Abstract 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

BACKGROUND:A long-term trial showed that the oral prostacyclin (PGl2) receptor (IP) agonist, selexipag, delayed disease progression in patients with pulmonary arterial hypertension (PAH). Transition to selexipag in patients treated with more burdensome inhaled therapies that target the prostacyclin pathway may be considered by patients and physicians. The Phase 3b, prospective, open-label TRANSIT-1 (Tolerability and Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Patients With Pulmonary Arterial Hypertension) study evaluated the safety and tolerability of transition from inhaled treprostinil to oral selexipag. METHODS:Patients receiving non-prostanoid oral PAH therapy and inhaled treprostinil at stable doses, in World Health Organization Functional Class II/III, with 6-minute walk distance ≥ 300 meters were enrolled. The 16-week main treatment period included downtitration of inhaled treprostinil over 8 weeks and parallel uptitration of selexipag over 12 weeks. Sustained treatment transition at Week 16 was defined as (1) receiving selexipag at Week 16; (2) no selexipag interruption(s) totaling ≥ 8 days; and (3) no inhaled treprostinil or other prostanoids after Week 8. Clinical parameters and patient-reported treatment satisfaction outcomes were assessed at Week 16. RESULTS:All 34 enrolled patients completed the study. At Week 16, 32 patients (94.1%) had stopped inhaled treprostinil and were receiving selexipag. Twenty-eight patients (82.4%) met all criteria for sustained treatment transition. During the study, 3 patients discontinued selexipag due to adverse events. Overall, most adverse events were typical of prostanoid therapies and started during the uptitration phase. In general, patients remained clinically stable throughout treatment and reported improved convenience. CONCLUSIONS:Transition to oral selexipag from inhaled treprostinil in PAH patients was successful and well tolerated in most patients, and associated with greater convenience. CLINICAL TRIAL NUMBER:NCT02471183.

PAH-SYMPACT® is a patient reported outcome (PRO) instrument; the draft consists of 16 symptom and 25 impact items. The PRO was developed based on interviews with patients with pulmonary arterial hypertension (PAH) following the process outlined in the FDA’s PRO guidance. Its psychometric characteristics are being evaluated using data from SYMPHONY - a phase IIIb PAH study with macitentan. The goal of the analyses was the finalization of item content and domain structure while ensuring the instrument is clinically and patient relevant. In SYMPHONY, patients completed generic and disease-specific questionnaires while clinicians provided assessment of severity and changes in symptomatology. Item performance, Rasch and Factor analyses of baseline data were used together with expert input to select the final items and define the domain structure. Data from 278 patients (79% female, mean age 60 years) were included in the analysis. 40% and 59% of patients were in WHO functional class II and III, respectively, and 41% were receiving background therapy with a phosphodiesterase type-5 inhibitor. As expected for a moderately severe population, some items had high (>50%) floor effects. Following removal of redundant or mis-fitting items, the final instrument has 11 symptom items (shortness of breath, fatigue, lack of energy, swelling in ankles/legs, swelling in stomach area, cough, heart palpitations, rapid heartbeat, chest pain, chest tightness, lightheadedness) across 2 domains (cardiopulmonary and cardiovascular symptoms), and 11 impact items (walk slowly/quickly on flat surface, walk uphill, carry things, light chores, need help, wash/dress self, think clearly, sad, worried, frustrated) across 2 domains (physical impacts and cognitive/emotional impacts). Compliance in completing the questionnaire was 83%. PAH-SYMPACT® is a clinically and PAH-patient relevant instrument. This PRO has the potential to become an important outcome measure for PAH in both clinical practice and clinical trials.