by Manasi Vaidya in New York.

Despite it being implicated in Covid-19, there is still equipoise on the role of angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis, there is a divided expert outlook on the subsequent impact of ACE inhibitors, angiotensin receptor blockers (ARBs) or recombinant ACE2 therapies in treating Covid-19.

One line of research is focused on repurposing antihypertensive ACE inhibitors and ARBs for Covid-19 based on their anti-inflammatory activity. Another theory, however, purports that those drug classes cause harm since they upregulate the expression of ACE2, which acts as a surface receptor used as an entry point by the SARS-CoV-2 virus. Vienna, Austria-based Apeiron Biologics is exploiting ACE2’s role in the virus life cycle by using a recombinant ACE2, APN-01.

A third of the world’s population is hypertensive and about 60% of these patients take drugs like ACE inhibitors or ARBs, said Dr Guido Iaccarino, professor of Internal Medicine, Department of Advanced Biomedical Sciences, University of Naples Federico II, Italy. While initial reports of potential upregulation of ACE2 by ACE inhibitors and ARBs led to some hesitance on their use, experts pointed out that there have been several observational studies since then suggesting that they did not increase Covid-19-associated mortality. Nonetheless, others pointed to the limitations of such studies, which has prompted the start of randomised trials exploring their use or stoppage.

Given the impact of the renin-angiotensin system (RAS) on inflammation, development of ACE inhibitors like ramipril or captopril and ARBs like losartan can be repurposed to address lung damage seen in Covid-19 patients, said experts. Interim results from one such study with losartan should be ready in 3–4 weeks now that the trial has completed 50% enrollment, said Dr Christopher Tignanelli, assistant professor, Division of Critical Care/Acute Care Surgery, University of Minnesota, Minneapolis.

Apeiron did not respond to a request for comment.

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Assessing continuation of antihypertensives in Covid-19

There is a clinical equipoise on whether ACE inhibitors and ARBs are helpful or harmful, said Dr Renato Lopes, professor of medicine, Divisions of Internal Medicine and Cardiology, Federal University of Sao Paulo. Letters published in journals like The British Medical Journal and The Lancet indicated they could be harmful and led to several patients stopping treatment, said Dr Jordana Cohen, assistant professor of Medicine and Epidemiology, University of Pennsylvania, Philadelphia.

The concern with using ACE inhibitors or ARBs arose due to the understanding that treatment with these drugs increases ACE2 receptor density, said Dr Rohit Loomba, professor of Medicine, Division of Gastroenterology, University of California, San Diego. The ACE2 receptor is widely expressed on the endothelium and acts as a gate for SARS-CoV-2, explained Iaccarino. Theoretically, higher ACE2 receptor expression could mean a higher viral load and a more severe infection, said Lopes. If the endothelium is not working well, virus-led inflammation leads to thrombosis, vasoconstriction and reduction in blood flow, he added.

However, Loomba referred to a retrospective analysis he coauthored on a group of 1,128 Covid-19 patients in Hubei province, China. The all-cause mortality for the 188 patients on ACE inhibitors or ARBs was lower than those not on those drugs (adjusted hazard ratio, 0.42 [95% CI, 0.19–0.92]; p = 0.03; Zhang et al; Circ Res. 2020 Jun 5; 126(12): 1671–1681).

Moreover, stopping ARBs would be risky, since patients taking them chronically probably have increased angiotensin 1 receptor expression in response to ARB treatment, which could be further capitalised by the increased angiotensin 2 implicated in Covid-19 complications, said Tignanelli. ARBs block the angiotensin 1 receptor (AT1), which binds the ligand angiotensin 2.

The initial observational studies also did not discriminate between age groups, said Iaccarino, and subgroup analyses would also be too small to be reliable. Further, some reports looked at reimbursement claims and not medical records, which gave limited information, said Iaccarino. However, even with medical records, as was the case in Iaccarino’s observational study, the indication and risk factors for which a patient is prescribed the drug—diabetes, hypertension or heart failure—is not always captured, said Cohen. Iaccarino explained that the observational study (NCT04331574) of 1,591 patients indicated antihypertensive therapy did not significantly interfere with Covid-19 lethality (Iaccarino et al; Hypertension 22 June epub). Cohen also pointed to a “mortal time bias” in large observational trials, which disregard when a patient was on such a drug.

Another factor to consider is that certain groups are thought to have a higher Covid-19 risk since there are polymorphisms and different levels of gene expression of angiotensin and the RAS system in different ethnic groups, said Dr George Thomson, medical professional, Acute Medicine, Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom. ACE inhibitors are known to be less effective in those of African ancestry than Caucasians, he explained, so it is likely that RAS has a significant impact on the pathogenicity of the SARS-CoV-2 virus.

Several studies are thus now randomising Covid-19 patients on ACE inhibitors or ARBs to evaluate whether to continue or suspend treatment, like the BRACE CORONA trial (NCT04364893) that Lopes is heading and an international trial (NCT04338009) in which Cohen is participating. Results from the BRACE CORONA study will be presented at the European Society of Cardiology meeting taking place 29 August–1 September, said Lopes.

Targeting ACE2’s role in facilitating viral entry

ACE inhibitors are designed to prevent the conversion of angiotensin 1 to angiotensin 2, and ACE2 further converts angiotensin 2 to angiotensin 1-7, acting as a counterbalance for the proinflammatory angiotensin 2. When the virus occupies all the ACE2 receptors on host cells, there is more angiotensin 2 free-flowing in the system to activate the RAS pathway, which leads to Covid-19 complications, said Loomba.

If the conversion of angiotensin 1 to angiotensin 2 is blocked by ACE inhibitors, the Covid-19 complications will be prevented, said Loomba, on the rationale behind a 560-patient Phase II study (NCT04366050) with the ACE inhibitor ramipril that he is heading. Ramipril has been shown to have a significant survival benefit in congestive heart failure, and millions of patients have been exposed to it, so it is safe to study, he added. ACE inhibitor captopril is also being evaluated in a 230-patient Phase II (NCT04355429). While the ramipril study measures efficacy as a composite of mortality, ICU needs or ventilator use and is scheduled to complete in April 2021, the captopril trial is measuring 14-day ventilation-free survival and is estimated to finish in this August.

Moreover, ACE inhibitors and ARBs are not the same even though they are often clubbed together, said Iaccarino. While ACE inhibitors inhibit the enzyme ACE1, ARBs act on the AT1 receptor, which mediates pro-inflammatory pathways and hence resolves inflammation.

Tignanelli said his group chose an ARB over an ACE inhibitor for their Phase II Covid-19 trial (NCT04312009), because the former blocks the RAS pathway downstream, allowing it to be as specific as possible. The study is collecting blood samples every third day to note viral load changes. The 200-patient Phase II is evaluating losartan’s effect on oxygen use measured as the difference in estimated (PEEP adjusted) P/F Ratio over a period of seven days.

Losartan also inhibits platelet activation and aggregation effectively acting as a blood thinner, which is relevant given the clot formation seen in Covid-19, said Tignanelli. Hypercoagulability is tightly linked to the RAS pathway, added Cohen. By blocking the side effects of inflammation with the use of ARBs, there is a potential to change Covid-19 to a common cold in terms of management, said Tignanelli.

While it is not known if patients should start ACE inhibitors as preventive medications, Iaccarino envisioned a scenario where the population at risk for Covid-19 could be put on a regimen of ACE inhibitors, high-dose vitamins or antioxidants to give them a better chance to survive in case they contract the virus.

Loomba saw the potential of using ACE inhibitors in combination with ACE2-blocking antibodies as useful as the latter could prevent viral entry into the cells and the former could then protect the patient from further injury if the virus is already there.

The rationale for Apeiron’s APN-01, a recombinant ACE2, is that the SARS-CoV-2 virus will dock on APN-01, thus not entering the host cells through the ACE2 on their surface, said an investigator on the study. Theoretically, this should stop the virus from propagating, while the body’s immune system should address the already infected cells, the investigator added. The 200-patient Phase II’s (NCT04335136) primary endpoint is all-cause death or invasive mechanical ventilation up to 28 days or hospital discharge and has a primary completion date of September.

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.