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APN 01

Drug Profile

APN 01

Alternative Names: APN-01; GSK-2586881; Recombinant-human-soluble-angiotensin-converting-enzyme-2-Apeiron-Biologics; rhACE2; rhACE2-Apeiron-Biologics

Latest Information Update: 02 Jun 2020

At a glance

  • Originator Apeiron Biologics
  • Developer Apeiron Biologics; GlaxoSmithKline; University of British Columbia
  • Class Antihypertensives; Antineoplastics; Cardiovascular therapies; Heart failure therapies; Recombinant proteins
  • Mechanism of Action ACE stimulants
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes

Highest Development Phases

  • Phase II Acute lung injury; Adult respiratory distress syndrome; COVID 2019 infections; Pulmonary arterial hypertension
  • Discontinued Cancer; Diabetic nephropathies; Heart failure; Hypertension; Myocardial infarction

Most Recent Events

  • 04 May 2020 Apeiron Biologics initiates enrolment in a phase II trial for COVID-19 infections in Denmark, Germany and Austria (IV)(NCT04335136) (EudraCT2020-001172-15)
  • 03 Apr 2020 Phase-II clinical trials in COVID-2019 infections in United Kingdom (IV) (EudraCT2020-001172-15)
  • 02 Apr 2020 Phase-II clinical trials in COVID-2019 infections in Denmark, Germany, Austria (IV) (NCT04335136)

Development Overview

Introduction

APN 01 is a recombinant human angiotensin converting enzyme 2 (rhACE2), being developed by Apeiron Biologics, for the treatment of acute lung injury/adult respiratory distress syndrome, pulmonary arterial hypertension, and COVID-2019 infections. Clinical development is underway in the US, Germany and Canada, for the treatment of acute lung injury/adult respiratory distress syndrome, and in the US, Germany and Spain, for the treatment of pulmonary arterial hypertension. In addition, clinical development is ongoing in China, Austria, Denmark, Germany and the United Kingdom, for the treatment of COVID-2019 infections.

GlaxoSmithKline has decided not to pursue the development of GSK 2586881. Apeiron previously evaluated the compound as a treatment for cancer, cardiovascular diseases (including hypertension, heart failure and myocardial infarction), and diabetic kidney diseases (including diabetic nephropathies); however, development has been discontinued in these indications.

The Renin Angiotensin System (RAS) affects the function of most organs, controlling important functions such as blood pressure, volume and electrolytes. Target indications of the rhACE2 enhancement therapy are diseases and conditions that have an imbalance of the RAS system and insufficient natural angiotensin converting enzyme-2 (ACE2) activity such as cardiovascular, pulmonary and diabetic kidney diseases. ACE2 acts on the vasoconstrictor peptide angiotensin II (ANG II) and other substrates and is the only active homologue of ACE. The ACE enzyme is also used by virusus to enter the cell. The virus binds to soluble ACE2/APN01, instead of ACE2 on the cell surface, thus rendering the virus incapable to cause infections. Researchers at Apeiron stipulate that by increasing the circulating levels of ACE2 (through the administration of rhACE2) a more rapid degradation of ANG II could be promoted resulting in the prevention of ANG II-induced hypertension.

The SARS-CoV-2 virus relies on the ACE2 receptor to infect human cells, thus, making it a target of choice to block viral spread while minimizing lung injury, in patients with COVID-2019 infections.

Company Agreements

In 2019, Apeiron Biologics obtained the APN 01 licenses back from GlaxoSmithKline (GSK) for further clinical development, after a strategic refocusing of GSK to oncology. Apeiron currently has the full licenses, clinical data and protocol from GSK, GMP production technology and stored GMP grade rhACE2 available for immediate use in trials in China. In February 2010, Apeiron Biologics AG (Apeiron) signed an agreement granting GlaxoSmithKline (GSK) exclusive rights to APN01 (recombinant human Angiotensin Converting Enzyme 2, rhACE2), an enzyme biotherapeutic currently in phase 1 development for the treatment of the acute respiratory distress syndrome (ARDS). Under the terms of the agreement, the total milestone payments could reach £207 million (approx. €236 million) in the event of launch in multiple indications. Apeiron will receive an up-front payment of £11 million (approx. €12.5 million) in cash and equity investment and will receive royalties on net sales.

This deal value was converted from £ at a rate of $US1.595 dated 2 February 2010. [1] [2]

Key Development Milestones

In April 2020, APEIRON Biologics initiated a phase II trial to assess safety and tolerability of APN 01 in patients with COVID-2019 infections (APN01-01COVID19; EudraCT2020-001172-15; NCT04335136). The primary objective of the trial is to assess the clinical efficacy and safety of APN 01 in severe COVID-19 patients using the need for invasive mechanical ventilation. Secondary objectives include the evaluation of measurable biological biomarker changes following treatment with APN 01. The randomised, double-blind trial has initiated enrolment of approximately 200 patients in Austria, Germany, Denmark, and the United Kingdom, and is expected to expand to other countries including the US, Canada and Russia [3] [4] .

APEIRON Biologics and University of British Columbia, in February 2020, reported of the initiation of a pilot investigator-initiated clinical trial, designed to evaluate APN 01, in patients with severe COVID-2019 infections. The unblinded study is expected to enrol approximately 24 patients in China. Data from the study is expected to support a potential phase IIb study in larger patient population [2] .

In 2019, APEIRON obtained the licenses related to APN 01 back from GlaxoSmithKline (GSK) for further clinical development, after a strategic refocusing of GSK to oncology. As per APEIRONs' pipeline APN 01 is still in phase II development for acute lung injury and pulmonal arterial hypertension [2] .

As at July 2019, GlaxoSmithKline decided to discontinue the development of GSK 2586881(GlaxoSmithKline pipeline July 2019).

In May 2019, GlaxoSmithKline completed a phase IIa dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of GSK 2586881 in patients with pulmonary arterial hypertension (206246; NCT03177603; EudraCT2017-000212-41). The open-label, parallel trial initiated in February 2018 and enrolled 23 patients in Spain, Germany and USA [5] .

GlaxoSmithKline completed a phase IIa trial in the US and Canada, which evaluated the tolerability, safety, pharmacokinetics and pharmacodynamics of GSK 2586881 in 44 patients with acute respiratory distress syndrome or acute lung injury, in October 2014 (NCT01597635; 114622). The trial was initiated in September 2012 and was conducted in two parts; an open-label phase and a double-blind, placebo-controlled phase [6] [7] .

In January 2019, GlaxoSmithKline terminated a phase I trial due to technical feasibility, operational considerations and futility in line with pre-specified criteria, that was designed to evaluate the effect of a single IV dose of GSK 2586881 on the acute hypoxic pulmonary vasoconstriction response, in healthy volunteers (204987; NCT03000686). The single-centre, randomised, crossover, placebo-controlled, double-blind trial intended to enrol approximately 25 volunteers in Germany [8] .

In December 2009, Apeiron completed a phase I trial of GSK 2586881 in 22 healthy volunteers in Switzerland (NCT00886353; APN01-1-01). The trial determined the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple intravenous doses of GSK 2586881. In the single dose, dose escalation part, four cohorts received GSK 2586881 (100, 200, 400 or 800 µg/kg) or placebo. In the multiple dose part, two cohorts received three and six administrations of GSK 2586881 daily, respectively; the planned dosage was 400 µg/kg. Study results showed GSK 2586881 to be safe; no side effects or toxicities were found [9] [10] .

In an ex vivo study, treatment with GSK 2586881 of undiluted heparinised plasma samples or effusions of patients with cancer resulted in the reduction of elevated angiotensin II. Apeiron filed for an application to initiate a clinical trial of GSK 2586881 in patients with advanced cancer; however, no recent development has been reported for this indication [9] .

Promising data from GSK 2586881 in murine models of hypertension were presented at the 18th European Society of Hypertension and the 22nd Scientific Meeting of the International Society of Hypertension Sessions (HYP-2008) [11] . However, no recent development has been reported for this indication.

COVID-19 infections

In March 2020, Apeiron Biologics withdrawed a clinical trial prior to enrollment, as there was no CDE Approval. The trial was designed to evaluate APN 01 in adult patients with COVID-19 infections (GIRH-APN01; NCT04287686). The randomised, open label, controlled clinical study intended to enrol patients in China [12] .

Drug Properties & Chemical Synopsis

  • Route of administration IV
  • Formulation Infusion, unspecified
  • Class Antihypertensives, Antineoplastics, Cardiovascular therapies, Heart failure therapies, Recombinant proteins
  • Target ACE
  • Mechanism of Action ACE stimulants
  • WHO ATC code

    A10X (Other Drugs Used in Diabetes)

    C01 (Cardiac Therapy)

    C02 (Antihypertensives)

    J05A-X (Other antivirals)

    L01 (Antineoplastic Agents)

    R07A (Other Respiratory System Products)

  • EPhMRA code

    A10X (Other Drugs Used in Diabetes)

    C1 (Cardiac Therapy)

    C2 (Antihypertensives)

    J5B9 (Antivirals, others)

    L1 (Antineoplastics)

    R7 (Other Respiratory System Products)

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

acute lung injury

not specified

secretoglobin, family 1A, member 1

Angiotensinogen

ACE2

1

1

1

acute lung injury

Inclusion

Bilirubin

1

acute lung injury

Outcome Measure

Uric acid

TNF-alpha

Surfactant protein D

Renin

RAGE

MPO

IL8

IL6

CRP

Bilirubin

Angiopoietin 2

Aldosterone

1

1

1

1

1

1

1

1

1

1

1

1

Pulmonary arterial hypertension

Outcome Measure

troponin I, cardiac

Nitric Oxide

NAD

BNP

Angiopoietin 2

1

1

1

1

1

respiratory distress syndrome

not specified

secretoglobin, family 1A, member 1

Angiotensinogen

ACE2

1

1

1

respiratory distress syndrome

Inclusion

Bilirubin

1

respiratory distress syndrome

Outcome Measure

Uric acid

TNF-alpha

Surfactant protein D

Renin

RAGE

MPO

IL8

IL6

CRP

Bilirubin

Angiopoietin 2

Aldosterone

1

1

1

1

1

1

1

1

1

1

1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
APN 01 ACE2 not specified
Aldosterone Outcome Measure
Angiopoietin 2 Outcome Measure
Angiotensinogen not specified
Bilirubin Inclusion, Outcome Measure
BNP Outcome Measure
CRP Outcome Measure
IL6 Outcome Measure
IL8 Outcome Measure
MPO Outcome Measure
NAD Outcome Measure
Nitric Oxide Outcome Measure
RAGE Outcome Measure
Renin Outcome Measure
secretoglobin, family 1A, member 1 not specified
Surfactant protein D Outcome Measure
TNF-alpha Outcome Measure
troponin I, cardiac Outcome Measure
Uric acid Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Acute lung injury - - Phase II Canada, USA IV / unspecified Apeiron Biologics 27 Feb 2012
Adult respiratory distress syndrome - - Phase II Canada, USA IV / unspecified GlaxoSmithKline 27 Feb 2012
Adult respiratory distress syndrome - In volunteers Phase I Germany IV / unspecified GlaxoSmithKline 17 May 2017
COVID 2019 infections - - Phase II Austria, Denmark, Germany, United Kingdom IV / Infusion Apeiron Biologics 03 Apr 2020
COVID 2019 infections - - Phase II China IV / Infusion Apeiron Biologics, University of British Columbia 26 Feb 2020
Cancer - In volunteers Discontinued (I) Switzerland IV / unspecified Apeiron Biologics 28 Jun 2017
Diabetic nephropathies - In volunteers Discontinued (I) Switzerland IV / unspecified Apeiron Biologics 28 Jun 2017
Heart failure - In volunteers Discontinued (I) Switzerland IV / unspecified Apeiron Biologics 28 Jun 2017
Hypertension - In volunteers Discontinued (I) Switzerland IV / unspecified Apeiron Biologics 28 Jun 2017
Myocardial infarction - In volunteers Discontinued (I) Switzerland IV / unspecified Apeiron Biologics 28 Jun 2017
Myocardial infarction - - Discontinued (Preclinical) USA IV / unspecified Apeiron Biologics 28 Jun 2017
Pulmonary arterial hypertension - - Phase II Germany, Spain, USA IV / Infusion Apeiron Biologics 21 Feb 2018

Commercial Information

Involved Organisations

Organisation Involvement Countries
Apeiron Biologics Originator Austria
Apeiron Biologics Owner Austria
University of British Columbia Collaborator Canada

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Acute Lung Injury Wrld (50% US) - Development Stopped - - - - 02 Apr 2020

Scientific Summary

Pharmacodynamics

Summary

After 3 days of infusion, serum ACE 2 activity was increased in mice receiving GSK 2586881 compared with control mice (3.93±0.97 versus 0.69±0.39 RFU/µl/hr). Infusion of ANG II alone increased plasma ANG II levels but when given together with GSK 2586881, ANG II levels decreased to the levels of the placebo-infused controls. This increase in blood pressure associated with ANG II infusion was was not observed in mice infused simultaneously with GSK 2586881 and ANG II (n=7) (139±3.6 mmHg versus 156±6.4) [11] .

Future Events

Expected Date Event Type Description Updated
07 Aug 2017 Trial Update GlaxoSmithKline plans a phase II trial for Pulmonary arterial hypertension in USA (IV, Infusion) (NCT03177603) 21 Aug 2017

Development History

Event Date Update Type Comment
04 May 2020 Trial Update Apeiron Biologics initiates enrolment in a phase II trial for COVID-19 infections in Denmark, Germany and Austria (IV)(NCT04335136) (EudraCT2020-001172-15) Updated 25 May 2020
03 Apr 2020 Phase Change - II Phase-II clinical trials in COVID-2019 infections in United Kingdom (IV) (EudraCT2020-001172-15) Updated 02 Jun 2020
02 Apr 2020 Financial Update Credit Suisse financial data update Updated 11 Apr 2020
02 Apr 2020 Phase Change - II Phase-II clinical trials in COVID-2019 infections in Denmark, Germany, Austria (IV) (NCT04335136) [3] Updated 06 Apr 2020
02 Apr 2020 Regulatory Status APEIRON Biologics receives regulatory approvals in Austria, Germany and Denmark, for a phase II trial for COVID-2019 infections [3] Updated 06 Apr 2020
17 Mar 2020 Trial Update Apeiron Biologics withdraws a clinical trial for COVID-2019-infections in China, prior to enrollment (NCT04287686) Updated 24 Mar 2020
26 Feb 2020 Phase Change - II Phase-II clinical trials in COVID-2019 infections in China (IV) [2] Updated 02 Jun 2020
26 Feb 2020 Licensing Status APEIRON Biologics obtains its license back from GlaxoSmithKline for APN 01 [2] Updated 28 Feb 2020
26 Feb 2020 Trial Update Apeiron Biologics plans a pilot investigator initiated clinical trial for COVID-2019-infections in China [2] (NCT04287686) Updated 28 Feb 2020
07 May 2019 Trial Update GlaxoSmithKline completes a phase II trial in Pulmonary arterial hypertension in USA, Germany and Spain (NCT03177603) Updated 26 Jun 2019
25 Jan 2019 Trial Update GlaxoSmithKline terminates a phase I trial in Adult respiratory distress syndrome (In volunteers) in Germany due to technical feasibility, operational considerations and futility in line with pre-specified criteria (IV) (NCT03000686) Updated 12 Feb 2019
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
04 May 2018 Trial Update GlaxoSmithKline re initiates phase I trial in Adult respiratory distress syndrome (In volunteers) in Germany (IV) (NCT03000686) Updated 16 May 2018
21 Feb 2018 Phase Change - II Phase-II clinical trials in Pulmonary arterial hypertension in Germany, USA (IV) (NCT03177603) Updated 26 Jun 2019
04 Dec 2017 Trial Update GlaxoSmithKline terminates phase I trial in Adult respiratory distress syndrome (In volunteers) in Germany, following an interim analysis to conduct a thorough data review (IV) (NCT03000686) Updated 11 Dec 2017
28 Jun 2017 Phase Change - Discontinued(I) Discontinued - Phase-I for Myocardial infarction, Hypertension, Heart failure, Diabetic nephropathies and Cancer (In volunteers) in Switzerland (IV) Updated 28 Jun 2017
28 Jun 2017 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Myocardial infarction in USA (IV) Updated 28 Jun 2017
24 May 2017 Phase Change - II Phase-II clinical trials in Pulmonary arterial hypertension in Spain (IV) (EudraCT2017-000212-41) Updated 21 Aug 2017
23 May 2017 Trial Update GlaxoSmithKline plans a phase II trial for Pulmonary arterial hypertension in USA (IV, Infusion) (NCT03177603) Updated 21 Aug 2017
17 May 2017 Phase Change - I Phase-I clinical trials in Adult respiratory distress syndrome (In volunteers) in Germany (IV) (NCT03000686) Updated 28 Jun 2017
22 Dec 2016 Trial Update GlaxoSmithKline plans a phase I pharmacodynamics trial in Healthy volunteers in Germany (IV, Infusion) (NCT03000686) Updated 26 Dec 2016
20 Jul 2015 Active Status Review Phase-II development is ongoing for Acute lung injury and Acute respiratory distress syndrome in Canada and USA Updated 20 Jul 2015
01 Oct 2014 Trial Update GlaxoSmithKline completes a phase II clinical trial in Acute lung injury and Acute respiratory distress syndrome in Canada and USA (IV) (NCT01597635) Updated 05 Mar 2015
29 May 2012 Phase Change - No development reported(I) No development reported - Phase-I for Cancer in Switzerland (IV) Updated 29 May 2012
29 May 2012 Phase Change - No development reported(I) No development reported - Phase-I for Diabetic nephropathies in Switzerland (IV) Updated 29 May 2012
29 May 2012 Phase Change - No development reported(I) No development reported - Phase-I for Heart failure in Switzerland (IV) Updated 29 May 2012
29 May 2012 Phase Change - No development reported(I) No development reported - Phase-I for Hypertension in Switzerland (IV) Updated 29 May 2012
29 May 2012 Phase Change - No development reported(I) No development reported - Phase-I for Myocardial infarction in Switzerland (IV) Updated 29 May 2012
29 May 2012 Phase Change - No development reported(Preclinical) No development reported - Preclinical for Myocardial infarction in USA (IV) Updated 29 May 2012
27 Feb 2012 Phase Change - II Phase-II clinical trials in Acute lung injury in Canada (IV) Updated 30 May 2012
27 Feb 2012 Phase Change - II Phase-II clinical trials in Acute lung injury in USA (IV) Updated 30 May 2012
27 Feb 2012 Phase Change - II Phase-II clinical trials in Adult respiratory distress syndrome in Canada (IV) Updated 29 May 2012
27 Feb 2012 Phase Change - II Phase-II clinical trials in Adult respiratory distress syndrome in USA (IV) Updated 29 May 2012
02 Feb 2010 Licensing Status GSK 2586881 licensed to GlaxoSmithKline worldwide [1] Updated 18 Feb 2010
30 Apr 2009 Phase Change - I Phase-I clinical trials in Cancer in Switzerland (IV) Updated 16 Jun 2010
02 Mar 2009 Phase Change - I Phase-I clinical trials in Adult respiratory distress syndrome in Switzerland (IV) Updated 02 Mar 2009
02 Mar 2009 Phase Change - I Phase-I clinical trials in Diabetic nephropathies in Switzerland (IV) Updated 02 Mar 2009
02 Mar 2009 Phase Change - I Phase-I clinical trials in Heart failure in Switzerland (IV) Updated 02 Mar 2009
02 Mar 2009 Phase Change - I Phase-I clinical trials in Hypertension in Switzerland (IV) Updated 02 Mar 2009
02 Mar 2009 Phase Change - I Phase-I clinical trials in Myocardial infarction in Switzerland (IV) Updated 02 Mar 2009
30 Jun 2008 Other The GMP-batch of GSK 2586881 is ready for first clinical trials Updated 02 Mar 2009
19 Jun 2008 Phase Change - Preclinical Preclinical trials in Adult respiratory distress syndrome in Austria (Parenteral) Updated 15 Jul 2008
19 Jun 2008 Phase Change - Preclinical Preclinical trials in Diabetic nephropathies in Austria (Parenteral) Updated 15 Jul 2008
19 Jun 2008 Phase Change - Preclinical Preclinical trials in Heart failure in Austria (Parenteral) Updated 15 Jul 2008
19 Jun 2008 Phase Change - Preclinical Preclinical trials in Hypertension in Austria (Parenteral) Updated 15 Jul 2008
19 Jun 2008 Phase Change - Preclinical Preclinical trials in Myocardial infarction in Austria (Parenteral) Updated 15 Jul 2008
31 Mar 2008 Phase Change - Preclinical Preclinical trials in Adult respiratory distress syndrome in USA (Parenteral) Updated 02 Mar 2009
31 Mar 2008 Phase Change - Preclinical Preclinical trials in Myocardial infarction in USA (Parenteral) Updated 02 Mar 2009

References

  1. Apeiron and GSK sign an exclusive licence agreement for Apeiron's therapeutic enzyme project APN01.

    Media Release
  2. APEIRON's respiratory drug product to start pilot clinical trial to treat coronavirus disease COVID-19 in China.

    Media Release
  3. APEIRON Biologics Initiates Phase II Clinical Trial of APN01 for Treatment of COVID-19.

    Media Release
  4. Recombinant human angiotensin-converting enzyme 2 (rhACE2) as a treat-ment for patients with COVID-19

    ctiprofile
  5. 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

    ctiprofile
  6. Apeiron initiates clinical study to investigate prevention of radiationinduced skin damage in breast cancer patients.

    Media Release
  7. A Two Part Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2586881 in Patients With Acute Lung Injury

    ctiprofile
  8. The Effects of GSK2586881 on the Responses to Acute Hypoxia and Exercise

    ctiprofile
  9. Samonigg H, Bauernhofer T, Schaefer R, Peball B, Janzek E, Schuster M, et al. Recombinant human ACE2 as a novel biotherapeutic for the treatment of patients with cancer. 46th-ASCO-2010 2010; abstr. e13653.

    Available from: URL: http://www.asco.org
  10. Double-Blind, Placebo-Controlled Dose-Escalation Phase I Study With Recombinant Human Soluble Angiotensin Converting Enzyme 2 (rhACE2) APN01 in Healthy Volunteers

    ctiprofile
  11. Ye M, Wysocki J, Rodriguez E, Schuster M, Loibner H, Penninger J, et al. Human recombinant ACE2 abrogates angiotensin II-dependent hypertension by effectively degrading angiotensin II. J-Hypertens 2008;26 (Suppl. 1)19 abstr. OS17/2.

  12. A Randomized, Open Label, Controlled Clinical Study to Evaluate the Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) in Adult Patients With COVID-19

    ctiprofile
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