Inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease with less severe haemodynamics: a post hoc analysis of the INCREASE study.

BACKGROUND: Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. METHODS: Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and <5 WU versus ≥5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. RESULTS: Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs -10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. CONCLUSION: Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

Resolution of Severe Portopulmonary Hypertension With Inhaled Treprostinil and Liver Transplantation.

Portopulmonary hypertension is a rare condition with a poor prognosis. Prompt management is essential for liver transplantation eligibility, a potentially curative option. This report presents a case of severe portopulmonary hypertension that resolved with a conservative therapeutic regimen of tadalafil, macitentan, and inhaled treprostinil, which ultimately enabled successful liver transplantation. There was no recurrence of pulmonary hypertension after transplantation, and the patient was weaned off most pulmonary arterial hypertension therapies. This case report is the first to provide evidence that inhaled treprostinil is a safe and effective alternative to continuous intravenous prostacyclins in portopulmonary hypertension.

Short term effect of intravenous treprostinil in term and preterm infants with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening condition in newborns. We aimed to assess the clinical and echocardiographic responses of term and preterm infants to treprostinil. METHODS: This retrospective study included newborns diagnosed with PH and treated with treprostinil as additional therapy after inhaled nitric oxide administration in the neonatal intensive care unit of a tertiary center. Term and preterm infants were compared in terms of echocardiographic findings and clinical findings 4 weeks after treprostinil treatment. RESULTS: During the study period, 11 term and 18 preterm infants were diagnosed with PH and received treprostinil. There were no differences in the echocardiographic findings of interventricular septal deviation, direction of shunt, and ratio of estimated pulmonary artery pressure over systolic blood pressure. Congenital diaphragmatic hernia was the most common condition occurring upon PH diagnosis among term infants, while severe bronchopulmonary dysplasia was the most common in preterm infants. Improvements in echocardiographic findings were more pronounced in term infants than in preterm infants (100% vs. 55.6%, P = 0.012). The inhaled nitric oxide dose was gradually tapered for term infants and was lower than that for preterm infants at 1, 2, and 3 weeks after treprostinil. CONCLUSION: Intravenous treprostinil could be an adjuvant therapy option for term and preterm infants with PH, especially for those who cannot receive oral medication. The efficacy and safety of treprostinil in this population with PH should be investigated further.

Treprostinil Effectiveness in Higher-Risk Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension.

BACKGROUND: Little is known about the effectiveness of treprostinil in higher-risk paediatric patients with various pulmonary arterial hypertension genotypes. This study was designed to investigate the prognosis of higher-risk paediatric patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) after treprostinil therapy. METHODS: Children with IPAH/HPAH who were stratified as higher risk and treated with treprostinil in our centre were included as the study cohort. Those who received only oral medications were included as the reference cohort. All patients in the study cohort received PAH-related genotyping. Survival was defined as no death. Event-free survival was defined as no death, Potts shunt, or atrial septostomy. RESULTS: Forty-nine children (median age 7.7 years [interquartile range (IQR) 4.2-11.5 years], 65% female) were included in the study cohort and 48 children were included in the reference cohort; 84% of the study cohort had genetic disorders after genetic testing with a dominance of BMPR2 and ACVRL1 mutations. After a median therapy duration of 5.56 months (IQR 2.66-11.12 months), all patients were alive with significant improvements in clinical characteristics. One-, 2-, and 3-year survival rates were 91%, 84%, and 69%, respectively with a median follow-up duration of 19.17 months (IQR 9.7-29.79 months), which was significantly superior to the reference cohort (P = 0.038). Multivariate Cox regression analysis identified World Health Organisation functional class after therapy as a predictor for survival. There was no significant difference in survival among patients with different genotypes. CONCLUSIONS: Treprostinil can significantly improve the prognosis in children with IPAH/HPAH who are at higher risk, despite genetic backgrounds.

Eficacia y seguridad de treprostinil o selexipag adicionado a sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional OMS III, con fracaso a sildenafilo más bosentán / Efficacy and safety of treprostinil or selexipag added to sildenafil plus bosentan, in adult patients with pulmonary arterial hypertension, WHO functional class III, with failure to sildenafil plus bosentan

ANTECEDENTES> En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el que expone la evaluación de la eficacia y seguridad de treprostinil o selexipag en adición a sildenafil más bosentán, comparado con el esquema sildenafil más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional de la Organización Mundial de la Salud (OMS) III, con fracaso a la administración conjunta de sildenafil más bosentán. Así, Oscar Nelson Aguirre Zurita, médico cardiólogo del Servicio de Cardiología del Instituto Nacional Cardiovascular - INCOR envió al IETSI la solicitud de autorización de uso del producto farmacéutico treprostinil no incluido en el Petitorio Farmacológico de EsSalud siguiendo la Directiva N° 003-IETSI-ESSALUD-2016. ASPECTOS GENERALES: Los aspectos generales de la hipertensión arterial pulmonar (HAP) se han descrito previamente en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N.° 012- DETS-IETSI-2021 (IETSI-EsSalud 2021). Brevemente, la HAP es una enfermedad compleja y progresiva caracterizada por un aumento de la presión en la arteria pulmonar. Los pacientes comúnmente experimentan dificultad para respirar, hinchazón de tobillos y piernas, mareos o desmayos. En promedio, los pacientes viven entre cinco y siete años después del diagnóstico. La enfermedad afecta más comúnmente a personas entre 20 y 40 años de edad, y es más común en mujeres que en hombres. La Organización Mundial de la Salud (OMS) ha desarrollado un sistema de clasificación de HAP basado en el nivel de función y los síntomas. Los pacientes pueden tener Clase Funcional (CF) I a IV, con números crecientes que reflejan una mayor gravedad (CADTH 2015a). La HAP es rara, con una incidencia estimada de hasta 7.6 casos por millón de adultos y una prevalencia de hasta 26-100 por millón de adultos. La morbilidad y la mortalidad siguen siendo significativas y el diagnóstico y tratamiento tempranos son esenciales (Hirani et al. 2020). METODOLOGÍA: Se realizó una búsqueda sistemática utilizando las bases de datos PubMed, Cochrane Library, y LILACS. Además, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissáo Nacional de Incorporagáo de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros. Asimismo, se revisó la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en hipertensión pulmonar, tales como: American College of Chest Physicians (CHEST), European Society of Cardiology (ESC) y la European Respiratory Society (ERS). Se realizaron búsquedas manuales complementarias en las listas de referencias de los textos completos evaluados. RESULTADOS: La búsqueda de literatura permitió identificar siete publicaciones: dos GPC realizadas por CHEST (Klinger et al. 2019) y ESC-ERS (Humbert et al. 2022); dos ETS elaboradas por HAS (HAS 2011) y CADTH (CADTH 2006); dos ECA (Simonneau et al. 2002; McLaughlin et al. 2003); y un estudio observacional (Barst et al. 2006). CONCLUSIÓN: Por todo lo expuesto, el IETSI no aprueba el uso de treprostinil o selexipag adicionado a sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional OMS III, con fracaso a sildenafilo más bosentán.

Safety, Tolerability, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder for Pulmonary Hypertension: A Phase 1, Randomized, Double-Blind, Single- and Multiple-Dose Study.

INTRODUCTION: Treprostinil is a prostacyclin vasodilator widely used for the treatment of pulmonary arterial hypertension (PAH) and, in its inhaled form, for pulmonary hypertension associated with interstitial lung disease (PH-ILD). Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of treprostinil palmitil (TP), an ester prodrug of treprostinil. TPIP is designed to provide sustained release of treprostinil in the lung over a prolonged period, potentially enabling a once-daily (QD) dosing regimen and significantly higher tolerated doses compared with currently available treprostinil formulations. This phase 1 study assessed the safety, tolerability, and pharmacokinetics of TP and treprostinil following single and multiple QD administrations of TPIP in healthy volunteers. METHODS: Healthy adults (aged 18-45 years) were randomized to receive single or multiple QD inhalation doses of TPIP. Participants in the single-dose phase received TPIP 112.5, 225, 450, or 675 µg (n = 6/dose) or placebo (n = 2). Participants in the multiple-dose phase received TPIP 225 µg QD for 7 days (n = 6), 112.5 µg QD for 4 days followed by 225 µg QD for 3 days (n = 6), or placebo for 7 days (n = 4). RESULTS: Overall, 41 of 42 participants (97.6%) completed the study. In the single-dose phase, 70.8% (n = 17/24) of TPIP-treated participants experienced a treatment-emergent adverse event (TEAE) vs 0% (n = 0/2) of placebo-treated participants; the most common TEAEs (≥ 20%) were cough (45.8%), dizziness (29.2%), and throat irritation (20.8%). In the multiple-dose phase, 83.3% (n = 10/12) of TPIP-treated participants experienced a TEAE vs 50.0% of placebo-treated participants (n = 2/4); the most common TEAEs were cough (58.3% TPIP vs 50.0% placebo), headache (50.0% vs 0%), nausea (33.3% vs 0%), chest discomfort (33.3% vs 0%), and dizziness (25.0% vs 0%). Most TEAEs were mild; only seven patients experienced a moderate TEAE, and no severe or serious TEAEs occurred. In the multiple-dose phase, participants whose doses were titrated from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 225 µg QD at treatment initiation (66.7% vs 100.0%), and all TEAEs with dose titration were mild. After a single dose of TPIP, treprostinil elimination t1/2 was 8.67-11.6 h and exposure was dose proportional, with mean (CV%) Cmax 78.4-717 pg/mL (38.6-72.9%) and AUC0-∞ 1090-5480 pg·h/mL (11.5-30.0%). At steady state (TPIP 225 µg), the mean (CV%) of Cmax, Cmin, and AUCτ were 193-228 pg/mL (32.9-46.4%), 17.6-22.8 ng/mL (43.7-64.4%), and 1680-1820 pg·h/mL (28.7-36.6%), respectively. The elimination t1/2 was 6.84-8.82 h after repeat dosing. No steady-state accumulation was observed. Plasma concentrations of TP were below the limit of quantification (100 pg/mL) at all time points measured. CONCLUSION: TPIP was well tolerated at the doses tested, and dose titration improved tolerability. Treprostinil pharmacokinetics were linear and supportive of a QD treatment regimen. These results support further development of TPIP in patients with PAH and PH-ILD.

[Progress in the development of treprostinil for the treatment of pulmonary hypertension].

Pulmonary arterial hypertension is a progressive pulmonary vascular disease, which can cause right heart failure and even death in severe cases. Treprostinil is a stable prostacyclin analogue and a powerful drug for dilating pulmonary vessels. It can be administered in different ways, with a long half-life, good stability and is suited for diverse types of PAH. It is approved for the treatment of Group 1 PAH, but some studies show that treprostinil is effective in patients with Group 3 or Group 4 PAH. Therefore, this article will review the progress of evidence-based medicine evidence of traprostanil in the treatment of type 1, 3 and 4 pulmonary hypertension.

The Antifibrotic Effects of Inhaled Treprostinil: An Emerging Option for ILD.

Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The targeting of fibroblasts and myofibroblasts with antifibrotic treatments is a potential therapeutic target for these potentially fatal diseases. Treprostinil is unique among the prostacyclin mimetics in that it has distinct actions at additional prostaglandin receptors. Preclinical and clinical evidence suggests that treprostinil has antifibrotic effects through the activation of the prostaglandin E receptor 2 (EP2), the prostaglandin D receptor 1 (DP1), and peroxisome proliferator-activated receptors (PPAR). In vivo studies of EP2 and the DP1 have found that administration of treprostinil resulted in a reduction in cell proliferation, reduced collagen secretion and synthesis, and reduced lung inflammation and fibrosis. In vitro and in vivo studies of PPARß and PPARγ demonstrated that treprostinil inhibited fibroblast proliferation in a dose-dependent manner. Clinical data from a post hoc analysis of the INCREASE trial found that inhaled treprostinil improved forced vital capacity in the overall population as well as in idiopathic interstitial pneumonia and idiopathic pulmonary fibrosis subgroups. These preclinical and clinical findings suggest a dual benefit of treprostinil through the amelioration of both lung fibrosis and pulmonary hypertension.

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia.

BACKGROUND: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH. METHODS: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied. FINDINGS: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure. INTERPRETATION: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH. FUNDING: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).

Study design and rationale for the TETON phase 3, randomised, controlled clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) greatly impacts quality of life and eventually leads to premature death from respiratory failure. Inhaled treprostinil was associated with improvements in forced vital capacity (FVC) and reduced exacerbations of underlying lung disease in post hoc analyses from a phase 3 study in patients with precapillary pulmonary hypertension due to interstitial lung disease. These results, combined with preclinical evidence of treprostinil's antifibrotic activity, support its investigation in the treatment of IPF. METHODS AND ANALYSIS: The TETON programme consists of two replicate, 52-week, randomised, double-blind placebo-controlled, phase 3 studies, each enrolling 396 subjects (NCT04708782, NCT05255991). Eligible subjects must have a diagnosis of IPF confirmed by central imaging review, along with an FVC ≥45%. Stable background use of pirfenidone or nintedanib is allowed. The primary endpoint is change in absolute FVC at week 52. Secondary endpoints include time to clinical worsening (first event of death, respiratory hospitalisation or ≥10% decline in % predicted FVC), time to first acute exacerbation of IPF, overall survival, change in % predicted FVC and change in the King's Brief Interstitial Lung Disease Questionnaire at week 52. Safety parameters include adverse events, hospitalisations, oxygenation and laboratory parameters. Patients who complete week 52 will be eligible to enter an open-label extension study. ETHICS AND DISSEMINATION: Studies will be conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice, Declaration of Helsinki principles, and local regulatory, ethical and legal requirements. Results will be published in a peer-reviewed publication.

Ultrasonography evaluation on the protective effect of combination therapy of beraprost sodium and aspirin on arteries occlusion and stiffness in patients with type 2 diabetes mellitus - a prospective, randomized study.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are susceptible to developing symptomatic peripheral arterial disease (PAD). As a proven vasodilator and antiplatelet agent, the efficiency of Beraprost sodium (BPS) on the prevention of arteries occlusion and stiffness in T2DM patients with PAD has not yet been fully investigated. METHODS: From July 2010 to April 2012, 64 Patients enrolled were randomly assigned to the combined therapy group (n=32), which received combination therapy with BPS (60 µg/day) and aspirin (100 mg/day), or to the control group (n=32), which only received aspirin (100 mg/day). After randomization, the patients were followed up at years 0, 1, 2, 3, 4, and 5 with the evaluation of carotid intima-media thickness (CIMT), pulse wave velocity (PWV), inner artery diameter, stenosis rate, and medial arterial calcification (MAC) of lower limb arteries via high-resolution ultrasound measurement. Adverse events were also recorded in each visit. RESULTS: There was no significant change of the CIMT during the follow-up in both groups when compared to the baseline. Similar results were also observed in the PWV measurement. Significantly increases in the inner artery diameter of the dorsal pedal artery and posterior tibial artery were observed in patients with BPS and aspirin administration during the follow-up. Patients in the combined therapy group experienced marked improvement of MAC in the dorsal pedal artery and posterior tibial artery at the end of the follow-up. No significant difference in the adverse events was found between the combined therapy group and the aspirin group. CONCLUSION: The combined therapy of BPS and aspirin showed a protective effect on arteries occlusion and stiffness in T2DM patients with PAD, along with a significant improvement of inner artery diameter and MAC in lower limbs. TRIAL REGISTRATION: http://www.chictr.org.cn , ChiCTR-TRC-10000919. Prospectively registered on 2010/06/29.

Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension.

OBJECTIVE: Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity. METHODS: Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients. RESULTS: GWAS identified three loci for association with P < 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures. CONCLUSIONS: The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.

Targeted treprostinil delivery inhibits pulmonary arterial remodeling.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a fatal disease caused by the progressive remodeling of pulmonary arteries (PAs). Treprostinil (TPS) is a tricyclic benzidine prostacyclin clinically used for PAH treatment. However, due to low bioavailability, short half-times, and severe systemic side effects, TPS efficacy remains limited. METHODS: In this study, glucuronic acid (GlcA)-modified liposomes were developed to improve the site-specific delivery of TPS to pulmonary arterial smooth muscle cells (PASMCs) by targeting the glucose transporter-1 (GLUT-1) in vitro and in vivo. RESULTS: Non-GlcA-modified and GlcA-modified liposomes encapsulating TPS were 106 ± 1.12 nm in diameter. The drug encapsulation efficiency (EE) was 92%. Data from rat PASMCs showed that GlcA-liposomes enhanced the inhibitory effects of TPS on PASMC proliferation and migration by suppressing growth factor expression, including transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), and cAMP, which was possibly mediated by the cAMP-C/EBP-α p42-p21 signaling pathway. In PAH model rats, GlcA-modified liposomes significantly improved TPS bioavailability and sustained its release over time. Most importantly, the selective inhibition of pulmonary arterial pressure, rather than systemic arterial pressure, indicated the increased pulmonary-specific accumulation of TPS. Of the three TPS formulations, TPS-loaded GlcA-modified liposomes exhibited the most potent activity by inhibiting PA remodeling and muscularization, decreasing PA medial thickening, suppressing collagen deposition in PAs, and attenuating right ventricle hypertrophy (RVH) in sugen-5416-induced PAH rats. CONCLUSIONS: The GLUT-1-targeted delivery of TPS increased pulmonary specificity and enhanced TPS anti-PAH activities in vivo and in vitro.

Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension.

Oral treprostinil has been shown to improve exercise capacity and delay disease progression in patients with pulmonary arterial hypertension (PAH), but its effects on hemodynamics are not well-characterized. The FREEDOM-EV trial was a Phase III, international, placebo-controlled, double-blind, event-driven study in 690 participants with PAH who were taking a single oral PAH therapy. FREEDOM-EV demonstrated a significantly reduced risk for clinical worsening with oral treprostinil taken three times daily and did not uncover new safety signals in PAH patients. Sixty-one participants in the FREEDOM-EV trial volunteered for a hemodynamics sub-study. Pulmonary artery compliance (PAC), a ratio of stroke volume to pulmonary pulse pressure, significantly increased from Baseline to Week 24 in the oral treprostinil group compared with the placebo group (geometric mean 26.4% active vs. -6.0% placebo; ANCOVA p=0.007). There was a significant increase in cardiac output in the oral treprostinil group compared to the placebo group (geometric mean 11.3% active vs. -6.4% placebo; ANCOVA p=0.005) and a corresponding significant reduction in pulmonary vascular resistance (PVR) (geometric mean -21.5 active vs. -1.8% placebo; ANCOVA p=0.02) from Baseline to Week 24. These data suggest that increased compliance contributes to the physiological mechanism by which oral treprostinil improves exercise capacity and delays clinical worsening for patients with PAH.

Treprostinil palmitil inhibits the hemodynamic and histopathological changes in the pulmonary vasculature and heart in an animal model of pulmonary arterial hypertension.

Treprostinil palmitil (TP) is a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE). In this study, TP was delivered by inhalation (treprostinil palmitil inhalation suspension, TPIS) in a rat Sugen 5416 (Su)/hypoxia (Hx) model of pulmonary arterial hypertension (PAH) to evaluate its effects on hemodynamics, pulmonary vascular remodeling, and cardiac performance and histopathology. Male Sprague-Dawley rats received Su (20 mg/kg, s.c), three weeks of Hx (10% O2) and 5 or 10 weeks of normoxia (Nx). TPIS was given during the 5-10 week Nx period after the Su/Hx challenge. Su/Hx increased the mean pulmonary arterial blood pressure (mPAP) and right heart size (Fulton index), reduced cardiac output (CO), stroke volume (SV) and heart rate (HR), and increased the thickness and muscularization of the pulmonary arteries along with obliteration of small pulmonary vessels. In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 µg/kg, QD, dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge. The PDE5 inhibitor sildenafil, administered at an oral dose of 50 mg/kg, BID for 10 weeks, was not as effective as TPIS. These results in Su/Hx challenged rats demonstrate that inhaled TPIS may have superior effects to oral sildenafil. We speculate that the improvement of the pathobiology in this PAH model induced by TPIS involves effects on pulmonary vascular remodeling due to the local effects of TRE in the lungs.