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Background Pulmonary arterial hypertension (PAH) is a rare and fatal disease characterised by a progressive increase of pulmonary artery pressure leading to right heart failure. While current PAH therapies provide symptomatic relief and some improvement in quality of life, they show limited benefit in preventing disease progression and often have severe side effects. Recent studies by us reported that a novel thromboxane A2 receptor (TP) antagonist NTP42 attenuated multiple disease hallmarks of PAH in two preclinical models of the disease. Purpose The aim of this study was to assess the efficacy of a novel oral formulation of NTP42 developed for pharmaceutical use on monocrotaline (MCT)-induced PAH in rats across a range of cardiopulmonary parameters, and when compared with standard of care (SOC) PAH therapies. It also aimed to evaluate the expression of the TP, the target receptor for NTP42, in tissues from the MCT-induced PAH model and related disease models. Methods PAH was induced by subcutaneous injection of 60 mg/kg MCT. Rats were randomly assigned to 7 groups: (1) No MCT; (2) MCT Only; (3) MCT+NTP42 Formulation (1 mg/kg); (4) MCT+Sildenafil (50 mg/kg); (5) MCT+Macitentan (30 mg/kg), (6) MCT+Selexipag (1 mg/kg), and (7) MCT+Riociguat (5 mg/kg), where in all cases twice-daily oral dosing was initiated 7 days post-MCT and continued for 22 days. Results The results show that the formulated NTP42 reduced the severity of MCT-induced PAH as determined from haemodynamic measurements of mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), Fulton's Index of cardiac hypertrophy and histological assessments of pulmonary vascular remodelling, pulmonary oedema, inflammation and fibrosis, and right ventricular fibrosis. In addition, these assessments showed that NTP42 inhibited these effects at least to a similar extent relative to the SOC drugs Sildenafil, Macitentan, Selexipag and Riociguat. Notably, unlike most of the PAH SOCs, NTP42 had no adverse effects on liver weight and or on hepatic histopathology. Importantly, NTP42 had no effects on either the systemic mean arterial pressure (mAP) or heart rate (HR). Furthermore, while abundant expression of the target TP was noted in numerous cell and tissue types of both cardiac and pulmonary tissue, there were highly significant upregulations of TP expression observed following PAH-induction (RV, >2-fold, p=0.0002). Conclusions Taken together, these data demonstrate that NTP42 significantly attenuates MCT-induced PAH and to a similar or greater extent relative to market leader PAH SOC drugs. Notably, we reveal that expression of the TP, the target receptor for NTP42, was shown to be highly significantly upregulated throughout the cardiopulmonary system, validating the potential importance of this largely ignored PAH target ripe for pharmaceutical intervention. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Horizon 2020 SME Instrument

Aims Electronic (e)-cigarettes have been marketed as a ‘healthy’ alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms. Methods and results Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined by flow-mediated dilation. In mice, e-cigarette vapour without nicotine had more detrimental effects on endothelial function, markers of oxidative stress, inflammation, and lipid peroxidation than vapour containing nicotine. These effects of e-cigarette vapour were largely absent in mice lacking phagocytic NADPH oxidase (NOX-2) or upon treatment with the endothelin receptor blocker macitentan or the FOXO3 activator bepridil. We also established that the e-cigarette product acrolein, a reactive aldehyde, recapitulated many of the NOX-2-dependent effects of e-cigarette vapour using in vitro blood vessel incubation. Conclusions E-cigarette vapour exposure increases vascular, cerebral, and pulmonary oxidative stress via a NOX-2-dependent mechanism. Our study identifies the toxic aldehyde acrolein as a key mediator of the observed adverse vascular consequences. Thus, e-cigarettes have the potential to induce marked adverse cardiovascular, pulmonary, and cerebrovascular consequences. Since e-cigarette use is increasing, particularly amongst youth, our data suggest that aggressive steps are warranted to limit their health risks.

Introduction Restrictive inclusion criteria can exclude some CHD-PAH patients from clinical trials. The OPsumit® USers (OPUS) Registry and the OPsumit® Historical USers (OrPHeUS) data sets provide real-world data in PAH patients newly started on macitentan, including patients with CHD-PAH regardless of defect type. Purpose To describe the characteristics, safety and clinical outcomes of CHD-PAH patients newly treated with macitentan. Methods OPUS is a prospective, US, multicentre, observational drug registry ongoing since April 2014. OrPHeUS was a retrospective, US, multicentre chart review; observation period Oct 2013–Mar 2017. This analysis reports information on CHD-PAH patients in the combined OPUS/OrPHeUS data set, descriptively compared with idiopathic/heritable PAH (I/HPAH) patients. Results As of Sept 2019, there were 4268 PAH patients with follow-up data, of whom 264 (6%) had CHD-PAH and 2396 (56%) had I/HPAH. For CHD-PAH and I/HPAH patients respectively at macitentan initiation: median age (Q1, Q3) was 48 (36, 62) and 65 (53, 73) years; 199 (75%) and 1748 (73%) were female; 67/114 (59%) and 802/1301 (62%) were WHO functional class III/IV; median (Q1, Q3) 6-minute walk distances were 350 (274, 420) and 289 (195, 375) m for the 82 and 840 patients with measurements; median (Q1, Q3) time from PAH diagnosis to macitentan initiation was 37.3 (4.5, 113.1) and 7.4 (1.4, 38.3) months; and 99 (38%) and 1056 (44%) initiated macitentan as monotherapy. The number of patients with ≥1 hepatic adverse event (HAE) was similar for CHD-PAH and I/HPAH (22 [8%] and 184 [8%]), as were the adverse event (AE) profiles (collected from OPUS only). Exposure, discontinuations, outcomes and most common AEs are shown in the table. Conclusions In general, compared with I/HPAH patients, CHD-PAH patients were younger and a greater proportion had prevalent disease than I/HPAH patients. Safety and outcomes were similar between the groups. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd

Introduction PAH impacts right ventricular (RV) structure and function but also leads to changes in the LV due to RV/LV interaction and underfilling. REPAIR, the first PAH study to use a primary endpoint assessed by cardiac MRI (cMRI), reported that RV stroke volume (RVSV) increased by 12 mL and pulmonary vascular resistance (PVR) decreased by 38% from baseline (BL) to Week 26 with macitentan. Purpose To assess the effect of macitentan on LV function in patients with PAH. Methods REPAIR (NCT02310672) was a 52-week, multicentre, open-label, single-arm, phase 4 study assessing the effect of macitentan primarily on RV structure and function, determined by cMRI and right heart catheterisation. Macitentan 10 mg was initiated in treatment-naïve patients, in patients receiving stable background phosphodiesterase type-5 inhibitor (PDE5i) at BL, or in initial combination with PDE5i. Exploratory LV endpoints were assessed by cMRI at Weeks 26 and 52. Safety was assessed up to end of study treatment +30 days in all patients who received ≥1 dose of macitentan (N=87). Patients with BL and Week 26 assessments for both PVR and RVSV were included in the modified Full Analysis Set (mFAS; N=71). Results In the mFAS, 57 (80%) patients were female. At BL, median age was 45 years; median (Q1, Q3) six-minute walk distance was 395 (323, 483) m; 48%/51% of patients were WHO functional class II/III; 59% had idiopathic PAH. Compared to BL, at Weeks 26 and 52 there were significant changes in LV cMRI parameters (table). The most common AEs were peripheral oedema (22%), headache (21%) and dizziness (14%). Conclusions Macitentan led to improvements in LV mass, volume and function, including clinically-relevant increases in LV stroke volume, at both 26 and 52 weeks in patients with PAH. Safety was consistent with other macitentan clinical trial data. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd

Introduction Guidelines for the management of PAH recommend combination therapy for most patients, yet real-world data on treatment patterns in PAH are limited. Purpose To describe the characteristics, safety and clinical outcomes of PAH patients newly treated with double combination therapy with macitentan and PDE5i in the OPsumit® USers (OPUS) Registry and the OPsumit® Historical USers cohort study (OrPHeUS) combined dataset. Methods OPUS is a prospective, US, multicentre, observational drug registry (NCT02126943) ongoing since April 2014. OrPHeUS was a retrospective, US, multicentre chart review (NCT03197688); Oct 2013–Mar 2017. This cohort included patients initiating combination therapy with macitentan and a PDE5i (in any order) ≤60 days apart. Baseline was defined as the start date of the second therapy (i.e., start of combination therapy). Patient characteristics at baseline, changes in 6-minute walk distance (6MWD) and WHO functional class (FC) from baseline to follow-up, safety and outcomes are described. Results Of the 4428 OPUS/OrPHeUS PAH patients initiating macitentan, 2490 received this in combination with a PDE5i; of these patients, 740 (29.7%) initiated macitentan and a PDE5i concurrently (≤60 days apart). Data on disease duration was recorded in 729 patients at baseline; of these, 588 (80.7%) patients were incident (≤6 months since diagnosis) and 141 (19.3%) were prevalent (>6 months since diagnosis); median time from diagnosis to start of combination therapy of was 1.4 (Q1=0.6, Q3=3.6) months. At baseline, median age was 60 (Q1=49, Q3=70) years and 73.6% of patients were female. Mean baseline 6MWD was 264.5 (SD=119.8) m, recorded in 240 (32.4%) patients. WHO FC was recorded at baseline for 347 (46.9%) patients; 263 (75.8%) were in FC III/IV. Median combination therapy exposure was 10.2 (Q1=3.4, Q3=21.8) months, with 58.8% of patients ongoing at data cut. Changes from baseline to follow up in FC and 6MWD are shown in the figure. There was ≥1 adverse event (AE) reported in 455 (61.5%) patients and ≥1 hepatic AE (HAE) in 76 (10.3%) patients. In total, 232 (31.4%) patients discontinued macitentan; 122 (16.5%) due to AEs, 4 (0.5%) due to HAEs, 98 (13.2%) not due to an AE/HAE, and 8 (1.1%) for unknown reasons. Of the 305 patients who discontinued combination therapy, 137 (18.5%) discontinued macitentan only, 73 (9.9%) discontinued PDE5i only, and 95 (12.8%) discontinued both drugs at the same time. Kaplan-Meier estimates (95% CI) showed that 60.7% (56.4, 64.8) of patients were free from hospitalisation and 88.7% (85.7, 91.1) were alive at 12 months. Conclusions In this real-world setting, less than one third of patients treated with macitentan received initial oral combination therapy, despite current expert consensus favouring such therapeutic approaches. Patients initiating macitentan+PDE5i ≤60 days apart had improved 6MWD and WHO FC from baseline to follow-up. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd

Introduction Long-term outcomes are important in PAH. Purpose To evaluate the long-term efficacy and safety of initial triple oral therapy with selexipag, macitentan and tadalafil vs initial double oral therapy with macitentan and tadalafil in PAH. Methods TRITON, a multicentre, double-blind, placebo-controlled, phase 3b study, randomised 1:1 newly diagnosed, treatment-naïve PAH patients to initial triple vs double therapy. Macitentan and tadalafil were initiated at randomisation and selexipag/placebo at day 15 (uptitrated to wk 12). Efficacy and safety were assessed in a blinded manner until the last patient randomised completed wk 26 (end of observation period). Pulmonary vascular resistance (PVR; primary endpoint) and 6-minute walk distance (6MWD) were assessed at wk 26. Other secondary endpoints included time to first disease progression event (centrally adjudicated) to end of observation period +7 days. Time to all-cause mortality up to end of observation period was analysed post-hoc. Results 247 patients were randomised to initial triple (n=123) or initial double therapy (n=124); baseline characteristics were balanced between groups. Median follow-up was 77.6 (initial triple) and 75.8 wks (initial double). Initial triple and initial double therapy improved PVR (by 54% and 52%) and 6MWD (by 55 and 56 m), with no difference between groups. A 41% reduction in the risk of first disease progression event driven by PAH-related hospitalisation and all-cause death was observed with initial triple vs initial double therapy (hazard ratio 0.59, 95% CI 0.32–1.09, p=0.087; Figure). Two patients died in the initial triple vs 9 in the initial double therapy group (hazard ratio 0.23, 95% CI 0.05–1.04). Adverse events were consistent with the known safety profiles of the study drugs. Conclusions In TRITON, assessments at wk 26 showed marked improvements in both treatment arms, with no difference between groups. Exploratory analysis indicated a signal for improved long-term outcome with initial triple versus initial double therapy. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd.

Introduction Currently there is no evidence-based strategy for PAH drug application adjusted for patients with HIV-associated PAH. Data regarding the use of sildenafil and endothelin receptors antagonists (ERA) are limited case series. Purpose To present the long-term data on treatment with sildenafil, macitentan and ambrisentan in pts with HIV-PAH. Material and methods In prospective study were consecutively enrolled 18 treatment-naïve pts with HIV-PAH (7 males, 34.5 yrs; 29; 53 yrs), mean follow-up was 1.64yrs; 0,16–59–9.28 yrs. 4 pts were in IV FC, 5-III FC and 9 in II FC PAH (WHO). RHC, ECHO, 6MWT, ergospirometry and NTproBNP level were evaluated at a baseline. Intravenous drug abuse reported in 72% pts, all of them were co-infected with hepatitis. Nine pts (50%) treated with HAART therapy at a baseline. Five pts did not have PAH-specific therapy, 11 pts received sildenafil, 1 IV FC PAH pt with HAART – sildenafil+macitentan and 1 III FC PAH pt with HAART-sildenafil+ambrisentan. Follow-up data (FC, 6MWT, ECHO, ergospirometry, NT-proBNP) were available for 8 PAH-treated pts. Results Pts on PAH therapy had achieved improvement in 6 MWT with mean distance increase 69.3±52 m (p=0.01); NTproBNP level decrease (p=0.018) and FC PAH improvement in 7 pts. In pts with PAH therapy the size of right atrium decreased (56.4±7.8 vs 47.8±6.7 mm, p=0.027). The combinations of sildenafil and macitentan and sildenafil with ambrisentan were well tolerated and resulted 6MWT increase, low NTproBNP and FC improvement. Nevertheless there was no significant changes in peak VO2 consumption. Two pts with sildenafil therapy lost for follow up. Three pts with sildenafil but without HAART therapy dead: in one case due to pneumonia, other 2 cases due to pulmonary embolism. Four pts without HAART and PAH therapy dead. In our population strong association between survival and HAART therapy presence was revealed (p=0.01). Conclusion No adverse reactions of PAH-specific therapy were reported in pts on HAART. PAH therapy had a positive influence on FC, exercise capacity, heart remodeling and NT-proBNP level. There were no deaths in pts who receive HAART and PAH therapy. Nevertheless in our population strong association between survival and HAART therapy presence was revealed. Funding Acknowledgement Type of funding source: None

Aims The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored. Methods and results Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28–0.86; HR 0.72, 95% CL 0.42–1.22; and HR 0.22, 95% CL 0.15–0.33, respectively). Conclusions For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality.

Introduction The OPsumit® Historical USers cohort (OrPHeUS) is a multicentre, US, retrospective medical chart review conducted to supplement the OPsumit® USers (OPUS) Registry to fulfil the FDA request to characterise the safety of macitentan in clinical practice. Purpose To describe patient characteristics, treatment patterns, hepatic safety and survival in patients with pulmonary hypertension (PH) newly treated with macitentan. Methods OrPHeUS (NCT03197688) aimed to include 2200 new users of macitentan, between October 2013 and March 2017, who were not enrolled in OPUS. Here we present patients with follow-up data, including characteristics and treatment patterns at macitentan initiation, hepatic adverse events (HAEs) identified using preferred terms in chart entries and pharmacovigilance reporting, hospitalisations and survival. Results OrPHeUS included 2982 patients newly treated with macitentan and with follow-up data; the reason for macitentan prescription was pulmonary arterial hypertension (PAH) in 2362 (79.3%) patients, other PH aetiologies in 612 (20.6%) patients and 8 patients with other/unknown reasons. At macitentan initiation, the median (Q1, Q3) age of the patients was 62 (51, 72) years and 73.9% were female. WHO functional class (FC) was documented in 654 (21.9%) patients, 35.6% of patients were in FC I/II and 64.4% in FC III/IV; median (Q1, Q3) 6-minute walk distance, documented in 411 (13.8%) patients, was 293 (200, 383) metres. At macitentan initiation, 41.5% (n=1239) of patients were not receiving PAH therapy, 46.3% (n=1382) were already receiving one PAH therapy and 11.9% (n=356) were already receiving two PAH therapies. The median (Q1, Q3) exposure to macitentan was 14.9 (5.6, 27.1) months; 57% and 43% of patients had exposures of >12 and >18 months. During the exposure period, 933 (31.3%) patients discontinued treatment, including 474 (15.9%) patients who discontinued due to an adverse event (AE), 6 (0.2%) due to a HAE, 449 (15.1%) for reasons other than an AE/HAE, and 4 (0.1%) for unknown reasons. There were 275 (9.2%) patients who experienced ≥1 HAE (incidence rate [IR]: 0.07 [95% CI, 0.06, 0.08] per 1 person-year); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3x upper limit of normal (ULN) were experienced by 113 (3.8%) patients (IR: 0.028 [95% CI, 0.023, 0.033] per 1 person-year); ALT/AST ≥x3 ULN and bilirubin ≥2x ULN was experienced by 33 (1.1%) patients (IR: 0.008 [95% CI, 0.006, 0.011] per 1 person-year). There were 1148 (38.5%) patients who experienced at least one hospitalisation (IR: 0.36 [95% CI, 0.34, 0.39] per 1 person-year). The 12-month Kaplan-Meier survival estimate was 92% (95% CI, 91, 93). Conclusion OrPHeUS provides additional real-world evidence in patients newly treated with macitentan, confirming the hepatic safety profile of macitentan. Acknowledgement/Funding Actelion Pharmaceuticals Ltd

Purpose: In SERAPHIN ([NCT00660179][1]), a Phase III trial in pulmonary arterial hypertension (PAH), macitentan reduced the risk of morbidity and mortality (primary outcome) and risk of PAH-related death or hospitalisation (PAHDH; secondary outcome). The effect of macitentan on 6-minute walk distance (6MWD) and the association between 6MWD and PAHDH were explored. Methods: 742 PAH patients were randomised to placebo, 3 or 10mg macitentan, once daily. Treatment-by-visit interaction and placebo-corrected treatment effects were calculated using repeated measures analysis on 6MWD change from baseline at Months 3, 6, 12 in the all-randomised set. Hazard ratios were calculated to measure the association between interquartile ranges of baseline 6MWD, 6MWD changes, or values at Month 6 (± adjustment for significant covariates) and PAHDH. This was performed independently of treatment in patients with available data for 6MWD at Month 6 and from Month 6 up to end of treatment for PAHDH Results: Baseline mean±SD 6MWD for placebo (n=249), 3mg (n=248) and 10mg macitentan (n=242) was 352±111m, 364±96m and 363±93m, respectively. No significant treatment-by-visit interaction (p=0.47) suggested that beneficial effects of macitentan on 6MWD (3mg: 21.5m [10.0–33.0]; p=0.0003 and 10mg: 25.4m [13.8–37.0]; p