Pediatric pulmonary arterial hypertension is an uncommon but severe disorder characterized by progressive pulmonary vascular remodeling and reduced quality of life (QoL). Limited randomized evidence exists for pediatric-specific pharmacotherapies. The TOMORROW trial published in the Journal of Pediatrics evaluated pharmacokinetics (PK), clinical outcomes, and safety of macitentan compared with standard of care (SoC) in pediatric patients with PAH.
The multicenter, open-label phase 3 study included patients aged ≥2 to <18 years with World Health Organization functional class (WHO-FC) I-III PAH. Participants were randomized 1:1 to receive bodyweight-based macitentan dosing or SoC consisting of up to two PAH-specific therapies. The primary outcome assessed steady-state trough plasma concentrations (Ctrough) of macitentan and its active metabolite aprocitentan at week 12. Secondary endpoints included time to first clinical event committee-confirmed disease progression, safety and tolerability, changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), and QoL.
A total of 148 patients were randomized (macitentan n=73; SoC n=75). The PK profile was consistent with adult data, with mean (SD) steady-state Ctrough concentrations were 185 (114.3) ng/mL for macitentan and 983 (324.1) ng/mL for aprocitentan. Mean treatment duration was 183.36 weeks in the macitentan group and 130.59 weeks in the SoC group. Hazard ratios for disease progression (0.828), PAH hospitalization (0.912), and PAH mortality (1.530) were not statistically significant. NT-proBNP levels were 72% of baseline with macitentan versus 101% with SoC at week 12 (P = 0.086). Macitentan demonstrated improvements in QoL assessments at week 24 for children (P = 0.043) and parents (P = 0.020). The observed safety findings were consistent with those previously reported in adult populations.
Macitentan dosing achieved pharmacokinetic exposure comparable to adults in pediatric PAH. Clinical outcomes were generally comparable with SoC, with signals of improved quality-of-life measures observed.
