TY - JOUR
T1 - 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
AU - Simon, Marc A.
AU - Hanrott, Kate
AU - Budd, David C.
AU - Torres, Fernando
AU - Grünig, Ekkehard
AU - Escribano-Subias, Pilar
AU - Meseguer, Manuel L.
AU - Halank, Michael
AU - Opitz, Christian
AU - Hall, David A.
AU - Hewens, Deborah
AU - Powley, William M.
AU - Siederer, Sarah
AU - Bayliffe, Andrew
AU - Lazaar, Aili L.
AU - Cahn, Anthony
AU - Rosenkranz, Stephan
N1 - Funding Information:
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.
Funding Information:
The authors would like to thank the participants of the study as well as all study staff for their contributions to the study. The listed authors have authorized the submission of their manuscript via a third party and approved any statements or declarations listed in this manuscript. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Kirsty Millar, MSc, Zofia Zgrundo, MSc, and Andrew Briggs, BA, of Ashfield MedComms (Macclesfield, UK), an Ashfield Health company, and was funded by GlaxoSmithKline plc. (study 206246). Trademarks are owned by or licensed to Certara LP (Phoenix WinNonlin).
Publisher Copyright:
© 2021 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - arterial hypertension
KW - hemodynamics
KW - recombinant human angiotensin-converting enzyme 2
KW - renin-angiotensin system
KW - rhACE2
UR - http://www.scopus.com/inward/record.url?scp=85127278667&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127278667&partnerID=8YFLogxK
U2 - 10.1002/pul2.12024
DO - 10.1002/pul2.12024
M3 - Article
C2 - 35506108
AN - SCOPUS:85127278667
VL - 12
JO - Pulmonary Circulation
JF - Pulmonary Circulation
SN - 2045-8932
IS - 1
M1 - e12024
ER -