Macitentan in Pediatric PAH: TOMORROW Randomized Trial

Key Takeaways

• TOMORROW was a randomized phase 3 pediatric pulmonary arterial hypertension trial comparing bodyweight-based macitentan with standard of care.
• Adult-consistent pharmacokinetic exposure was observed, time-to-event analyses were not statistically significant, and quality-of-life scores improved at week 24.
• Safety was consistent with adults, and the investigators concluded that dosing appeared adequate with indications of possible benefit.

In the randomized pediatric TOMORROW trial, 148 patients aged 2 to younger than 18 years were assigned 1:1 to bodyweight-based macitentan or standard of care. Pharmacokinetic exposure aligned with adult levels, and week-24 quality-of-life results favored macitentan for children and parents. Time-to-event analyses were not statistically significant, and safety was consistent with adult experience. The comparison centered on exposure, long-term clinical events, biomarkers, and quality-of-life change in a pediatric population. The investigators concluded that bodyweight-based dosing appeared adequate in this population and that the findings suggested possible benefit without establishing efficacy.

TOMORROW was a multicenter, open-label, phase 3 clinical trial in patients aged 2 to younger than 18 years with WHO functional class I to III pulmonary arterial hypertension. Participants were randomized 1:1 to bodyweight-based macitentan or standard of care, which could include up to two PAH-specific therapies. Seventy-three patients entered the macitentan group and 75 entered standard of care. The primary endpoint was steady-state Ctrough plasma concentration of macitentan and aprocitentan at week 12. Secondary endpoints included time to first clinical event committee-confirmed disease progression, safety and tolerability, change in NT-proBNP, and quality of life.

At steady state, mean trough concentrations were 185 (114.3) ng/mL for macitentan and 983 (324.1) ng/mL for aprocitentan, described as adult-consistent exposure. Hazard ratios were 0.828 for disease progression, 0.912 for pulmonary arterial hypertension hospitalization, and 1.530 for pulmonary arterial hypertension mortality, with all P values above .05. Corresponding 95% confidence intervals were 0.460 to 1.492, 0.393 to 2.118, and 0.429 to 5.457, respectively. NT-proBNP was 72% versus 101% of baseline at week 12 and 76% versus 78% at week 24, with P values of .086 and .884. Quality-of-life assessments showed clinically meaningful week-24 improvements with macitentan versus standard of care in children and parents, with P values of .043 and .020.

Safety with macitentan was consistent with the adult profile, and specific adverse events were not listed. Mean treatment duration was 183.36 weeks in the macitentan group and 130.59 weeks in the standard-of-care group. Observation extended well beyond the initial week-12 pharmacokinetic endpoint in both groups.

The authors concluded that these results confirmed dosing adequacy in this pediatric population and suggested possible benefit over standard of care.