Universität zu Köln

Simon, Marc A., Hanrott, Kate, Budd, David C., Torres, Fernando, Gruenig, Ekkehard, Escribano-Subias, Pilar, Meseguer, Manuel L., Halank, Michael, Opitz, Christian, Hall, David A., Hewens, Deborah, Powley, William M., Siederer, Sarah, Bayliffe, Andrew, Lazaar, Aili L., Cahn, Anthony and Rosenkranz, Stephan (2022). 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. Pulm. Circ., 12 (1). HOBOKEN: WILEY. ISSN 2045-8940

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Simon, Marc A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hanrott, Kate UNSPECIFIED UNSPECIFIED UNSPECIFIED Budd, David C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Torres, Fernando UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruenig, Ekkehard UNSPECIFIED UNSPECIFIED UNSPECIFIED Escribano-Subias, Pilar UNSPECIFIED UNSPECIFIED UNSPECIFIED Meseguer, Manuel L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Halank, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Opitz, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hall, David A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hewens, Deborah UNSPECIFIED UNSPECIFIED UNSPECIFIED Powley, William M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Siederer, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Bayliffe, Andrew UNSPECIFIED UNSPECIFIED UNSPECIFIED Lazaar, Aili L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cahn, Anthony UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenkranz, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-693912
DOI:	10.1002/pul2.12024
Journal or Publication Title:	Pulm. Circ.
Volume:	12
Number:	1
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	2045-8940
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ANGIOTENSIN-CONVERTING ENZYME; ALDOSTERONE SYSTEM; SMOOTH-MUSCLE; PROTECTION; THERAPY Multiple languages Cardiac & Cardiovascular Systems; Respiratory System Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69391