An open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of GSK2586881 in participants with pulmonary arterial hypertension.

Autor: Simon MA; Division of Cardiology, Department of Medicine University of California San Francisco California USA., Hanrott K; Research and Development, Medicines Research Centre GlaxoSmithKline plc. Stevenage UK., Budd DC; Research and Development, Medicines Research Centre GlaxoSmithKline plc. Stevenage UK., Torres F; UT Southwestern Medical Center Dallas Texas USA., Grünig E; Centre for Pulmonary Hypertension Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany., Escribano-Subias P; CIBER-CV Cardiology Department, Pulmonary Hypertension Unit Hospital Universitario 12 de Octubre Madrid Spain., Meseguer ML; Lung Transplant and Pulmonary Vascular Diseases Department Hospital Universitari Vall d'Hebron Barcelona Spain., Halank M; Department of Internal Medicine I University Hospital Carl Gustav Carus Dresden Germany., Opitz C; Department of Cardiology DRK Kliniken Berlin Germany.; Department of Cardiology, University Heart Center Berlin Charité University Medicine Berlin Germany., Hall DA; Research and Development, Medicines Research Centre GlaxoSmithKline plc. Stevenage UK., Hewens D; Research and Development, Medicines Research Centre GlaxoSmithKline plc. Stevenage UK., Powley WM; Research and Development, Medicines Research Centre GlaxoSmithKline plc. Stevenage UK., Siederer S; Research and Development, Medicines Research Centre GlaxoSmithKline plc. Stevenage UK., Bayliffe A; Research and Development, Medicines Research Centre GlaxoSmithKline plc. Stevenage UK.; Marengo Therapeutics and Apple Tree Partners Cambridge Massachusetts USA., Lazaar AL; Discovery Medicine, Clinical Pharmacology and Experimental Medicine GlaxoSmithKline plc. Collegeville Pennsylvania USA., Cahn A; Research and Development, Medicines Research Centre GlaxoSmithKline plc. Stevenage UK., Rosenkranz S; Department III of Internal Medicine, Cologne Cardiovascular Research Center (CCRC) Cologne University Heart Center Cologne Germany.
Jazyk: angličtina
Zdroj: Pulmonary circulation [Pulm Circ] 2022 Jan 20; Vol. 12 (1), pp. e12024. Date of Electronic Publication: 2022 Jan 20 (Print Publication: 2022).
DOI: 10.1002/pul2.12024
Abstrakt: Preclinical and early clinical studies suggest that angiotensin-converting enzyme type 2 activity may be impaired in patients with pulmonary arterial hypertension (PAH); therefore, administration of exogenous angiotensin-converting enzyme type 2 (ACE2) may be beneficial. This Phase IIa, multi-center, open-label, exploratory, single-dose, dose-escalation study (NCT03177603) assessed the potential vasodilatory effects of single doses of GSK2586881 (a recombinant human ACE2) on acute cardiopulmonary hemodynamics in hemodynamically stable adults with documented PAH who were receiving background PAH therapy. Successive cohorts of participants were administered a single intravenous dose of GSK2586881 of 0.1, 0.2, 0.4, or 0.8 mg/kg. Dose escalation occurred after four or more participants per cohort were dosed and a review of safety, tolerability, pharmacokinetics, and hemodynamic data up to 24 h postdose was undertaken. The primary endpoint was a change in cardiopulmonary hemodynamics (pulmonary vascular resistance, cardiac index, and mean pulmonary artery pressure) from baseline. Secondary/exploratory objectives included safety and tolerability, effect on renin-angiotensin system peptides, and pharmacokinetics. GSK2586881 demonstrated no consistent or sustained effect on acute cardiopulmonary hemodynamics in participants with PAH receiving background PAH therapy ( N  = 23). All doses of GSK2586881 were well tolerated. GSK2586881 was quantifiable in plasma for up to 4 h poststart of infusion in all participants and caused a consistent and sustained reduction in angiotensin II and a corresponding increase in angiotensin (1-7) and angiotensin (1-5). While there does not appear to be a consistent acute vasodilatory response to single doses of GSK2586881 in participants with PAH, the potential benefits in terms of chronic vascular remodeling remain to be determined.
Competing Interests: Marc A. Simon: Consultancy for Acceleron, Actelion, Altavant Sciences, Bial—Portela C S.A., and United Therapeutics. Research grants from Novartis. Hemodynamic core lab work for Aadi. Supported by NIH grants R01AG058659 and P01HL103455. Fernando Torres: Personal fees from Actelion, Bayer, Reata, and Arena and grants from Gilead, United Therapeutics, Medtronic, Eiger, and Bellerophon. Ekkehard Grünig: Research grants and lecture fees from Actelion/Janssen and Bayer/MSD, research grants from GSK, United Therapeutics, and Novartis, and lecture fees from SCOPE, OrPha Swiss GmbH, and Zurich Heart House. Pilar Escribano‐Subias: Consultancy and/or lectures for Acceleron, Actelion, Janssen, MSD United Therapeutics, Ferrer, and Abbott. Research grants to institutions from Janssen and Ferrer. Manuel López Meseguer: Remunerations for consultancy and/or lectures from Janssen, MSD, and GSK. Michael Halank: Wages for consultancy and/or lectures from Acceleron, Actelion, AstraZenca, Bayer, BerlinChemie, GSK, Janssen, MSD, and Novartis. Christian Opitz: Institution has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. Stephan Rosenkranz: Remunerations for consultancy and/or lectures from Abbott, Acceleron, Actelion, AstraZeneca, Bayer, BMS, Janssen, MSD, Novartis, Pfizer, United Therapeutics. Research grants to institution from Actelion, AstraZeneca, Bayer, Novartis; Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), and Else‐Kröner‐Fresenius‐Stiftung (EKFS). Kate Hanrott, David A. Hall, Deborah Hewens, William M. Powley, David C. Budd, Sarah Siederer, Aili L. Lazaar, and Anthony Cahn are employees and stock/shareholders of GlaxoSmithKline plc.
(© 2021 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)
Databáze: MEDLINE
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