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.
The National Library of Medicine’s clinicaltrials.gov registry of federally funded clinical studies lists 15 current research initiatives involving baricitinib and COVID-19. Dr. Stebbing suggested that data generated so far are helping to guide ongoing studies on dose and duration of treatment – in other words, who it works for, when to give it, and at what dose it should be taken and for how long.
Manufacturer Eli Lilly, which markets baricitinib in 2-mg or 4-mg tablets, announced in October that initial data are starting to emerge from 1,000-plus patients enrolled in ACTT-2 (the Adaptive COVID-19 Treatment Trial 2). ACTT-2 compared patients on the broad-spectrum intravenous antiviral drug remdesivir (Veklury) with those receiving remdesivir in combination with baricitinib. Based on ACTT-2 results that suggested a reduced time to recovery and improved clinical outcomes for the combination group, the FDA issued an emergency-use authorization on Nov. 19 for the combination of baricitinib and remdesivir for the treatment of suspected or laboratory confirmed COVID-19 in hospitalized adults and pediatric patients aged 2 years or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.
Interrupting the cytokine outbreak
Baricitinib has the potential to reduce or interrupt the passage of SARS-CoV-2 into cells, and thus to inhibit the JAK1- and JAK2-mediated cytokine outbreak, researcher Heinz-Josef Lenz, MD, professor of medicine and preventive medicine at the University of Southern California’s Norris Comprehensive Cancer Center in Los Angeles, said in a comment. Baricitinib was also identified, using BenevolentAI’s proprietary, artificial intelligence-derived knowledge graph, as a numb-associated kinase inhibitor, with high affinity for AP2-associated protein kinase 1, an important endocytosis regulator.
Dr. Heinz-Josef Lenz
Early clinical data suggest a potent biologic effect of baricitinib 2 mg or 4 mg daily on circulating interleukin-6 levels and other inflammatory markers, including C-reactive protein. Dr. Lenz said the evidence for advantageous action of baricitinib on viral endocytosis and excessive cytokine release constitutes the rationale for using it in combination with other antivirals such as remdesivir in patients with moderate to severe COVID-19 illness.
“Although baricitinib may display antiviral activity on its own, its anti-inflammatory effects could hypothetically delay viral clearance,” Dr. Lenz added. “The data from Stebbing et al. confirm the dual actions of baricitinib, demonstrating its ability to inhibit viral entry into primary human hepatocyte spheroids and the reduction in inflammatory markers in COVID-19 patients.”
Other JAK inhibitors were not advanced as promising candidates for the research team’s attention by its artificial intelligence search, Dr. Stebbing noted. “The history of the pandemic has taught us the importance of well-designed observational studies as well as randomized, controlled trials. When it comes to COVID, pyrite looks much like gold, as failed studies of four antivirals have shown.”
Although the current translational research study did not use a placebo group, it is an important next step toward future randomized, controlled trials. “What’s great about this study is its high degree of collaboration, done with real urgency,” he added. “It’s harder to produce a paper that crosses multiple boundaries, like this one does, than a single-focused piece of work. But we wanted to link all of these threads together.”
The study was supported by the Imperial Biomedical Research Centre and Experimental Cancer Medicine Centre, the National Institute for Health Research, and the U.K. National Health Service’s Accelerated Access Collaborative. Dr. Stebbing has served on scientific advisory boards for Eli Lilly and other companies. Dr. Lenz had no relevant disclosures to report.
SOURCE: Stebbing J et al. Sci Adv. 2020 Nov 13. doi: 10.1126/sciadv.abe4724.
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