Vachiéry, Jean‐Luc

Abstract Rationale Seralutinib is an investigational, first-in-class tyrosine kinase inhibitor designed for inhalation and selective for PDGFRα, PDGFRβ, CSF1R, and cKIT, targeting proliferation, inflammation, and fibrosis ─ three core drivers of pulmonary vascular remodeling in PAH. The phase 2 TORREY trial of seralutinib added to standard-of-care treatment in adults with PAH WHO FC II or III met its primary endpoint of a statistically significant reduction in pulmonary vascular resistance (PVR) vs. placebo at 24 weeks. Methods PROSERA (NCT05934526), a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, evaluated the efficacy and safety of inhaled seralutinib in PAH patients treated for up to 48 weeks. Eligible patients (WHO Group 1 PH, FC II or III; REVEAL Lite 2 Risk Score ≥5 or NT-proBNP ≥300 ng/L or PVR ≥800 dyne•s/cm5) on standard background therapy were randomized 1:1 to seralutinib 90 mg or placebo delivered by dry powder inhaler twice daily. The primary endpoint was change in six-minute walk distance (6MWD) from baseline to week 24 in the seralutinib treatment group vs. placebo. Key secondary endpoints included: time to clinical worsening (TTCW), proportion of patients with clinical improvement at week 24, change in NT-proBNP from baseline to week 24, and proportion of patients with ≥1-point decrease from baseline in REVEAL Lite 2 Risk Score at week 24. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs). Patients who completed blinded treatment could be eligible to participate in an open-label extension study. Preliminary Blinded Results 390 patients were randomized at 132 sites worldwide. At baseline, mean age was 50.0 years. PAH etiologies included 61.0% idiopathic, 9.7% heritable, and 22.3% associated with connective tissue disease. 25.6% of patients were WHO FC II and 74.4% FC III. Mean time from diagnosis was TBD years. Most patients were receiving 2 (39.2%) or ≥ 3 (54.6%) PAH medications, 29.2% were receiving parenteral prostacyclin. Baseline PVR was 798.4 dyne•s/cm5, 6MWD was 373.7 m, and NT-proBNP was 986.8 ng/L. The difference in 6MWD from baseline to week 24 between seralutinib and placebo was TBD [SD] m (p=TBD). Secondary endpoints of TTCW, clinical improvement, NT-proBNP, and REVEAL Lite 2 Risk Score will be reported. The most common AEs were TBD (x%) and TBD (y%). SAEs and discontinuations related to AE will be reported. Conclusions The PROSERA study demonstrates⋯ [to be updated following unblinding of the data]. Funding Gossamer Bio, Inc. This abstract is funded by: Gossamer Bio, Inc.

The results underscore a multifaceted interaction among cardiopulmonary hemodynamics, right heart pressures, ventilatory response, and autonomic regulation. In particular, altered RV-PA coupling correlated with heightened sympathetic drive, indicating that cardiopulmonary efficiency and hemodynamics may influence central autonomic outputs. This suggests that mechanical stress or overload in the right heart could modulate sympathovagal balance, thereby contributing to altered autonomic responses during exercise in patients with cardiopulmonary disorders.

ABSTRACTLung transplantation is indicated for selected patients with advanced pulmonary arterial hypertension (PAH). We used a modified Delphi process to develop recommendations on care of patients with PAH undergoing lung transplantation. This Delphi panel was recruited from the Pulmonary Vascular Research Institute's Innovative Drug Discovery Initiative ‐ Lung Transplantation Workstream, consisting of clinical and research experts in PAH and lung transplantation. In this process, 29 panelists were given open‐ended questions, querying topics related to lung transplantation in PAH. A steering group converted the responses into discrete statements. Panelists then rated agreement using a Likert scale in two further survey rounds: −5 (strongly disagree) to 5 (strongly agree). Consensus was defined as mean ≥ 2.5 or ≤ −2.5, with a standard deviation not crossing zero. Consensus was reached on 141 of 223 statements. Notable areas of consensus were for early discussions about transplantation, and agreement with previously published referral and listing criteria. There was agreement that lung transplantation could be offered in sick candidates, including those with concurrent renal or hepatic insufficiency. Bilateral lung transplantation was considered the procedure of choice for most patients, with rare indications for heart‐lung transplantation. Consensus on bridging strategies included use of veno‐arterial extracorporeal membrane oxygenation and preemptive awake cannulation in those with severe right ventricular dysfunction. Consensus was also achieved on intraoperative use of invasive hemodynamic monitoring, and prolonged postoperative circulatory support guided by hemodynamic response and echocardiography. Patients with PAH undergoing transplantation require specialized management, which differs somewhat from other candidates.

Abstract Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.

Abstract Background Impaired RV-PA coupling portends a poor prognosis in PAH, and right ventricular free wall strain/systolic pulmonary artery pressure (RVFWS/sPAP) has been reported as a measure of RV-PA coupling. Furthermore, increased RVFWS and right atrial area (RAA), as well as decreased pulmonary artery compliance (PAC) are associated with increased mortality risk in PAH. Seralutinib is a novel, small molecule kinase inhibitor that targets PDGFR, CSF1R, and c-KIT administered via dry powder inhaler. TORREY, a phase 2, double-blind, randomised, placebo-controlled study of inhaled seralutinib in patients with PAH (NCT04456998) met its primary endpoint, demonstrating a significant reduction in pulmonary vascular resistance (PVR) from baseline (BL) to Week 24 compared to placebo. In addition, seralutinib significantly decreased NT-proBNP. Purpose To test the hypothesis that seralutinib would improve RVFWS/sPAP and other measures of right heart function after 24 weeks of treatment compared to placebo in the TORREY study. Methods Eighty-six patients with WHO Group 1 PH (Functional Class II, III), ages ≥18 years, pulmonary vascular resistance ≥400 dyne*s/cm5, and on stable PAH standard of care therapy (the majority of whom were on double and triple therapy with approved PAH medications) were enrolled. Right heart catheterisation (RHC) and full echocardiography were performed at BL and Week 24 and at BL, Week 12, and Week 24, respectively; both were analysed in a blinded central laboratory. To calculate RVFWS/sPAP, the pulmonary artery systolic pressure from RHC was used. PAC was calculated from RHC data with the formula (SV/(PAS-PAD)). Statistical analysis was performed using ANCOVA. Results At Week 24, the change in RVFWS/sPAP was lower in the seralutinib group compared to placebo (Table). The changes in RVFWS and RAA were lower in the seralutinib group vs placebo at Week 12 and Week 24 (Table). Change in NT-proBNP correlated with change in RAA (r = 0.43). At Week 24, change in PAC was greater in the seralutinib group (-0.02 ± 0.085 placebo, 0.19 ± 0.089 seralutinib; LSMD 0.22 (0.104) p = 0.04). There was no effect of seralutinib on left ventricular ejection fraction. Conclusion Treatment with seralutinib was associated with a significant reduction of RVFWS/sPAP. In addition, significant differences in RVFWS itself, RAA, and PAC were observed. These treatment effects support improved RV-PA coupling and right heart function. In conjunction with concordant reductions in PVR and NT-proBNP, these data suggest potential favourable effects of seralutinib in PAH. Seralutinib is in clinical development as a potential new treatment option for patients with PAH.

AbstractRight heart (RH) structure and function are major determinants of symptoms and prognosis in pulmonary arterial hypertension (PAH). RH imaging provides detailed information, but evidence and guidelines on the use of RH imaging in treatment decisions are limited. We conducted a Delphi study to gather expert opinion on the role of RH imaging in decision‐making for treatment escalation in PAH. A panel of 17 physicians with expertise in PAH and RH imaging used three surveys in a modified Delphi process to reach consensus on the role of RH imaging in PAH. Survey 1 used open‐ended questions to gather information. Survey 2 contained Likert scale and other questions intended to identify consensus on topics identified in Survey 1. Survey 3 contained Likert scale questions derived from Survey 2 and summary information on the results of Survey 2. The Delphi panel reached consensus that RH imaging is likely to improve the current risk stratification algorithms and help differentiate risk levels in patients at intermediate risk. Tricuspid annular plane systolic excursion, right ventricular fractional area change, right atrial area, tricuspid regurgitation, inferior venae cavae diameter, and pericardial effusion should be part of routine echocardiography in PAH. Cardiac magnetic resonance imaging is valuable but limited by cost and access. A pattern of abnormal RH imaging results should prompt consideration of hemodynamic evaluation and possible treatment escalation. RH imaging is an important tool for decisions about treatment escalation in PAH, but systematically collected evidence is needed to clarify its role.