Rolf M. F. Berger, D. Dunbar Ivy, Julian I. Borissoff, Sofija Cerovic, Dénes Csonka, Tatiana Remenová, Dominik Richard, Matthieu Villeneuve, Maurice Beghetti
Beatrix Children’s Hospital, University Medical Center Groningen and University of Groningen. Children’s Hospital Colorado. Johnson & Johnson. University Hospitals of Geneva.
Netherlands, United States and Switzerland
Journal of Pediatrics
J Pediatr 2026;
DOI: 10.1016/j.jpeds.2026.115057
Abstract
Objectives: To evaluate pharmacokinetics (PK), efficacy, and safety of macitentan vs standard of care (SoC) in pediatric pulmonary arterial hypertension (PAH).
Study design: TOMORROW was a multi-center, open-label, phase 3 clinical trial in patients aged ≥2-<18 years with WHO-FC I-III. Patients were randomized (1:1) to macitentan (bodyweight-based dosing) or SoC (≤2 PAH-specific therapies). The primary endpoint was steady-state Ctrough plasma concentration of macitentan and aprocitentan (active metabolite) at week 12. Secondary endpoints included: time-to-first clinical event committee (CEC)-confirmed disease progression, safety/tolerability, change in NT-proBNP, and quality of life (QoL).
Results: We randomized 148 patients (macitentan: n=73; SoC: n=75). The PK profile was consistent with adults; mean (SD) steady-state Ctrough concentrations were 185 (114.3) and 983 (324.1) ng/mL. Mean treatment duration was 183.36 weeks (macitentan) and 130.59 weeks (SoC). Hazard ratios (95% CI) for time-to-event analyses (macitentan vs SoC) were 0.828 (0.460-1.492) for disease progression, 0.912 (0.393-2.118) for PAH hospitalization and 1.530 (0.429-5.457) for PAH mortality (P>0.05 for all). Percentage of baseline NT-proBNP was 72% (macitentan) vs 101% (SoC) at week 12 (P=0.086) and 76% vs 78% at week 24 (P=0.884). Macitentan showed clinically meaningful improvements in QoL assessments vs SoC for children (P=0.043) and parents (P=0.020) at week 24. The safety profile of macitentan was consistent with that seen in adults.
Conclusions: TOMORROW was a novel study assessing PK and the long-term efficacy and safety of macitentan vs SoC in pediatric PAH. The results confirm the adequacy of the macitentan dosing in this population and provided signals of potential benefit of macitentan over SoC for children with PAH.
Category
Medical Therapy. Efficacy or Lack of Efficacy
Medical Therapy. Adverse Effects or Lack of Adverse Effects
Medical Therapy. Pharmacokinetics and Pharmacology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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