Back in late January, a British artificial intelligence (AI) venture known as BenevolentAI was employed to investigate thousands of potential drug targets against SARS-CoV-2, the virus behind COVID-19. One of those targets identified was Lilly’s baricitinib. More recently, Sweden’s Karolinska Institutet as well as Imperial College London, University of Pisa, Italy and Complejo Hospitalario Universitario de Albacete, Spain led translational research investigating the efficacy of the rheumatoid arthritis drug baricitinib. It would appear that the AI didn’t lead the investigators down the incorrect path. The findings are promising: the Janus kinase (JAK) inhibitor, approved in both the United States and the European Union for rheumatoid arthritis, blocks viral entry and reduces mortality in patients with moderate to severe COVID-19. Published in the journal Science Advances, the study merits larger investment in clinical trials.
TrialSite offers a brief breakdown of this latest information. The full study can be reviewed in Science Advances.
Artificial Intelligence-Discovered the Correlation
As it turns out, back in late January, London-based BenevolentAI was employed to rapidly examine many thousands of existing drug targets for evidence that they could be responsive to SARS-CoV-2. According to a recent press release from the British AI venture, one of this most recent study’s investigators, Professor Justin Stebbing serves as a scientific advisor to BenevolentAI. Hence the results recently showcased support the clinical trials now sponsored ongoing by the National Institute of Allergy and Infectious Diseases (NIAID) notably ACTT-II and Eli Lilly’s placebo-controlled trial COVID-BARRIER, to test baricitinib efficacy in COVID-19 patients.
Founded in 2013, the UK-based AI venture has raised nearly $300 million from investors. The firm is led by highly networked Baroness Joanna Shields.
What is Baricitinib?
This drug approved by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is used for the treatment of rheumatoid arthritis (RA) in adults whose disease was not well controlled using other RA medications called tumor necrosis factor (TNF) antagonists.
A once-daily oral drug, this drug is designed to be an inhibitor of JAK, a type of enzyme that acts as an “on” or “off” switch in many cellular functions. Importantly, this drug shows the potential to not only serve as an inhibitor of inflammatory processes of the immune system but also to directly block viral entry of the SARS-CoV-2 pathogen.
The drug was approved in Europe in 2017 and finally in America in 2018. By 2020 the U.S. FDA granted breakthrough therapy designation to baricitinib for the treatment of alopecia areata. The drug was developed by Eli Lilly.
What are the study details?
As reported by research center lead Karolinska Institutet in Sweden, the study involved 83 hospitalized patients with COVID-19 pneumonia in both Italy and Spain. In both cases, the patients were treated with baricitinib plus the standard of care. Of all the patients, 17 percent suffered an adverse outcome that resulted in death or invasive mechanical ventilation. This compared to 35 percent in the matched control group of 83 patients who received standard of care only. The media age of these patients was 81 yeas so they were in a high risk category of COVID—19 patients.
Was the drug well tolerated?
Yes. Overall, the drug was generally well tolerated reports the investigational center. The investigators observed a reduction in inflammation form the first treatment days and it is known that side-effects associated with long-term use of the drug include coagulopathy and thrombosis but they weren’t evidence in this study. That however could be the case because the patients also received anti-coagulating medicine.
But the investigators did observe select adverse events such as bacterial infections and gastrointestinal as well as cardiovascular complications. But these observations were made of the control group so its’ not clear what, if anything can be ascribed to the Lilly drug.
Why did the Research use Mini-livers?
The team in Sweden used 3D mini organs of human liver cells, RNA sequencing and super-resolution microscopy to demonstrate that baricitinib reversed ACE 2 gene expression changes triggered by interferons which served to reduce SARS-CoV-2 infectivity. The team found that interferons actually impacted the ACE2 receptor in lung organoids differently pointing out that these signaling proteins affect pulmonary and liver organs differently.
Who funded this study?
The research was sponsored by the Swedish Research Council, the Strategic Research Programs in Diabetes and Stem Cells and Regenerative Medicine, EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative, Ricerca Corrente Linea 1 and 3, the National Science Foundation, the National Institutes of Health, Department of Energy, CIBERFES Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain. Other institutions in Europe were involved as well.
What research sites were involved?
This clinical trial involved investigators at Imperial College London, UK; Complejo Hospital Universitario de Albacete in Spain and the University of Pisa, Italy. Note Karolinska Institutet led the mechanistic investigations into 3D human tissue models.
Researcher Point of View
Volker Lauschke, corresponding author and associate professor of personalized medicine and drug development at the Department of Physiology and Pharmacology Karolinska Institutet declared of the study results, “We are pleased to report a 71 percent reduction in mortality for the group receiving baricitinib in addition to standard of care.” The professor out of Sweden continued, “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.”
Imperial College London’s Professor Justin Stebbing was a co-lead author and reports that, “We urgently need to find more effective treatments for COVID-19 while we wait for a vaccine to become widely available. 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 the virus.”
Some of the authors have received consulting fees from Eli Lilly however this is quite common and doesn’t mean anything by itself. TrialSite will monitor ongoing studies to track future outcomes. A full set of conflict disclosures can be reviewed in the published article.
Volker Lauschke, PhD, Assistant Professor
Justin Stebbing, MA, PhD, Imperial College London
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