Background: A novel formulation of bosentan was evaluated in children with pulmonary arterial hypertension (PAH) in FUTURE-1, which characterized its pharmacokinetic and clinical proﬁle. The subsequent phase III, open-label, long-termextension study, FUTURE-2, aimed to provide long-termtolerability, safety and exploratory efﬁcacy data.
Methods: Children (≥2andb12 years) with idiopathic or heritable PAH, who completed 12-week treatment in FUTURE-1 and for whom bosentan was considered beneﬁcial were enrolled, and continued to receive bosentan 4 mg/kg twice-daily, which could be down-titrated to 2 mg/kg if not tolerated. Safety and tolerability were evaluated via treatment-emergent adverse events (AEs), serious AEs, growth, and laboratory measurements. Exploratory efﬁcacy endpoints included time to PAHworsening and long-termsurvival. All analyses were conducted on pooled data of both studies.
Results: 36 patients were enrolled in FUTURE-1 and 33 continued in FUTURE-2. The overall median duration of exposure to bosentan was 27.7 (range 1.9–59.6) months. Treatment-emergent AEs occurred in 32 (88.9%) patients; AEs considered treatment-related in 15 (41.7%) patients. Of 51 serious AEs, three were considered treatment-related: two incidences of reported PAH worsening and one of autoimmune hepatitis. Six deaths occurred; none were considered treatment-related. Kaplan–Meier event-free estimates of PAH worsening were 78.9% and 73.6% at 2 and 4 years, respectively.
Conclusions: The pediatric bosentan formulation was generally well tolerated, its safety proﬁle comparable to that of the adult formulation when used in children. The results are in line with the efﬁcacy proﬁle of bosentan in previous pediatric and adult PAH studies of shorter duration.