TRACLEER - Use in Pediatrics With PAH or Newborns With PPHN

SUMMARY

• BREATHE-3 was an open-label, prospective, non-controlled, single- and multiple-dose study to investigate the pharmacokinetics (PK) of bosentan in pediatric patients aged 315 years with pulmonary arterial hypertension (PAH). Bosentan was associated with significant improvements in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRI), however the improvement in cardiac index did not reach significance. The most frequent adverse events (AEs) were flushing, headache, edema, and elevated transaminase activity.¹
• FUTURE-1 was an open-label, multicenter, single-arm, non-controlled, prospective study to assess whether at a selected dose, the exposure to bosentan in pediatric patients ages ≥2 and <12 years with idiopathic PAH (IPAH) or heritable PAH (HPAH) was similar to adults with PAH. The ratio of the geometric means for the area under the plasma concentration-time curve (AUC_t) between pediatric and adult patients was 0.54 (95% confidence interval [CI], 0.37-0.78), indicating that children had lower exposure to bosentan than adults. The most frequent (frequency >5%) AEs were abdominal pain, vomiting, upper abdominal pain, aggression, asthenia, bronchitis, chest pain, fatigue, flushing, headache, nasal congestion, pain in extremity, pulmonary hypertension, tonsillitis, and viral infection.²
• FUTURE-2 was a phase 3, open-label, long-term extension study of FUTURE-1.³ Results of the study are summarized below.
• FUTURE-3 was an open-label, prospective, randomized, multicenter, multiple-dose, phase 3 study investigating whether increasing the TRACLEER dosing frequency from 2 mg/kg twice daily (BID) to 2 mg/kg three times daily (TID) in children with PAH (≥3 months to <12 years of age) would increase exposure. The geometric mean (95% CI) for AUC_0-24C was 8535 h⋅ng/mL (6936-10,504) and 7275 h⋅ng/mL (5468-9679) for 2 mg/kg BID and TID, respectively (geometric mean ratio [95% CI] 0.85 [0.61-1.20]). The proportions of patients who experienced ≥1 AE were similar in the BID and TID groups and were comparable across age groups.⁴ Fifty-eight patients who completed the end-of-study visit and were still receiving TRACLEER at week 24 of the core study were eligible for participation in the 48-week extension study. Results of the extension study are summarized below.⁵
• FUTURE-4 was a phase 3, multicenter, double-blind, placebo-controlled, randomized, prospective study to investigate TRACLEER as adjunctive therapy to inhaled nitric oxide in the management of persistent pulmonary hypertension of the newborn (PPHN) in neonates >34 weeks gestation and <7 days of age. This study has been terminated due to slow recruitment. Available results are summarized below.⁶
• A brief summary of published studies (N>50),^7-11 safety analyses,^12,13 and published studies (N<50)^14,15 in pediatrics and neonates are presented below.
• Additional case reports are included as citations in the REFERENCES section.^16-23
• Please refer to your local labeling for the approved use of TRACLEER.

CLINICAL DATA

Clinical Trials

BREATHE-3

Design

Open-label, prospective, non-controlled, single- and multiple-dose study conducted over 12 weeks at 2 centers in the United States. A total of 19 patients, aged 3-15 years with IPAH or PAH related to congenital heart disease in WHO functional class (FC) II or III were stratified by weight and epoprostenol use to receive bosentan. The primary objective of this study was to investigate the PK of bosentan in pediatric patients with PAH. Exploratory measures included the efficacy, safety, and tolerability of bosentan in these patients.¹

Dosing

BREATHE-3 utilized the available adult formulation of bosentan as the study drug. Patients weighing 10-20 kg, 20-40 kg, or >40 kg received bosentan 31.25 mg daily, 31.25 mg BID, or 62.5 mg BID, respectively for the first 4 weeks. The dose was then up titrated to the target dose (31.25 mg, 62.5 mg BID, or 125 mg BID) for the remainder of the study.

In this study, the 31.25 mg dose was obtained by cutting a 62.5 mg tablet into 2 halves using a tablet cutter provided with the study medication. The protocol recommended that the cutting of the tablets be performed only on the day of use.¹

Outcome

Bosentan showed a PK profile similar to that in healthy adults. Concomitant administration of epoprostenol, body weight, gender, and age, had no significant effect on the PK of bosentan. Bosentan was associated with significant improvements in mPAP and PVRI, however the improvement in cardiac index did not reach significance. At week 12, mPAP decreased by 8.0 mmHg (95% CI, -12.2 to -3.7 mmHg; P<0.05), and PVRI decreased by 300 dyn⋅s⋅m²/cm⁵ (95% CI, -576 to -24; P<0.05). Further evaluation of hemodynamic parameters noted no statistically significant differences in patients who received concomitant epoprostenol compared to bosentan alone. There was no significant difference from baseline to week 12 in the exercise capacity of pediatric patients aged ≥8 years (n=12) in terms of peak oxygen consumption or mean walk distance. By week 12, 5 of 18 patients who completed the study had improved by one WHO FC (3 from FC III to II and 2 from FC II to I), with only 1 child deteriorating from FC II to III.¹

Safety

The most frequent AEs were flushing (21%, n=4), headache, edema, and elevated transaminase activity (16%, n=3 in each). Small decreases in systemic blood pressure were also observed at week 12, although symptomatic hypotension was not observed in any patient. Two patients had serious AEs: tachycardia, systemic hypertension, tremor and dizziness in 1 patient and a marked increase in alanine aminotransferase (ALT) level in another patient who was subsequently diagnosed with ulcerative colitis and associated sclerosing cholangitis. In another patient, elevated ALT levels (>3 × upper limit of normal [ULN]) was observed at week 12, which resolved after discontinuation of bosentan. There was no evidence of drug-drug interactions with concomitant epoprostenol and no deaths were reported.¹

FUTURE-1

Design

Open-label, multicenter, single-arm, non-controlled, prospective study conducted over 12 weeks at 11 centers in 7 countries. A total of 36 pediatric patients ≥2 and <12 years old with IPAH or HPAH in WHO FC II or III. The primary objective of this study was to demonstrate that, at a selected dose, the exposure to bosentan in pediatric patients with IPAH or HPAH was similar to adults with PAH (historical control). In addition, the efficacy, safety, and tolerability of the pediatric formulation were explored.²

Dosing

Patients with a body weight <30 kg were treated for 4 weeks with 2 mg/kg BID of the pediatric formulation of bosentan, then up titrated to the maintenance dose of 4 mg/kg BID for the remainder of the study. Patients with a body weight ≥30 kg received 64 mg BID of the pediatric formulation of bosentan for 4 weeks and then 120 mg BID as the maintenance dose. The oral, dispersible, pediatric formulation of bosentan utilized in FUTURE-1 is not available in the United States.²

Outcome

The ratio of the geometric means for the AUC_t between pediatric and adult patients was 0.54 (95% CI, 0.37 to 0.78), indicating that children had lower exposure to bosentan than adults. Bosentan exposure was similar in patients receiving either bosentan 2 or 4 mg/kg BID. Similar to BREATHE-3, age, gender, FC, background epoprostenol therapy, or previous exposure to bosentan had no effect on the PK of bosentan. Exploratory efficacy using WHO FC and quality-of-life analyses indicated that most patients remained unchanged from baseline to end of study. Improvements in WHO FC occurred mainly in bosentan-naïve patients (2/23 patients improved from FC II to I; 3/12 from FC III to II; 20/23 remained stable at FC II and 9/12 at FC III). Rare worsening occurred mainly in patients already on bosentan prior to study initiation.²

Safety

The pediatric formulation was well-tolerated. When compared with adult patients, no new safety findings were observed. One child discontinued because of ‘bad’ taste of the medication and 1 child died. A total of 22 patients (61%) experienced at least 1 AE. The most frequent (frequency >5%) individual AEs were abdominal pain (11.1%, n=4), vomiting (8.3%, n=3), upper abdominal pain, aggression, asthenia, bronchitis, chest pain, fatigue, flushing, headache, nasal congestion, pain in extremity, pulmonary hypertension, tonsillitis, and viral infection (5.6%, n=2 each). Overall, 4 patients (11.1%) experienced 8 serious adverse events, all requiring hospitalization. One death occurred 1 day after discontinuation of treatment, considered by the investigator to be unrelated to study treatment. Worsening of pulmonary hypertension occurring in 1 patient was the only event judged as related to study treatment by the investigator. No patients experienced transaminase elevations over the course of this study.²

FUTURE-2

FUTURE-2 was a phase 3, open-label, long-term extension study of FUTURE-1. Children who completed 12-week treatment in FUTURE-1 and for whom TRACLEER was considered beneficial were enrolled in FUTURE-2. The main objective of FUTURE-2 was to assess the long-term safety and tolerability of the pediatric formulation of TRACLEER via treatmentemergent AEs, serious AEs, growth, and laboratory measurements. Exploratory efficacy endpoints included time to PAH worsening and long-term survival.³

Of the 36 patients enrolled in FUTURE-1, 33 continued to FUTURE-2 (2 did not complete FUTURE-1 and 1 elected to not enroll in FUTURE-2). The overall median (range) duration of exposure to TRACLEER during the study (from study treatment start date in FUTURE-1 to study treatment end in FUTURE-2) was 27.7 (1.9-59.6) months. Treatment-emergent AEs occurred in 32 (88.9%) patients and AEs considered TRACLEER-related occurred in 15 (41.7%) patients. Overall, the most common AEs were abdominal pain (n=7; 19.4%) and nasopharyngitis (n=7; 19.4%). Fifty-one serious AEs occurred in 18 (50%) patients, 3 were considered treatment-related: 2 incidences of reported PAH worsening and 1 of autoimmune hepatitis. Six deaths occurred during the study period, and all were reported as unrelated to TRACLEER. Measurements of laboratory abnormalities, body weight, height, and vital signs did not reveal new safety concerns with TRACLEER. Kaplan-Meier event-free estimates of PAH worsening were 78.9% (95% CI, 60.7-89.3%) and 73.6% (95% CI, 53.186.2%) at 2 and 4 years, respectively. Estimated long-term survival at 2 and 4 years after start of treatment in FUTURE-1 were 91.2% (95% CI, 75.0-97.1%) and 84.0% (95% CI, 65.593.1%), respectively.³

FUTURE-3

FUTURE-3 was an open-label, prospective, randomized, multicenter, multiple-dose, phase 3 study investigating whether increasing the TRACLEER dosing frequency from 2 mg/kg BID to 2 mg/kg TID in children with PAH (from ≥3 months to <12 years of age) would increase exposure. Overall, 64 patients were randomized 1:1 to receive oral doses of TRACLEER 2 mg/kg BID (n=33) or TID (n=31). The main PK endpoint was the daily exposure to TRACLEER over 24 h corrected to the 2 mg/kg dose (AUC_0-24C). The maximum plasma concentration corrected to the 2 mg/kg dose (C_maxC), the time to reach the maximum plasma concentration (t_max), and safety endpoints were also assessed.⁴

The geometric mean (95% CI) for AUC_0-24C was 8535 h⋅ng/mL (6936, 10,504) and 7275 h⋅ng/mL (5468, 9679) for 2 mg/kg BID and TID, respectively (geometric mean ratio [95% CI] 0.85 [0.61, 1.20]). The geometric mean (95% CI) for C_maxC was 743 ng/mL (573963) and 528 ng/mL (386-722) for 2 mg/kg BID and TID, respectively (geometric mean ratio [95% CI] 0.71 [0.48-1.05]). The median (range) for t_max was 3.0 h (0.0-7.5) and 3.0 h (1.0-8.0) for 2 mg/kg BID and TID, respectively. The proportions of patients who experienced ≥1 AE were similar in the BID (66.7%) and TID (67.7%) groups and were comparable across age groups. Overall, there was a slightly higher proportion of serious adverse events (SAEs) in the TID dosing regimen (19.4%) compared with BID (12.1%) and all SAEs were assessed by the investigator as unrelated to study drug administration.⁴

48-Week Extension Study

Patients who completed the end-of-study visit and were still receiving TRACLEER at week 24 of the core study were eligible for participation in the 48-week extension study; 58 patients (90.6%) continued to the extension study and 45 patients completed the full extension study for a total of 72 weeks of treatment.⁵

In this exploratory post-hoc analysis, associations of worsening from baseline to week 24 were observed in echocardiographic parameters, such as systolic left ventricular eccentricity index and E/A ratio mitral valve flow, which were associated with outcomes in time to death and time to PAH worsening. At Week 72, WHO FC was stable for 50 patients (78.1%), worsened for 8 patients (12.5%), and improved for 6 patients (9.4%). By end of treatment plus 7 days, PAH worsened for 15 patients (23.4%). This included 11 patients (17.2%) who had new or worsening rightsided heart failure, 10 patients (15.6%) who died, 7 patients (10.9%) who were hospitalized due to PAH progression, and 4 patients (6.3%) who began new therapy for PAH.⁵

FUTURE-4

FUTURE-4 was a phase 3, multicenter, double-blind, placebo-controlled, randomized, prospective study to investigate TRACLEER as adjunctive therapy to inhaled nitric oxide in the management of PPHN.⁶ This study has been terminated due to slow recruitment. Eligible patients were >34 weeks gestation, <7 days of age, with persistent respiratory failure (defined as oxygenation index [OI] ≥12) despite at least 4 hours of inhaled nitrous oxide (iNO) treatment, and PPHN confirmed by echocardiography. During the 2-year study period, 21 eligible neonates (13 TRACLEER, 8 placebo) received TRACLEER 2 mg/kg or matching placebo by nasogastric tube BID for at least 48 hours, up to 1 day after iNO weaning, and a maximum duration of 14 days. The groups had similar gestational age, weight, and sex distribution. On day 1, TRACLEER concentrations were low and highly variable. Steady-state conditions comparable to those observed in adult PAH patients were achieved by Day 5. Treatment time (mean days ± standard deviation [SD]) was 5.0 ± 2.6 for the TRACLEER arm and 4.3 ± 1.3 for the placebo arm. Time to weaning from iNO (median days, 95% CI) was 3.7 (1.17-6.95) and 2.9 (1.26-4.23) for the TRACLEER and placebo groups, respectively, while the corresponding values for time to weaning from mechanical ventilation were 10.8 (3.21-12.21) and 8.6 (3.71-9.66). One patient in the TRACLEER arm required extracorporeal membrane oxygenation (ECMO), compared with none in the placebo arm. TRACLEER was well tolerated and did not adversely affect systemic blood pressure or hepatic transaminases. Blood transfusions were performed in 4/13 patients on TRACLEER compared with 1/8 patients on placebo. AEs of anemia (3/13 TRACLEER vs 1/8 placebo) and edema were more frequent in the TRACLEER group (3/13 TRACLEER vs 0/8 placebo). The authors concluded that the study results did not indicate any additional benefit of TRACLEER on top of iNO in this population. Note that these results are not consistent with those presented by Mohamed et al (see Table: Summary of Published Studies and Reviews With TRACLEER in Neonates With PPHN below).¹⁵

Information From a Literature Search

Several additional studies of TRACLEER administration in pediatric patients with PAH and neonates with PPHN were identified. These studies are briefly summarized in the tables below.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 27 February 2025.