Macitentan in Pediatric PAH: Results from the TOMORROW Trial

Treating pediatric pulmonary arterial hypertension (PAH) is challenging, with few therapies supported by randomized clinical trial data despite widespread off-label use. The phase 3 TOMORROW trial, however, published in The Journal of Pediatrics, evaluated the pharmacokinetics, safety, and clinical outcomes of macitentan—a dual endothelin receptor antagonist approved for adult PAH—in children with the disease. Here’s a brief look at what it found.

A Trial Built for Rare Disease

TOMORROW was a multicenter, open-label, randomized phase 3 trial conducted across more than 50 pediatric centers in 19 countries. The study enrolled 148 children aged 2 to <18 years with World Health Organization (WHO) functional class I-III PAH, who were randomized 1:1 to receive weight-based once-daily macitentan or physician-directed standard of care (SoC), consisting of up to two PAH-specific therapies. Recruitment challenges and the low number of clinical events, common obstacles in rare pediatric diseases, prompted a protocol amendment that shifted the primary endpoint from an event-driven outcome to pharmacokinetic assessment at week 12, with efficacy and safety evaluated as secondary endpoints.

The primary objective was achieved. Steady-state plasma concentrations of macitentan and its active metabolite, aprocitentan, were consistent with exposure previously observed in adults receiving macitentan 10 mg, supporting the body weight-based dosing regimen used in children.

Signals Without Statistical Separation

Because the study was not powered to detect statistically significant differences in clinical outcomes, efficacy results should be interpreted as exploratory.

Disease progression occurred in 21 patients (28.8%) receiving macitentan and 24 patients (32.0%) receiving SoC, corresponding to an adjusted hazard ratio of 0.83 (95% CI, 0.46-1.49; P=.567). Rates of PAH hospitalization and mortality were also similar between treatment groups, with no statistically significant differences observed.

Several secondary outcomes showed numerical trends favoring macitentan. At week 12, NT-proBNP decreased to 72% of baseline in the macitentan group compared with 101% in the SoC group, although the difference was not statistically significant (P=.086). By week 24, NT-proBNP levels were comparable between groups. A greater proportion of patients receiving macitentan were classified as WHO functional class I or II at both 12 and 24 weeks, although these analyses were also exploratory.

Health-related quality of life differed between treatment groups. At week 24, improvements in Pediatric Quality of Life Inventory (PedsQL) scores reported by both children and parents were significantly greater with macitentan than with SoC, exceeding the established minimal clinically important difference of approximately 4.5 points.

Safety Mirrors Adult Experience

The safety profile was generally consistent with previous adult studies of macitentan. Most adverse events were mild or moderate in severity, and when adjusted for treatment exposure, overall rates of adverse events and disease progression were similar between groups despite longer treatment duration in the macitentan arm.

Anemia was the most common adverse event of special interest, occurring in 15.3% of patients receiving macitentan compared with 2.7% receiving SoC. Two patients experienced alanine aminotransferase elevations greater than eight times the upper limit of normal, leading to treatment discontinuation per protocol. Seven deaths occurred in the macitentan group and six in the SoC group, none of which investigators considered treatment related. Given the small number of events, the trial was not designed to draw conclusions regarding mortality.

What This Means for Practice

The TOMORROW trial represents one of the largest randomized studies conducted in pediatric PAH and provides evidence supporting the pharmacokinetic rationale for weight-based macitentan dosing in children. Although the study did not demonstrate statistically significant differences in clinical efficacy compared with physician-directed standard care, the observed trends in functional status, NT-proBNP, and quality of life, together with a safety profile consistent with adult experience, contribute to the limited randomized evidence available for pediatric PAH management. These findings may help inform treatment decisions while highlighting the ongoing challenges of conducting adequately powered clinical trials in rare pediatric diseases.

Reference:

Berger RMF, Ivy DD, Borissoff JI, et al. Macitentan in Pediatric Pulmonary Arterial Hypertension (TOMORROW): A Randomized Clinical Trial.J Pediatr. 2026;293:115057. doi:10.1016/j.jpeds.2026.115057.