Weight-Based Macitentan Matches Adult Exposure in Children With PAH

Key Takeaways

• In children aged 2 to <18 years with pulmonary arterial hypertension (PAH), weight-based macitentan dosing produced steady-state trough concentrations consistent with those in adults.
• Disease progression, PAH hospitalization, and death did not differ significantly between macitentan and standard of care (SoC).
• Patient- and parent-reported quality of life improved more with macitentan at week 24.
• Anemia was more common with macitentan (15.3% vs 2.7%).

Few rigorously controlled trials have evaluated PAH therapies in children, and many adult-approved agents are used off-label without pediatric formulations. Regulators allow adult efficacy data to be extrapolated to children when pharmacokinetics, disease course, and treatment response are sufficiently similar. That makes pediatric dosing and safety data essential.

Investigators conducted the open-label, randomized phase 3 TOMORROW trial at more than 50 pediatric centers in 19 countries. It enrolled 148 patients aged 2 to <18 years with WHO functional class I–III PAH; 73 were assigned to macitentan and 75 to SoC. Most patients were in functional class I or II, and nearly half had idiopathic PAH. Macitentan was given once daily as a dispersible tablet, dosed by body weight from 3.5 mg to 10 mg. SoC followed each site’s practice and allowed up to 2 PAH-specific therapies, excluding macitentan and intravenous or subcutaneous prostanoids. The primary endpoint was the trough plasma concentration at week 12 of macitentan and of aprocitentan, its active metabolite. Because recruitment was difficult and events were few, a 2021 protocol amendment changed the trial from an event-driven design to a fixed-duration study. It was not powered for efficacy.

At week 12, mean trough concentrations were 185 ng/mL for macitentan and 983 ng/mL for aprocitentan. Both were consistent with levels in adults receiving 10 mg. A first confirmed disease progression event occurred in 28.8% of the macitentan group vs 32.0% of the SoC group (hazard ratio 0.828; 95% confidence interval [CI] 0.460–1.492). Hazard ratios were 0.912 for PAH hospitalization and 1.530 for death due to PAH, neither statistically significant. At week 24, 90.0% vs 82.5% of patients were in functional class I/II. NT-proBNP fell to 72% of baseline with macitentan vs 101% with SoC at week 12 (P = .086), and the groups were similar at week 24. The PedsQL quality-of-life score improved more with macitentan, by 5.28 points on patient report (P = .043) and 6.27 points on parent report (P = .020). Both differences exceeded the approximately 4.5-point minimal clinically important difference.

Median treatment duration was 168 weeks with macitentan vs 115 weeks with SoC. Adverse events occurred in 93.1% vs 68.0% of patients, and serious adverse events in 36.1% vs 21.3%. When disease progression events were included and rates were adjusted for exposure, incidence was similar between the groups. There were 7 deaths with macitentan and 6 with SoC, and none were attributed to macitentan.

The open-label design may have influenced patient-reported outcomes and adverse event reporting. The trial was small and included patients with diverse PAH etiologies. Johnson & Johnson sponsored the study, and several authors are company employees. Following these results, macitentan was approved for pediatric PAH in the EU, UK, and Australia.

The authors concluded that the trial confirmed appropriate macitentan dosing in children and showed signals of potential benefit over SoC.