From the Journals

Rationale for baricitinib’s use in COVID-19 patients demonstrated


 

FROM SCIENCE ADVANCES

It should not be surprising that the RA drug baricitinib (Olumiant), a Janus kinase (JAK) 1/2 inhibitor, might be beneficial in controlling the cytokine storm of hyperinflammation that can follow severe SARS-CoV-2 infections and lead to lung damage and acute respiratory distress syndrome – the leading cause of death from the virus.

Dr. Justin Stebbing

But to demonstrate within a matter of months, at least preliminarily, that baricitinib reduces mortality and morbidity in hospitalized patients with COVID-19 pneumonia required a widely cross-disciplinary international team of researchers from 10 countries working at breakneck speed, said Justin Stebbing, PhD , the principal investigator of a new baricitinib study published Nov. 13 in Science Advances . “We went from modeling and mechanistic investigations to clinical tests in a number of settings and laboratory analysis in record time.”

The international team of 50 researchers included medical specialists in rheumatology, virology, geriatrics, oncology, and general medicine, along with experts in molecular and cellular biology, bioinformatics, statistics and trial design, computer modeling, pathology, genetics, and super-resolution microscopy, Dr. Stebbing, professor of cancer medicine and medical oncology at Imperial College, London, said in an interview.

Artificial intelligence, provided by the London-based firm BenevolentAI, was used to sift through a huge repository of structured medical information to identify drugs that might block the SARS-CoV-2 infection process. It predicted that baricitinib would be a promising candidate to inhibit inflammation and reduce viral load in COVID-19. Previous reports by Dr. Stebbing and colleagues ( here and here) describe this AI-mediated testing, which was validated by the new study.

The researchers also used three-dimensional miniature human liver organoids in vitro and super-resolution microscopy to perform further lab investigations, which showed that baricitinib reversed expression of the SARS-CoV-2 receptor ACE2 triggered by type I interferons. Baricitinib inhibited the significant increase in ACE2 expression caused by interferon alpha-2, and thus cytokine-mediated inflammation, and also reduced infectivity, Dr. Stebbing said. “Our study of baricitinib shows that it has both antiviral and anticytokine effects and appears to be safe.”

71% mortality reduction

The team found a 71% reduction in mortality for a group of 83 hospitalized patients with COVID-19 pneumonia in Italy and Spain – early epicenters of the pandemic – who received baricitinib along with standard care, compared with propensity-matched groups that received only standard care. At that time, between mid-March and mid-April, standard COVID-19 care included antibiotics, glucocorticoids, hydroxychloroquine, low-molecular-weight heparin, and the antiretroviral combination lopinavir/ritonavir.

In the Spanish and Italian cohorts, baricitinib was generally well tolerated, although not without side effects, including bacterial infections and increases in liver enzyme levels, which may not have been related to baricitinib. Patients showed reductions in inflammation within days of starting treatment. “We did not observe thrombotic or vascular events in our cohorts, but most of the patients were receiving low molecular weight heparin,” he said.

The fact that baricitinib is approved by the Food and Drug Administration, is already well studied for safety, can be taken conveniently as a once-daily oral tablet, and is less expensive than many other antiviral treatments all make it an good target for further study, including randomized, controlled trials that are already underway, Dr. Stebbing noted. His study cohort also included elderly patients (median age, 81 years) who are the most likely to experience severe disease or death from COVID-19.

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