SUMMARY

• The phase 3 SERAPHIN and MAESTRO trials allowed inclusion of patients ≥12 years of age.^1,2
• Analyses of the pediatric subgroup in the SERAPHIN study did not indicate any inconsistent or unexpected efficacy and safety outcomes compared to 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.^1,3
• The ongoing phase 3 study, TOMORROW, will evaluate the effect of macitentan on delaying disease progression in children with pulmonary arterial hypertension (PAH) using a pediatric formulation.⁴
• A search of the scientific literature identified retrospective and prospective studies that evaluated the clinical efficacy and safety of macitentan.^5-9

CLINICAL DATA

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.¹ Select exclusion criteria included patients <40 kg.¹⁰ 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.³

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.³ 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.

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.³

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).¹ This composite endpoint was defined as death, atrial septostomy, lung transplantation, initiation of intravenous (IV) or subcutaneous (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 World Health Organization (WHO) functional class (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.³

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).³ 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.

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.

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 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). The primary endpoint was change from baseline to week 16 in exercise capacity, as measured by 6MWD. MAESTRO did not meet its primary objective. After 16 weeks of treatment, the mean change in 6MWD from baseline was an increase of 18.3 m in the OPSUMIT group and 19.7 m in the placebo group.²

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.²

Ongoing Clinical Studies

TOMORROW is a multicenter, open-label, randomized, event-driven study to assess the efficacy, safety, and pharmacokinetics of macitentan versus standard of care in delaying disease progression in children with PAH. The study plans to enroll children aged 1 month to 17 years.⁴

The primary outcome of this study is observed steady-state trough plasma concentration of macitentan and its active metabolite (ACT-132577) at week 4 for patients <2 years and week 12 for patients ≥2 years.

Secondary outcomes include the following:

• Time to first Clinical Event Committee (CEC)-confirmed disease progression event and hospitalization for PAH, time to CEC-confirmed death due to PAH, and time to death (all causes) occurring between randomization/visit 2 and end of core study period (EOCP; up to 7 years).
• Percentage of patients with WHO FC I or II vs III or IV at week 24.
• Changes in N-terminal pro-B-type natriuretic peptide (NTproBNP), tricuspid annular plane systolic excursion (TAPSE; measured by echocardiography), left ventricular eccentricity index (LVEI; measured by echocardiography), and pediatric quality of life inventory version 4.0 (PedsQL 4.0) generic core scales short form (SF-15) from baseline to week 24.
• Change in moderate to vigorous physical activity (measured by accelerometry) from baseline to week 48.

Patients will be randomized in a 1:1 ratio in 2 treatment groups, with oral macitentan versus standard of care as per each site's clinical practice which may comprise treatment with PAH non-specific treatment and/or up to 2 PAH-specific medications excluding macitentan and IV/SC prostanoids.

For additional information, including inclusion and exclusion criteria, please visit https://clinicaltrials.gov (identifier NCT02932410).

The pediatric formulation of macitentan is a round dispersible tablet that is neutral in taste. It will be available in 3 different dose strengths, containing 0.5 mg, 2.5 mg and 5.0 mg macitentan. To make them easier for children to swallow, the tablets are dispersible in water on a spoon.

Information From a Literature Search

Hutter and Pfammatter⁵ 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. In addition, 10 patients received concomitant treatment with diuretics and/or ACE inhibitors. 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 al⁶ conducted a 24-week, prospective, observational study looking at the clinical efficacy and safety of switching from bosentan to macitentan pediatric patients with PAH. Thirteen patients completed the study, the mean age was 20.3±6.5 years (12-35), and body weight was 54.0±14.5 kg (27-75). Eleven patients were in WHO FC II, 2 patients were in WHO FC III, and 5 patients were ≤18 years of age. Six patients were on monotherapy with bosentan while 7 patients were on combination therapy with bosentan. After screening, the patients were switched from bosentan to macitentan 10 mg daily. Macitentan improved 6MWD from baseline (mean: 466±35 m), at 12 weeks (mean: 494±78 m; +28 m; P<0.05), and at 24 weeks (mean: 507±58 m; +41 m; P<0.05). There was no significant change in resting oxygen saturation levels, oxygen saturation levels after 6MWD, brain natriuretic peptide, and systolic pulmonary arterial pressure. No patients had adverse events.

Aypar et al⁷ conducted a single-center, 24-month prospective study aimed to evaluate the clinical efficacy and safety of the switch from bosentan to macitentan in a larger patient population. 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 children (<18 years). Seventeen patients (63%) had Eisenmenger syndrome and/or PAH associated with congenital heart disease (PAH-CHD), 4 patients (22%) had residual PAH due to repaired congenital systemic-to-pulmonary shunts, 3 patients (11%) had idiopathic PAH (IPAH), 1 patient (4%) had PAH related to glycogen storage disease, 1 patient (4%) with unguarded tricuspid valve had PAH after Fontan surgery, and 1 patient (4%) had PAH related to complex CHD. 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 al⁸ conducted a single-center, prospective observational study to assess the efficacy and safety of oral 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-glutamyltransferase or bilirubin in the pediatric cohort.

Albinni et al⁹ 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 male and 10 female), 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-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 (-57%) and all echo parameters (TAPSE +21%, VTI +13%, PAAT +37%, RVSP -24%, RVED -12%) at 3 months (P≤0.01), whereas at 12 months, significant improvements (P<0.05) persisted in all, excluding RVSP and RVED. No significant changes were observed in patients with PAH-CHD at 3 and 12 months.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 19 March 2024.