)	67.87±5.97	67.27±10.36	−0.60±5.83 (−6.72, 5.52)
mRAP (mmHg)	6.0±4.5	6.3±4.2	0.3±1.2 (−0.9, 1.6)

Data are presented as mean±SD (95% confidence interval). ^AFor the pulmonary vascular resistance index (PVRI), changes are also expressed as a percentage of the baseline value and presented as the geometric mean (95% confidence interval). mPAP, mean pulmonary arterial pressure; mRAP, mean right atrial pressure; PVR, pulmonary vascular resistance; SvO₂, mixed venous oxygen saturation; TPR, total pulmonary resistance.

Table 5 presents changes in efficacy endpoints other than pulmonary hemodynamics from baseline to 64 weeks. The mean (±SD) change in 6MWD from baseline to 16 weeks was −2.0±66.8 m (95% CI −108.4, 104.4 m) in the 4 evaluable patients, showing little change. However, the mean (±SD) changes in 6MWD from baseline during the long-term treatment period were 35.8±60.0 m at 40 weeks (4 patients) and 11.0 m at 64 weeks (2 patients), showing a trend towards improvement. In the case of NT-proBNP, the mean (±SD) change from baseline to 16 weeks was −198.1±472.9 pg/mL (95% CI −694.3, 298.2 pg/mL), and the geometric mean of the after/before ratio (16 weeks/baseline) was 94.6% (95% CI 61.4%, 145.6%), showing a trend towards improvement. The mean (±SD) changes from baseline during the long-term treatment period were −741.4±1,989.4 pg/mL at 40 weeks (6 patients) and −1,232.6±2,528.0 pg/mL at 64 weeks (4 patients). At 16 weeks, WHO functional class had improved from baseline in 1 of 6 patients, and no patients had worsened. At 64 weeks, during the long-term treatment period, WHO functional class had improved from baseline in 2 of 4 patients, and no patients had worsened.

Table 5.

Changes in 6MWD, NT-proBNP, and WHO Functional Class From Baseline to Week 64 (Full Analysis Set)

		Baseline	Endpoint	Week 40	Week 64
6MWD (m)	n	4	4	4	2
		457.3±112.2	455.3±107.4	493.0±86.1	472.0
	Change	–	−2.0±66.8 (−108.4, 104.4)	35.8±60.0	11.0
NT-proBNP (pg/mL)	n	6	6	6	4
		975.4±2,104.7	777.3±1,633.5	234.0±164.2	172.8±59.5
	Change	–	−198.1±472.9 (−694.3, 298.2)	−741.4±1,989.4	−1,232.6±2,528.0
			94.6% (61.4%, 145.6)A
WHO functional class	n	6	6	6	4
		I: 0	I: 0	I: 0	I: 1
		II: 5	II: 6	II: 6	II: 3
		III: 1	III: 0	III: 0	III: 0
		IV: 0	IV: 0	IV: 0	IV: 0
	Change	–	Improved: 1	Improved: 1	Improved: 2
			Worsened: 0	Worsened: 0	Worsened: 0

Data are presented as mean±SD (95% confidence interval), unless stated otherwise. ^AFor NT-proBNP, changes are also expressed as a percentage of the baseline values and are shown as the geometric mean (95% confidence interval). 6MWD, 6-min walk distance; NT-proBNP, N-terminal pro B-type natriuretic peptide; WHO, World Health Organization.

The results of secondary endpoints for each patient are provided in Supplementary Tables 2 and 3.

Supplementary Table 4 presents the area under the curve up to 12 h after administration in steady state (AUC_τ,ss) and maximum serum concentration (C_max) of selexipag and its active metabolite. The mean(±SD) AUC_τ,ss and C_max of selexipag in 5 patients whose PVRI improved were 9.32±2.44 ng·h/mL and 2.97±1.28 ng/mL, respectively, and 31.4±14.8 ng·h/mL and 5.18±3.29 ng/mL, respectively, for the active metabolite. In contrast, the AUC_τ,ss and C_max of selexipag in the other patient whose PVRI did not improve were 4.57 ng·h/mL and 1.49 ng/mL, respectively, and 14.8 ng·h/mL and 2.39 ng/mL, respectively, for the active metabolite.

Safety

All ADRs (excluding those not related to selexipag) that occurred after selexipag administration and up to data cut-off are presented in Table 6. The ADRs that occurred in ≥2 patients were vomiting in 5 (83.3%), headache in 4 (66.7%), diarrhea in 3 (50.0%), and constipation, nausea, and pain in jaw in 2 (33.3%) each. Many of these reactions were consistent with those observed with other PGI₂ analogs or agonists, and most events resolved during selexipag treatment. The incidences of vomiting, headache, and nausea were high early in the treatment period. No ADRs occurred that showed an increase in incidence during the treatment period. No serious adverse events or adverse events led to discontinuation of treatment occurred.

Table 6.

Summary of ADRs Related to Selexipag Use in the Efficacy Evaluation and Long-Term Treatment Phases (Safety Analysis)

	No. patients with side effect (%)
All	6 (100.0)
Vomiting	5 (83.3)
Headache	4 (66.7)
Diarrhea	3 (50.0)
Pain in jaw	2 (33.3)
Nausea	2 (33.3)
Constipation	2 (33.3)
Abdominal discomfort	1 (16.7)
Abdominal pain	1 (16.7)
Discomfort	1 (16.7)
Malaise	1 (16.7)
Flushing	1 (16.7)
Hot flush	1 (16.7)

ADR, adverse drug reaction.

Blood pressure and pulse rate exhibited little variation, and no abnormal laboratory test values that could be considered a clinical problem were observed throughout the treatment period. One participant demonstrated an electrocardiogram change from no abnormal findings at baseline to abnormal findings during the treatment period and a right bundle branch block as an adverse event for which a causal relationship with selexipag was ruled out.

The details of the ADRs for each patient are provided in Supplementary Table 5.

Discussion

In this study, selexipag for pediatric patients with PAH achieved improvements in the prognostic factor PVRI and in risk classification by an important index for evaluating the severity/prognosis of pediatric PAH. We concluded that the administration of selexipag to pediatric patients with PAH is of clinical significance.

The change in resting PVRI at 16 weeks, the primary endpoint, was −5.55±6.88 Wood units·m², demonstrating a more than 2-fold improvement compared with the result of the AC-065A201 study of Japanese adult patients with PAH (−2.4±2.3 Wood units·m²).¹¹ Compared with the result of bosentan for pediatric patients with PAH (−300 dyn·s·m²/cm⁵; 95% CI −576, 24 dyn·s·m²/cm⁵),¹³ the present study showed similar or greater improvement. The geometric mean of the after/before ratio (16 weeks/baseline) also showed improvement similar to the change in PVRI. The PVRI of each subject at the end of the efficacy evaluation period was improved from baseline in 5 of 6 patients. Based on the pharmacokinetic results, it is possible that the patient whose PVRI did not improve had insufficient absorption and metabolism capacity compared with the other patients, and that the plasma concentrations of selexipag and its active metabolite were therefore less likely to rise. Moreover, PVR, mPAP, cardiac index, and TPR were improved from baseline. Although the small sample size makes it difficult to compare subgroups, greater efficacy was observed in patients without concomitant pulmonary vasodilators and a certain efficacy was observed in add-on patients. Moreover, a certain efficacy was observed with both PAH classifications in 1 patient with CHD-PAH and 5 patients with IPAH. Two of the patients with severe disease at baseline (Patients 3 and 4) had improved PVRI, whereas mPAP did not show significant improvement. It is possible that this was due to an increase in cardiac output resulting from improved cardiac function, which may have increased mPAP. There were no differences in efficacy by other subgroup classifications, such as age, sex, and body weight.

In the risk classification of pediatric PAH, Rosenzweig et al.⁶ defined cardiac index <2.5 L/min/m² as higher risk and >3.0 L/min/m² as lower risk. Regarding cardiac index in the present study, 2 of 6 patients who were at higher risk (cardiac index <2.5 L/min/m²) at baseline improved to >2.5 L/min/m² at 16 weeks. All 6 patients also showed improvement from baseline (Supplementary Table 2), with the mean (±SD) cardiac index increasing from 2.90±0.75 L/min/m² at baseline to 3.36±0.68 L/min/m² at 16 weeks, thereby improving to lower risk. Although it is difficult to accumulate cases of rare pediatric diseases in Japan alone, the study was able to enroll the target number of 6 cases and achieve the above results.

WHO functional class is commonly used as an index of severity based on the clinical symptoms of adult patients with PAH for prognostic prediction and treatment efficacy, and similar usefulness has been reported in pediatric patients with PAH.^3,14 This study revealed that WHO functional class in 2 of 6 patients improved and did not worsen, and that 1 of 2 patients markedly improved from the high-risk group (Class III) to the low-risk group (Class II) in the risk classification of pediatric PAH.¹ Two factors contributing to the lack of significant change in 6MWD from baseline to 16 weeks include the small number of patients (only 4) who performed the 6-min walk test and the large variability in age and body size, which were considered a limitation of the evaluation. The risk classification of pediatric PAH also defines 6MWD <350 m as higher risk and >350 m as lower risk.⁶ In the present study, all 4 patients had improved to lower risk at data cut-off (Supplementary Table 3). The mean change from baseline to 16 weeks for NT-proBNP revealed a trend towards improvement but varied widely; this result is explained by the large improvement in 1 patient. This is also supported by the fact that the geometric mean of the after/before ratio (16 weeks/baseline) with selexipag administration was 94.6% (95% CI 61.4%, 145.6%).

In terms of safety, although the incidence of prostacyclin-related adverse events was high, all events were non-serious and similar to the known safety profile of adult patients with PAH.^9,11 In this study, we used the newly developed 0.05-mg tablets for pediatric patients and the same formula as Uptravi tablets 0.2 mg. We determined the different doses for each body weight category (≥9–25, ≥25–50, and ≥50 kg). According to the dose setting, adverse events and their treatment showed no major differences after administration between pediatric and adult patients with PAH. Selexipag demonstrated good tolerability in pediatric patients with PAH and a similar known safety profile to that in adult patients with PAH. No serious adverse events occurred, and all events were of mild or moderate degree. Vomiting, headache, and nausea tended to occur more frequently in the early phase of treatment. No events were observed whose incidence increased with the duration of treatment. By dose at onset, only 2 cases of pain in jaw occurred at a high dose, both of which were mild and non-serious. There were no differences in the occurrence of ADRs by age, although patients who reached the maximum dose tended to be younger and to have a body weight <50 kg. Moreover, no adverse events associated with hypotension or thyroid dysfunction were observed.

This study has some limitations. Both the patients and the physicians knew the drug and its dosage because this was an open-label study. Compared with the objective parameter, the plasma NT-proBNP concentration, the possibility that subjective parameters, such as WHO functional class and 6MWD, were subject to bias cannot be ruled out. The patients were not compared to placebo or control groups in terms of efficacy or safety. The study included only 6 patients and was short-term, so that further long-term studies with a larger numbers of patients are warranted.

In the study, the results of pulmonary hemodynamics, exercise capacity, tolerability, and safety were quite similar to previous results for adult patients with PAH,⁹ supporting the use of selexipag as a treatment option for Japanese pediatric patients with PAH.

Acknowledgments

The authors thank the study group, investigators, study staff, and patients. The members of the study group are Atsuhito Takeda (Hokkaido University Hospital), Hidekazu Ishida (Osaka University Graduate School of Medicine), Hiroyuki Matsuura (Tokyo Shinagawa Hospital), Jun Maeda (Tokyo Metropolitan Children’s Medical Center), Jun Muneuchi (Japan Community Health Care Organization [JCHO] Kyushu Hospital), Kazushi Yasuda (Aichi Children’s Health and Medical Center), Keiichi Hirono (Toyama University Hospital), Kota Takei (Nagano Children’s Hospital), Shiro Baba (Kyoto University Hospital), and Susumu Hosokawa (Japanese Red Cross Musashino Hospital).

Sources of Funding

The Japanese Society of Pediatric Cardiology and Cardiac Surgery supported study planning, case enrollment and study promotion. The study was sponsored by Nippon Shinyaku Co., Ltd and Janssen Pharmaceutical K.K. Investigational products were provided by Nippon Shinyaku Co., Ltd. The sponsors were involved in the study design, data collection, statistical analysis, data interpretation, and medical writing.

Disclosures

Nippon Shinyaku Co., Ltd provided grants for the study group. K.K. received research funds from Nippon Shinyaku Co., Ltd and Janssen Pharmaceutical K.K. T.I., R.I., H.O., Y.S., H.Y., M.M., and S.Y. have no conflicts of interest to declare. C.H., N.S., S.T., and C.Y. are employees of Nippon Shinyaku Co., Ltd.

IRB Information

This study was approved by the Institutional Review Board of the National Cerebral and Cardiovascular Center, Osaka, Japan (Reference no. 1135), as well as institutional review boards at each study site.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0429

References

• 1.   Fukuda K, Date H, Doi S, Fukumoto Y, Fukushima N, Hatano M, et al. Guidelines for the treatment of pulmonary hypertension (JCS 2017/JPCPHS 2017). Circ J 2019; 83: 842–945.
• 2.   Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: A comparison between children and adults. Eur Respir J 2011; 37: 665–677.
• 3.   Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, et al. Pediatric pulmonary hypertension: Guidelines from the American Heart Association and American Thoracic Society. Circulation 2015; 132: 2037–2099.
• 4.   Hansmann G, Apitz C. Treatment of children with pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension: The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart 2016; 102(Suppl 2): ii67–ii85.
• 5.   Beghetti M, Gorenflo M, Ivy DD, Moledina S, Bonnet D. Treatment of pediatric pulmonary arterial hypertension: A focus on the NO-sGC-cGMP pathway. Pediatr Pulmonol 2019; 54: 1516–1526.
• 6.   Rosenzweig EB, Abman SH, Adatia I, Beghetti M, Bonnet D, Haworth S, et al. Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management. Eur Respir J 2019; 53: 1801916.
• 7.   Berger RM, Beghetti M, Humpl T, Raskob GE, Ivy DD, Jing ZC, et al. Clinical features of paediatric pulmonary hypertension: A registry study. Lancet 2012; 379: 537–546.
• 8.   Saji T. Update on pediatric pulmonary arterial hypertension: Differences and similarities to adult disease. Circ J 2013; 77: 2639–2650.
• 9.   Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015; 373: 2522–2533.
• 10.   Ivy DD, Abman SH, Barst RJ, Berger RM, Bonnet D, Fleming TR, et al. Pediatric pulmonary hypertension. J Am Coll Cardiol 2013; 62: D117-26.
• 11.   Tanabe N, Ikeda S, Tahara N, Fukuda K, Hatano M, Ito H, et al. Efficacy and safety of an orally administered selective prostacyclin receptor agonist, selexipag, in Japanese patients with pulmonary arterial hypertension. Circ J 2017; 81: 1360–1367.
• 12.   Tanabe N, Fukuda K, Matsubara H, Nakanishi N, Tahara N, Ikeda S, et al. Selexipag for chronic thromboembolic pulmonary hypertension in Japanese patients: A double-blind, randomized, placebo-controlled, multicenter phase II study. Circ J 2020; 84: 1866–1874.
• 13.   Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003; 73: 372–382.
• 14.   Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022; 43: 3618–3731.