ACE2 agonist C21 relieves respiratory difficulty in COVID-19

The advent of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to over 2.2 million deaths over a period of just over a year. The lack of effective drugs to combat the virus has led to intensive research to identify preventive and therapeutic antivirals.

A new preprint on the medRxiv* server describes a pilot study on the efficacy of a molecule called C21, which enhances the activity of the angiotensin-converting enzyme 2 (ACE2), the host cell receptor that facilitates viral entry.

ACE2 in COVID-19

The ACE2 receptor is part of the renin-angiotensin system (RAS). The angiotensin II (AngII) type 1 receptor (AT1R) is responsible for the vasoactive actions of AngII, such as vasoconstriction and sodium retention, as well as cell growth. Excessive AT1R activation has been observed in certain cardiovascular, renal and pulmonary diseases.

This is counteracted by the opposing actions of the angiotensin II type 2 receptor (AT2R). This receptor is activated by ligands such as Ang 1-7 and Ang 1-9, produced by ACE2-mediated cleavage of AngII.

The SARS-CoV-2-ACE2 binding is known to result in the inactivation of the receptor as well as a reduction in its expression. This may lead to imbalanced RAS activity, with abnormal AT1R activation and deficient AT2R activity in COVID-19. An increase in AT2R activity could therefore be beneficial in the treatment of this condition.

Type 2 pneumocyte progenitors express a high level of AT2R, and these are also the cells where the virus replicates within the lungs, causing alveolar dysfunction and reduced gas exchange as consequences of the infection.


C21 is a novel oral AT2R agonist that is being developed for the treatment of idiopathic pulmonary fibrosis. It was recently tested out in phase I trials, proving to be both safe and well-tolerated. The current study thus investigated its potential benefit in severe COVID-19. This is probably the first time an AT2R has been studied in the treatment of any medical condition in humans.

The study details

The study was called ATTRACT (Angiotensin II Type Two Receptor Agonist COVID-19 Trial), and was carried out between 21 July and 29 September 2020 at eight trial sites in India, on 106 patients aged 19 to 69 years. All had been admitted to hospital with COVID-19 as diagnosed by polymerase chain reaction (PCR) within the last four days.

At the time of entry into the trial, all had features of acute respiratory infection but did not require mechanical ventilation. All were put on standard care, almost all receiving glucocorticoids. Two in three were on remdesivir, and most also received antibacterial or antiviral drugs.

The patients had C-reactive protein (CRP) levels between 50 and 150 mg/L at baseline.

They were randomly assigned to receive either C21 or a placebo for a week. The C21 group had a higher number of individuals with hypertension and obesity or overweight, but not diabetes.

Patients who required mechanical ventilation were not given the drug thereafter, nor were those who were discharged before seven days had been completed. All were followed up at 7-10 days from the last dose. Three out of four were males, the mean age was 53 years, and most had coexisting illnesses.

The primary endpoint was a change in CRP, other endpoints being the need for oxygen supplementation or mechanical ventilation, the occurrence of adverse events, and changes in other biomarkers.

Of the 51 patients in the C21 group, six had the drug stopped early; one because mechanical ventilation was needed, one because consent was withdrawn, and the rest because they were discharged from hospitals. In the placebo group of 55 patients, 12 patients stopped early, four because they were put on mechanical ventilation, four who withdrew consent, and five were discharged.


At baseline, 58% of the patients required supplemental oxygen, with comparable proportions in both groups. After seven days, 28% and 46% of C21 and placebo patients still needed oxygen supplementation, and at day 14, one and 11 patients in either group, respectively.

There were four deaths, one and three in the C21 and placebo group, all due to respiratory failure in patients on mechanical ventilation. One more placebo patient required mechanical ventilation but did not succumb to the infection.

The CRP levels fell rapidly and steeply in both groups immediately after screening for trial entry. This is attributed to the high use of glucocorticoids, a trend that appeared after the RECOVERY trial.

Among the severely ill patients on supplemental oxygen at baseline, the CRP fell by 84% in the C21 group versus 72% in the placebo group after seven days of treatment. Other biomarkers including IL-6, IL-10, TNF, CA125 and ferritin showed no difference following treatment.

What are the implications?

The researchers concluded that C21 was useful in treating patients with COVID-19, lowering the risk for prolonged supplemental oxygen requirements. It is also likely that it prevented severe respiratory disease, as fewer patients required mechanical ventilation, and the number of deaths due to respiratory failure was lower in the treatment group.

The drug may enhance alveolar gas exchange, as suggested by the rapid waning of the need for supplemental oxygen. The site of action may possibly be the type 2 pneumocyte progenitor cells, which are quite possibly the primary targets for viral replication in the lungs. By its activity on these cells, C21 may reduce lung function.

No anti-inflammatory activity was observed, since IL-6 and TNF (both inflammatory cytokines) levels failed to drop. The CRP fell to a greater extent in the treatment group relative to the placebo group.

Again, the rapid reduction in severity and duration of the acute phase of impaired lung function, after being put on oxygen supplementation, could protect against long-term complications such as lung fibrosis. In fact, the number of days on supplemental oxygen is a risk factor for poor diffusion capacity and a more abnormal CT scan score at three months from the start of infection. In this area too, C21 is being developed as an inhibitor of pulmonary fibrosis.

C21 on top of standard of care, including glucocorticoids and remdesivir, significantly improved respiratory function reflected by a reduced need for supplemental oxygen in hospitalized COVID-19 patients.”

These findings certainly justify a further trial to document the efficacy of C21 in severe COVID-19.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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