A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome

Akram Khan, Cody Benthin, Brian Zeno, Timothy E Albertson, John Boyd, Jason D Christie, Richard Hall, Germain Poirier, Juan J Ronco, Mark Tidswell, Kelly Hardes, William M Powley, Tracey J Wright, Sarah K Siederer, David A Fairman, David A Lipson, Andrew I Bayliffe, Aili L Lazaar, Akram Khan, Cody Benthin, Brian Zeno, Timothy E Albertson, John Boyd, Jason D Christie, Richard Hall, Germain Poirier, Juan J Ronco, Mark Tidswell, Kelly Hardes, William M Powley, Tracey J Wright, Sarah K Siederer, David A Fairman, David A Lipson, Andrew I Bayliffe, Aili L Lazaar

Abstract

Background: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury.

Methods: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up.

Results: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score.

Conclusions: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes.

Trial registration: ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Keywords: Acute lung injury; Acute respiratory failure; Adult; Angiotensin-converting enzyme 2; Humans; Interleukin-6; Renin-angiotensin system; Respiratory distress syndrome.

Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

After institutional review board approval was provided at each institution (available as part of Additional file 2), written informed consent was obtained from each patient or the patient’s legally authorized surrogate prior to conduct of study-specific procedures.

Consent for publication

Not applicable.

Competing interests

AK has received funding from GlaxoSmithKline, AstraZeneca, United Therapeutics, and Actelion Pharmaceuticals to conduct industry-sponsored research studies. TEA has received funding from GlaxoSmithKline to conduct industry-sponsored research studies. JDC has received institutional funding from GlaxoSmithKline and Bristol-Myers Squibb to conduct investigator-initiated observational studies. RH has received funding from GlaxoSmithKline, Asahi Kasei Pharma, La Jolla Pharmaceutical, Eli Lilly, AstraZeneca, and Pfizer to conduct industry-sponsored research studies. KH, WMP, TJW, SKS, DAF, DAL, AIB, and ALL are employees of GSK and own shares in the company. The other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
(Consolidated Standards of Reporting Trials (CONSORT) diagram of subject disposition
Fig. 2
Fig. 2
Change from baseline in plasma concentrations of angiotensin II (Ang II) (a), Ang 1–7 (b), and Ang 1–5 (c) following treatment with placebo or GSK2586881 (recombinant human angiotensin-converting enzyme 2 [rhACE2]). Data are expressed as adjusted median ± 95% credible interval (CrI). n* is number of subjects available for each measurement
Fig. 3
Fig. 3
Change from baseline in plasma concentrations over time and in ratio to placebo for interleukin (IL)-6 (a, b) and surfactant protein D (SP-D) (c, d). Data are expressed as adjusted median ± 95% credible interval. n* is the number of subjects available for each measurement. rhACE2 Recombinant human angiotensin-converting enzyme 2
Fig. 4
Fig. 4
Change from baseline in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2, a), plateau pressure (Pplat, b), and static compliance (Cstat, c). Data are expressed as adjusted median ± 95% credible interval. n* is the number of subjects available for each measurement

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