Al‐Hiti, Hikmet

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.

BACKGROUND: Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. We aimed to analyze transpulmonary gradients of proteins consumed or elaborated across the lungs to identify mediators of PVD by unbiased proteomics. METHODS: Overall, 21 controls and 160 patients with HF with reduced ejection fraction underwent pulmonary artery catheterization with blood sampling from postcapillary (wedged balloon) and precapillary (unwedged) position to obtain transpulmonary gradients. The samples from controls and HF from the highest (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using the proteomic proximity extension assay (Olink) of 275 proteins. Venous blood concentrations or transpulmonary gradients were analyzed to identify biomarkers or potential mediators of PVD. RESULTS: Comparison of Q1 and Q4 of PVR identified PSP-D (pulmonary surfactant-associated protein D) as a marker of PVD. Examination of gradients across the lungs in high PVR HF revealed significant uptake of 18 proteins, mostly associated with inflammation (chemokines, oncostatin-M, MMP9 [matrix metalloproteinase 9]) or with TGF (transforming growth factor)/activin pathway (GDF2 [growth differentiation factor 2]/BMP9 [bone morphogenic protein 9]), and release of 5 proteins, notably IL (interleukin) 6 and IL33. In contrast, these protein gradients were negligible in controls and low PVR patients with HF. Active pulmonary release of IL6 contributed to systemic elevation of IL6 and correlated with right ventricular function. CONCLUSIONS: The lungs of patients with HF with high PVR display abnormal uptake and release of proinflammatory cytokines from IL6/gp130 family (IL6, IL33, oncostatin-M), along with increased transpulmonary uptake of GDF2/BMP9. The study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 pulmonary hypertension, are also operating in patients with PVD due to HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06331208.

Abstract Background Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Unbiased analysis of transpulmonary gradients may identify not only markers but also mediators of PVD by identifying proteins that may be consumed or elaborated across the lungs. Purpose Examine hemodynamics and transpulmonary proteome gradients in HFrEF and controls. Methods 21 non-HF controls and 160 patients with advanced HFrEF underwent pulmonary artery (PA) catheterization with blood sampling from the PA catheter in the wedged position (02sat > 90%, indicating pulmonary venous blood) and the un-wedged position to obtain transpulmonary proteome gradients. Samples from controls and HF from the highest quartile (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using proteomic PEA assay of 275 proteins (Olink Target 96, panels CVII, CVIII, Inflammation). Pulmonary artery concentrations ("markers") or transpulmonary fold-change gradients (i.e. putative "mediators") of normalized protein expression (NPX) were plotted against significance; Benjamini–Hochberg FDR<0.05 considered as significant. Results Patients displayed typical characteristics of HFrEF (age 56±8y, NYHA 3.0 ±0.6, 87% males, LVEF 24±9.6%), Controls had similar anthropometrics, gender and age. Comparing all HF to Con, 38 markers of HF were identified (NPX fold-change>2), including 33 up (top 5: NTproBNP, BNP, GDF15, FGF23, IL8) and 5 down. HF patients in Q1 had median PVR 1.5 (IQR: 0.3-1.7) WU and those in Q4 had PVR 5.4 (4.3-6.6) WU. Comparison of Q1 and Q4 identified 3 protein markers of high PVR in PA blood from HF: chemokine CCL3, TNFRSF13B and surfactant protein-D (PSP-D). Examination of protein gradients from HF lungs (Figure) showed significant uptake of 14 protein mediators, most of which were associated with inflammatory responses (top 5: OSM, MMP9, CCL19, BNP, TR), and release of 8 mediators (top 4: IL-6, IL33, CCL4, CXCL10). In contrast, protein gradients were negligible in controls. Patients in Q4 PVR group were characterized by the highest pulmonary uptake of OSM (Oncostatin-M), lymphatic chemokine CCL19, BNP, MMP9, and had more significant transpulmonary release of IL6 and IL33. Across all patients, OSM lung uptake was the strongest correlate of transpulmonary pressure gradient (r=-0.3, p<0.001). Conclusions Lungs of patients with HF, and particularly those with high PVR, display abnormal uptake and release of proinflammatory CC and CXC chemokines and cytokines from IL1 and IL6 family, along with increased pulmonary uptake of IL6-type cytokine Oncostatin-M, a known mediator of lung inflammation and fibrosis, that acts via gp130/JAK/STAT, suggesting a novel role in PVD due to HF.Transpulmonary proteome in HF patients