DUBLIN – Could a recombinant human protein drug rejected by Glaxosmithkline plc in 2019 benefit patients with COVID-19 infection? Apeiron Biologics AG disclosed Wednesday Feb. 26 that an investigator-initiated pilot study of APN-01 is getting underway in Guangzhou, China. The drug, a recombinant form of human angiotensin-converting enzyme 2 (ACE2), was the subject of a 2010 license agreement potentially worth up to $329 million between London-based GSK and Vienna-based Apeiron.

GSK conducted two phase II trials, in acute lung injury or acute respiratory distress syndrome and in pulmonary arterial hypertension, as well as a phase I study in healthy volunteers to assess its effects on hypoxia after exercise. However, it dropped the drug in 2019 as part of a widespread cull of its respiratory disease pipeline.

Apeiron is dusting the drug off now because of a key finding reported by one of the first teams of scientists who responded to the SARS-CoV-2 outbreak in Wuhan. The group, led by Zheng-Li Shi, at the Wuhan Institute of Virology of the Chinese Academy of Sciences, was one of several to identify the novel coronavirus as the cause of the pneumonia outbreak in Wuhan, and it deposited three of the early genome sequences from which international groups have designed PCR tests that have kickstarted the global response to the outbreak.

Crucially, they also conducted virus infectivity studies using HeLa cells, expressing or not expressing ACE2 from humans, Chinese horseshoe bats, civet, pig and mouse. From those, they identified ACE2 from all of those species, with the expectation of mice, as the receptor SARS-CoV-2 uses to gain entry to cells. They also eliminated the possibility that SARS-CoV-2 can enter cells using two other known coronavirus receptors, aminopeptidase N and dipeptidyl peptidase 4. That work was published online in Nature on Feb. 3, 2020, in a paper, titled “A pneumonia outbreak associated with a new coronavirus of probable bat origin.”

The work is essential to understanding the pathophysiology of the current coronavirus, but it is no great surprise from a virology perspective. The coronavirus strain responsible for the 2002-2003 SARS outbreak, SARS-CoV, also employed ACE2 as a functional receptor to gain cellular entry, as a group led by Hyeryun Choe and Michael Farzan, who are both now based at Jupiter, Fla., campus of The Scripps Research Institute, reported in 2003. That study was also conducted using cellular infectivity assays.

Apeiron’s scientific founder, Josef Penninger, scientific director of the Life Sciences Institute at the University of British Columbia, Vancouver, built on that work by demonstrating the role of ACE2 in vivo. His group in collaboration with Chengyu Jiang, of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, and other workers, reported in Nature Medicine in 2005 that injection of the SARS-CoV spike protein – which is essential for infectivity – worsened acute lung failure. The effect was reduced by blocking the renin-angiotensin pathway. At the same time, they also reported in Nature that ACE2 protected mice from severe acute lung failure in two different models.

However, the same compound, then called GSK-2586881, was found wanting in a pilot study in patients with acute lung injury or acute respiratory distress syndrome (ARDS). The trial was terminated after 39 of a planned 60 patients were treated, following a planned futility analysis. It had failed to demonstrate any improvement in physiological or clinical measures of ARDS, according to a report published online on Sept. 7, 2017, in Critical Care.

ARDS is, of course, not the same disease as COVID-19. Those in the earlier trial developed ARDS from a variety of causes, including pneumonia, sepsis, infection or aspiration, whereas the upcoming study will have a more homogeneous patient population. A big question is whether an intravenous infused biologic drug will have sufficient effects in the airways of infected patients. Although the biological activity of APN-01 might suggest it could act as a decoy receptor and prevent SARS-CoV-2 viruses from infecting the airway epithelia, its more likely role is its inactivation of angiotensin II and interruption of renin-angiotensin-system (Ras) signaling, which is broadly implicated in the pathology of acute lung injury.

The unblinded study will recruit 24 patients with severe SARS-CoV-2 infection, who will receive the drug for seven days in order to assess its effects on biological, physiological and clinical parameters. The trial will be overseen by Nanshan Zhong and Yimin Li, both of the Guangzhou Institute of Respiratory Health at Guangzhou Medical University, who will be supported Arthur Slutsky and Haibo Zhang, both of the University of Toronto, as well as Penninger. The data will feed into a go/no-go decision on undertaking a phase IIb trial in a larger group of patients.

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