Use of OPSUMIT in Pediatric Patients With Pulmonary Arterial Hypertension

SUMMARY

• The safety and effectiveness of OPSUMIT in pediatric patients have not been established for the treatment of pulmonary arterial hypertension (PAH). An open-label randomized trial in pediatric patients (aged 2 to 17 years) did not demonstrate a clinical benefit of OPSUMIT compared with standard of care in the treatment of PAH.¹
• TOMORROW was a prospective, multicenter, open-label, randomized, controlled, parallel-group phase 3 study that enrolled 148 pediatric patients aged 2 to 17 years with PAH. The study included patients who were PAHspecific treatmentnaïve or receiving targeted monotherapy or double combination therapy, excluding macitentan and intravenous (IV)/subcutaneous (SC) prostanoids, with World Health Organization functional class (FC) I–III PAH.Patients were randomized to receive macitentan (n=73) or standard of care (SoC) (n=75).²
  • The primary endpoint assessed steady-state trough (pre-dose) plasma concentrations of macitentan and its active metabolite, aprocitentan, at week 12.²
  • Macitentan and aprocitentan exposure in the pediatric population was consistent with the known profile in adult patients.^2,3
  • Adverse events (AE) related to macitentan were reported in 15 (20.8%) patients. Additionally, 26 (36.1%) patients in the macitentan arm and 16 (21.3%) patients in the SoC arm experienced 1 or more serious AEs.²
• The phase 3 SERAPHIN and MAESTRO trials allowed inclusion of patients ≥12 years of age.^4,5
  • Analyses of the pediatric subgroup in the SERAPHIN study did not indicate any inconsistent or unexpected efficacy and safety outcomes compared with the overall SERAPHIN population. However, the number of pediatric patients is too small to form a conclusion about the efficacy and safety of macitentan in this population.^4,6
• A search of the scientific literature identified retrospective and prospective studies that evaluated the clinical efficacy and safety of macitentan.^7-11

CLINICAL DATA

Information From the TOMORROW Study

TOMORROW was a prospective, multicenter, open-label, randomized, controlled, parallel-group phase 3 study that enrolled 148 pediatric patients aged ≥1 month to <18 years with PAH. The study included PAHspecific treatmentnaïve patients or those receiving targeted monotherapy or double combination therapy, excluding macitentan and IV/SC prostanoids, with WHO FC I–III PAH (NCT02932410), and incorporated an ongoing singlearm extension period. In November 2021, the study protocol was amended to shift from an event-driven design to a fixed-duration study assessing pharmacokinetics (PK), safety, and efficacy due to recruitment difficulties and a low event rate. The primary aim of TOMORROW was to assess the PK of macitentan in pediatric patients and to provide additional information on efficacy and safety compared with the SoC.²

Data from the cohort of children aged ≥ 1 month to <2 years (n=9) who completed the randomized core period after February 23, 2024, are not presented. A total of 148 patients were randomized in a 1:1 ratio to receive macitentan (monotherapy or added to phosphodiesterase type-5 inhibitor [PDE-5i] therapy) or SoC. Macitentan was supplied as dispersible tablets and administered orally once daily. Dosing was adjusted by body weight based on population PK modeling, with daily doses of 3.5 mg for patients weighing 10 to <15 kg, 5.0 mg for 15 to <25 kg, 7.5 mg for 25 to <50 kg, and 10 mg for ≥50 kg. Among the 73 patients randomized to the macitentan arm, 72 received macitentan, while all 75 patients randomized in the comparator arm received SoC. Following a disease progression event, background treatment could be escalated in both arms, including the use of IV/SC prostanoids, with patients in the SoC arm having the option to cross over to the macitentan arm.²

Demographics and baseline characteristics for the study population are presented in Table: Demographics and Baseline Characteristics.²

The primary endpoint in TOMORROW assessed the steady-state trough (pre-dose) plasma concentrations of macitentan and its active metabolite, aprocitentan, at week 12.² Macitentan and aprocitentan exposure in the pediatric population was consistent with the known profile in adult patients.^2,3 For macitentan (n=47), the mean concentration was 185 ng/mL (standard deviation [SD] 114.3), with a median of 158 ng/mL (range 6.8-581). For aprocitentan (n=47), the mean concentration was 983 ng/mL (SD 324.1), with a median of 986 ng/mL (range 339-1660). Weight-based analyses are presented in Table: Trough Concentrations of Macitentan and Aprocitentan at Steady State.²

Secondary endpoints included time to first clinical events committee (CEC)-confirmed disease progression, hospitalization for PAH, and death due to PAH; time to all-cause death; WHO FC at weeks 12 and 24; N-terminal pro B-type natriuretic peptide (NT-proBNP) expressed as a percentage of baseline at weeks 12 and 24; and change from baseline to week 24 in health-related quality of life (HRQoL), along with an assessment of safety and tolerability.^2,12

The Kaplan-Meier (KM) curves indicated the following: CEC-confirmed disease progression hazard ratio (HR), 0.828 (95% confidence interval [CI], 0.46-1.492); hospitalization for PAH HR, 0.912 (95% CI, 0.393-2.118); death due to PAH HR, 1.53 (95% CI, 0.429-5.457); and all-cause death HR, 1.171 (95% CI, 0.392-3.5). None of these showed statistical significance.²

At week 12, the proportion of patients classified as WHO FC I/II was 88.7% (63/71) in the macitentan arm and 81.7% (58/71) in the SoC arm (odds ratio [OR], 4.635; 95% CI, 0.829-25.910). At week 24, the corresponding proportions were 90.0% (63/70) and 82.5% (52/63), respectively (OR, 6.415; 95% CI, 1.107-37.164). NT‑proBNP expressed as a percentage of baseline was 72% in the macitentan arm and 101% in the SoC arm at week 12 (P=0.086), and 76% and 78%, respectively, at week 24 (P=0.884).²

Between baseline and week 24, the least‑squares mean differences in Pediatric Quality of Life Inventory (PedsQL) scores were 5.28±2.570 for patient‑reported scores (P=0.043) and 6.27±2.666 for parent‑reported scores (P=0.020). Improvements in both parent- and patient-reported scores from baseline to the end of the randomized treatment period were numerically higher in the macitentan group.²

The safety profile was consistent with the known profile in adults.^1,2 Median (range) treatment duration was 168.43 (12.9-312.4) weeks in the macitentan arm and
115.00 (0.1-316.4) weeks in the SoC arm. Incidence of AEs was higher in the macitentan arm than in the SoC arm. Mean changes in clinical laboratory parameters were generally similar between treatment groups; however, hematologic abnormalities were reported more frequently with macitentan.² AEs reported within the macitentan and SoC arms in the safety analysis set are listed in Table: Safety Profile.²

Pediatric Patients Included in Trials for WHO Group I Pulmonary Hypertension

Information From the SERAPHIN Study

The safety and efficacy of OPSUMIT in the treatment of symptomatic PAH in patients aged ≥12 years was evaluated in a phase 3, randomized, placebo-controlled, event-driven study, SERAPHIN.⁴ Select exclusion criteria included patients <40 kg.¹³ Of the 742 patients in SERAPHIN, 20 patients (2.7%) aged 12-17 years were enrolled and equally distributed between the 3 treatment groups: 7 (2.8%) in the macitentan 3 mg group, 6 (2.5%) in the OPSUMIT group, and 7 (2.8%) in the placebo group.⁶

The median duration of exposure to macitentan among pediatric patients was 99.6 weeks and 98.7 weeks in the macitentan 3 mg and 10 mg groups, respectively. Of the 20 pediatric patients, 14 (70%) discontinued study treatment prematurely (85.7% in macitentan 3 mg, 50% in OPSUMIT, and 71.4% in placebo group), with disease progression as the main reason for treatment discontinuation.⁶

Baseline characteristics and duration of treatment for the pediatric subgroup are presented in Table: Baseline Characteristics and Mean Treatment Duration for the Pediatric Subgroup (12-17 Years) in the SERAPHIN Study.⁶

The primary endpoint in SERAPHIN was time from treatment initiation to first morbidity or mortality event in all randomized patients up to end of treatment (EOT).⁴ This composite endpoint was defined as death, atrial septostomy, lung transplantation, initiation of IV/SC prostanoids, or worsening of PAH (deterioration in 6minute walk distance [6MWD] and worsening of PAH symptoms and need for additional PAH treatment). Secondary endpoints included change from baseline to month 6 in 6MWD and WHO FC, death due to PAH or hospitalization for PAH up to EOT, and all-cause mortality up to EOT and end of study (EOS). Results of the primary and secondary endpoint analyses in the pediatric subgroup are summarized in Table: Summary of Efficacy Endpoint Analyses of the Pediatric Subgroup (12-17 Years) in the SERAPHIN Study.⁶

In the pediatric subgroup of SERAPHIN, worsening of PAH was the most frequently reported adverse event (n=4 in placebo, n=4 in macitentan 3 mg and n=1 in OPSUMIT group).⁶ Right ventricular failure was reported in 3 pediatric patients in the macitentan 3 mg group, 1 pediatric subject in the OPSUMIT group and no pediatric patients in the placebo group. Elevated liver transaminases (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] >3 × upper limit of normal (ULN) and total bilirubin >2 × ULN), irrespective of temporal relationship, were reported in 1 pediatric subject in the OPSUMIT group. In this subject, liver enzyme elevations were secondary to ischemic hepatitis combined with hepatitis B. None of the pediatric patients presented with a hemoglobin value below 10 g/dL.⁶

These data are limited to a very small number of patients. Although there were no unexpected or inconsistent efficacy or safety outcomes in these patients compared to the overall SERAPHIN population, these data cannot be used to form any conclusions about the efficacy and safety of macitentan in pediatric patients.⁶

Information From the MAESTRO Study

MAESTRO was a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group, study to evaluate the effects of macitentan on exercise capacity (change in 6MWD from baseline to week 16) in patients with Eisenmenger Syndrome. This study included patients aged ≥12 years. A total of 226 patients were randomized in a 1:1 ratio to receive either once daily OPSUMIT (n=114) or placebo (n=112). MAESTRO did not meet its primary endpoint. Among the patients enrolled in MAESTRO, 15 (6.6%) were aged 12-17 years, 13 of whom were in the OPSUMIT group and 2 of whom were in the placebo group. A separate analysis specific to the pediatric subject subgroup has not been performed.⁵

Information From a Literature Search

Hutter and Pfammatter (2016)⁷ conducted a retrospective analysis of 11 pediatric patients with PAH (age 3.1±7.8 years) who were treated with OPSUMIT daily for a duration of 11.8±10.5 months. Enrolled newborns and young children (9 males, 2 females) were hospitalized for initiation of therapy. A total of 4 patients were switched from sildenafil, and 3 patients were switched from bosentan. There was 1 death due to a co-morbid genetic disorder, and 1 patient successfully discontinued treatment after 1 year. No safety concerns were reported.

Aypar et al (2020)⁸ conducted a single-center, 24-month prospective study aimed to evaluate the clinical efficacy and safety of the switch from bosentan to macitentan. Twenty-seven patients (10 male and 17 female) were included in the study. Mean age was 21.1±6.3 years (12-36), and weight was 53.1±15.7 kg (26-87). Eight patients (30%) were <18 years old. Macitentan significantly improved 6MWD from baseline (mean: 458±79 m [300-620]) at 6 months (mean: 501±73 m [325-616] +43 m; P<0.05), at 12 months (mean: 514±82 m [330-626] +56 m; P<0.05), and at 24 months (mean: 532±85 m [330-682] +74 m; P<0.05). Although a statistically significant improvement in 6MWD during the first 6 months was observed, an incremental improvement after 6 months was not observed (P>0.05). Macitentan did not significantly change WHO FC, oxygen saturation, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels (P>0.05). None of the patients experienced anemia, hepatotoxicity, or peripheral edema.

Schweintzger et al (2020)⁹ conducted a single-center, prospective observational study to assess the efficacy and safety of macitentan in pediatric pulmonary hypertension patients. Eighteen patients (10 male and 8 female) with a median age of 8.5 years were included in the study. Nine children were switched from bosentan to macitentan. Macitentan was associated with improvement in the ratio of mPAP to mean systemic arterial pressure with a decrease from a median 62% (min: 30%, max: 87%) to 49% (min: 30%, max: 69%). Additionally, pulmonary vascular resistance index decreased from a median of 7.6 WU·m² (min: 3.3, max: 11.5) to 4.8 WU·m² (min: 2.5, max: 10, P<0.05). 6MWD and New York Heart Association (NYHA) FC did not change significantly. There were no incidents of anemia, peripheral edema or increases in ALT, AST, gamma-glutamyl transferase or bilirubin in the pediatric cohort.

Albinni et al (2023)¹⁰ conducted a single-center, prospective, observational study to assess the mid- and long-term effects of macitentan in children with advanced pulmonary hypertensive vascular disease. Starting doses were administered as a single daily dose and were titrated to target doses, based on body weight. Twenty-four patients (14 males and 10 females), with a mean age of 10.7±7.6 years and a median observation period of 36 months, were enrolled. Macitentan was initiated as monotherapy in 6 patients, dual therapy in 10 patients, and triple therapy in 8 patients. Two patients discontinued the study due to symptomatic peripheral edema in the first 2 weeks after macitentan initiation. A subgroup analysis was also conducted based on patients with (n=10) and without (n=12) PAH-associated with congenital heart disease (PAH-CHD). Within the entire cohort, brain natriuretic peptide (BNP) levels and all echo parameters (right ventricular systolic pressure [RVSP], right ventricular end-diastolic diameter [RVED], TAPSE, pulmonary velocity time integral [VTI], and pulmonary artery acceleration time [PAAT]) improved significantly after 3 months (P≤0.01), whereas at 12 months, significant improvements (P<0.05) persisted only for BNP levels (-16%), VTI (+14%), and PAAT (+11%). On subgroup analysis, patients without PAH-CHD showed significant improvements in BNP levels and all echo parameters at 3 months, whereas at 12 months, significant improvements persisted in all, excluding RVSP and RVED. No significant changes were observed in patients with PAH-CHD at 3 and 12 months.

Ogando et al (2025)¹¹ conducted a multi-center, observational study to assess the efficacy and safety of macitentan in pediatric patients with PAH using the Spanish Registry of pediatric pulmonary hypertension (REHIPED). Seventy-four patients (40 males and 34 females), with a median age of 9.6 years (range, 2.5 months-17.2 years), were enrolled. Macitentan was administered as add-on and switch therapies in 18 and 56 patients, respectively, according to their body weight (<10 kg, 0.3 mg/kg; 10-15 kg, 3.5 mg; 15-25 kg, 5 mg; 25-50 kg, 7.5 mg; >50 kg, 10 mg), and starting at the target dose. The median macitentan dose was 0.28 mg/kg (min-max, 0.07-1.52). After 6 months of macitentan treatment, 22% of patients shifted from WHO FC III/IV to WHO FC II/III, and WHO FC III/IV rates decreased from 48% to 22% (P=0.001), with similar improvements in add-on and switch groups; mean 6MWD (n=42) increased from 403.1±119.4 m to 447.6±103.5 m (P=0.032); mean NT‐proBNP levels decreased from 959.6±1634 pg/ml to 520.79±876 pg/ml (P=0.015). The proportion of patients who fulfilled the 3 low risk criteria for pulmonary hypertension (PH; WHO FC I-II, TAPSE ≥12, and NTproBNP ≤300) increased by 17% (P=0.002). Four patients (5.4%) reported side effects with macitentan during follow-up; 1 had nasopharyngitis, 1 had headaches, and 2 had elevated liver enzymes (1 had mild and transient increase in liver enzymes with an acute viral infection and the other showed increased AST and ALT levels from 33/50 U/L to 381/707 U/L for which macitentan was discontinued after 3 months). Six patients experienced clinical worsening due to disease progression; 4 were started on IV/SC prostanoids, 1 underwent atrial septostomy, and 1 with CHD required lung transplantation. No deaths were reported.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 January 2026.