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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-term extension study, FUTURE-2, aimed to provide long-term tolerability, safety and exploratory efficacy data.Children (≥2 and12 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 2mg/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 PAH worsening and long-term survival. All analyses were conducted on pooled data of both studies.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.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.

The MELODY-1 study evaluated macitentan for pulmonary hypertension because of left heart disease (PH-LHD) in patients with combined post- and pre-capillary PH.63 patients with PH-LHD and diastolic pressure gradient ≥7 mmHg and pulmonary vascular resistance (PVR) >3WU were randomised to macitentan 10 mg (n=31) or placebo (n=32) for 12 weeks. The main end-point assessed a composite of significant fluid retention (weight gain ≥5% or ≥5 kg because of fluid overload or parenteral diuretic administration) or worsening in New York Heart Association functional class from baseline to end of treatment. Exploratory end-points included changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) and haemodynamics at week 12.Seven macitentan-treated and four placebo-treated patients experienced significant fluid retention/worsening functional class; treatment difference, 10.08% (95% CI −15.07–33.26; p=0.34). The difference, driven by the fluid retention component, was apparent within the first month. At week 12, versus placebo, the macitentan group showed no change in PVR, mean right atrial pressure or pulmonary arterial wedge pressure; a non-significant increase in cardiac index (treatment effect 0.4 (95% CI 0.1–0.7) L·min−1·m−2) and decrease in NT-proBNP (0.77 (0.55–1.08)) was observed. Adverse events and serious adverse events were numerically more frequent with macitentan versus placebo.Macitentan-treated patients were quantitatively more likely to experience significant fluid retention versus placebo. Macitentan resulted in no significant changes in any exploratory end-points.

Background: The randomized, double blind, phase 2 MELODY-1 study evaluated macitentan for pulmonary hypertension (PH) due to left heart disease in patients with combined post- and pre-capillary PH. Methods: Patients were randomized 1:1 to macitentan 10 mg (n=31) or placebo (n=32) for 12 weeks. The

In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary arterial hypertension (PAH). 43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-μg increments from 200 μg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 μg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results. A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7- -12.2; p=0.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect. Our results encourage the further investigation of selexipag for the treatment of PAH. Copyright©ERS 2012.