Baricitinib, the rheumatoid arthritis drug, has shown promise as a treatment that could help to reduce COVID-19 mortality, an early-stage study has found.
An international team of researchers, co-ordinated by the Karolinska Institutet in Sweden, found that there was a 71% reduction of mortality in a group of patients who were prescribed baricitinib in addition to standard care.
The authors say their findings, published in Science Advances, support the continuation of further randomised clinical trials.
Corresponding author Volker Lauschke, associate professor of personalised medicine and drug development at the Karolinska Institutet Department of Physiology and Pharmacology, said: “These results are especially encouraging seeing as the study included a large cohort of elderly patients, a group that is often excluded in other trials.”
The study involved 83 patients, who had a median age of 81, all of whom were receiving hospital treatment in Italy and Spain. All were treated with baricitinib in addition to standard care.
Of these, 17% suffered an adverse outcome that resulted in death or invasive mechanical ventilation compared to 35% in the matched control group of 83 patients who received standard care only.
The research team notes that baricitinib was generally well tolerated and reduced inflammation from the first treatment days.
Previously reported side-effects of long-term baricitinib use, which include coagulopathy and thrombosis, were not seen in any of the patients, although the researchers say this could be because the patients were being treated with anti-coagulating medicine.
However, the study team reported some adverse events, including bacterial infections and gastrointestinal and cardiovascular complications, but add these were also observed in the control group.
The current study was carried out following their previous research in which they used artificial intelligence (AI) to identify baricitinib as a promising repurposing candidate for COVID-19 because it inhibited inflammation and reduced the viral load of SARS-CoV-2.
They have now demonstrated that interferons significantly increased the expression of the ACE2 receptor, which acts as an entry point for SARS-CoV-2 into human cells.
Liver injury is commonly observed in severe COVID-19 and the team found that by combining 3D mini organs of human liver cells, RNA sequencing and super-resolution microscopy, baricitinib reversed ACE2 gene expression changes triggered by interferons and reduced SARS-CoV-2 infectivity.
However, interferons did not have the same effect on the ACE2 receptor in lung organoids, which they say suggests that these signalling proteins affect pulmonary and liver organs differently.
Co-author Ali Mirazimi, adjunct professor at the Department of Laboratory Medicine, Karolinska Institutet, said: “Our findings explain the dual anti-cytokine and anti-viral actions of baricitinib and support further evaluation in randomised control trials.”
Fellow researcher Professor Justin Stebbing, from Imperial College, London, said: “This is one of the first COVID-19 treatments to go from computer to clinic and laboratory. It was first identified by an AI algorithm in February, which scanned thousands of potential drugs that could work against this virus.
"The study suggests this drug can aid recovery of patients with moderate to severe COVID-19 and may provide a new weapon in our arsenal against the virus. Large-scale clinical trials of this drug, to further investigate its potential, are now under way."
The clinical study was led by researchers at Imperial College London, UK, Complejo Hospitalario Universitario de Albacete, Spain, and the University of Pisa, Italy, while the mechanistic investigations on 3D human tissue models were conducted at Karolinska Institutet.
Stebbing J, Nievas GS, Falcone M et al. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Science Advances. 13 November 2020; doi: 10.1126/sciadv.abe4724
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