JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality

ABSTRACT. Using AI we identified baricitinib as possessing anti-viral and anti-cytokine efficacy. We now show a 71% (95% CI 0.15-0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age 81 years). A further 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-alpha-2 (IFNα2) significantly increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by >5-fold. RNA-Seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and super-resolution microscopy, baricitinib exerts activity rapidly through the inhibition of host proteins (numb associated kinases), uniquely amongst anti-virals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivizes further randomized controlled trials. – Download PDF

  • Professor Volker Lauschke, of the Karolinska, who led the study, said: ‘These results are especially encouraging seeing as the study included a large cohort of elderly patients, a group often excluded.’ – Daily Mail

Baricitinib treatment linked to reduced mortality in COVID-19 patients

The rheumatoid arthritis drug baricitinib can block viral entry and reduce mortality in patients with moderate to severe COVID-19, according to translational research by an international team coordinated by researchers from Karolinska Institutet in Sweden. The findings, published in the journal Science Advances, support the continuation of ongoing randomized clinical trials.

“We are pleased to report a 71 percent reduction in mortality for the group receiving baricitinib in addition to standard care,” says Volker Lauschke, corresponding author and associate professor of personalized medicine and drug development at the Department of Physiology and Pharmacology, Karolinska Institutet. “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.”

In the study, 83 patients hospitalized with COVID-19 pneumonia in Italy and Spain were treated with baricitinib in addition to standard care. Of these, 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 care only. The patients had a median age of 81 years.

The drug was generally well tolerated with a reduction in inflammation from the first treatment days, according to the researchers. Previously reported side-effects of long-term baricitinib use, including coagulopathy and thrombosis, were not evident in any of the patients, possibly due to treatment with anti-coagulating medicine. However, some adverse events including bacterial infections and gastrointestinal and cardiovascular complications were noted, although these were also observed in the control group so it is unclear what, if anything, can be ascribed to baricitinib.

In a prior study, the same team of researchers reported how they used artificial intelligence (AI) to identify baricitinib as a promising repurposing candidate for COVID-19. That study also showed how the drug inhibited inflammation and reduced the viral load of SARS-CoV-2.

In the current study, the researchers elaborated on those findings by demonstrating that interferons, cytokines made and released by host cells in response to viruses, significantly increases the expression of the ACE2 receptor, which acts as an entry point for SARS-CoV-2 into human cells. While liver injury is commonly observed in severe COVID-19, mechanisms and dynamics of SARS-CoV-2 infections had not been investigated in this organ.

By combining 3D mini organs of human liver cells, RNA sequencing and super-resolution microscopy, the scientists were able to show that barcitinib reversed ACE2 gene expression changes triggered by interferons and reduced SARS-CoV-2 infectivity. Interestingly, interferons did not have the same effect on the ACE2 receptor in lung organoids, suggesting that these signaling proteins affect pulmonary and liver organs differently.

“Our findings explain the dual anti-cytokine and anti-viral actions of baricitinib and support further evaluation in randomized control trials,” says Ali Mirazimi, adjunct professor at the Department of Laboratory Medicine, Karolinska Institutet, and co-author of the study.

The researchers note that a limitation of the study was the lack of a placebo control group, which is included in industry-sponsored randomized controlled trials that are currently ongoing.

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The clinical study was led by researchers at Imperial College London, U.K., 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.

The research was funded by the Swedish Research Council, the Strategic Research Programmes 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, the Department of Energy, CIBERFES, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, España. Ayuda cofinanciada por el Fondo Europeo de Desarrollo Regional FEDER Una Manera de hacer Europa, Imperial BRC, ECMC, the NIHR and AAC.

The authors of the paper have reported several conflicts of interest, including lecture fees and research grants from pharmaceutical companies that own baricitinib. Some of the authors have founded companies that feature technologies mentioned in this study. For a complete list of disclosures, please see the full article.

Publikation: “JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality,” Justin Stebbing, Ginés Sánchez Nievas, Marco Falcone, Sonia Youhanna, Peter Richardson, Silvia Ottaviani, Joanne X. Shen, Christian Sommerauer, Giusy Tiseo, Lorenzo Ghiadoni, Agostino Virdis, Fabio Monzani, Luis Romero Rizos, Francesco Forfori, Almudena Avendaño Céspedes, Salvatore De Marco, Laura Carrozzi, Fabio Lena, Pedro Manuel Sánchez-Jurado, Leonardo Gianluca Lacerenza, Nencioni Cesira, David Caldevilla Bernardo, Antonio Perrella, Laura Niccoli, Lourdes Sáez Méndez, Daniela Matarrese, Delia Goletti, Yee-Joo Tan, Vanessa Monteil, George Dranitsaris, Fabrizio Cantini, Alessio Farcomeni, Shuchismita Dutta, Stephen K. Burley, Haibo Zhang, Mauro Pistello, William Li, Marta Mas Romero, Fernando Andrés Pretel, Rafaela Sánchez Simón-Talero, Rafael García-Molina, Claudia Kutter, James H. Felce, Zehra F. Nizami, Andras G. Miklosi, Josef M. Penninger,Francesco Menichetti, Ali Mirazimi, Pedro Abizanda and Volker M. Lauschke, Science Advances, online November 13, 2020, doi: 10.1126/sciadv.abe4724

Facts: Baricitinib

  • Baricitinib is a once-daily oral drug used for treatment of adult patients with moderate to severe rheumatoid arthritis.
  • It acts as an inhibitor of janus kinase, a type of enzyme that acts as an “on” or “off” switch in many cellular functions.
  • The drug has dual functions and acts by interfering with the inflammatory processes of the immune system as well as by directly inhibiting viral entry. It is seen as a potential treatment candidate for COVID-19.

Baricitinib has Significant Effect on Recovery Time, Most Impactful in Patients with COVID-19 Requiring Oxygen

Further results from NIAID-sponsored ACTT-2 Trial

TORONTOOct. 16, 2020 /CNW/ – Eli Lilly and Company and Incyte shared additional data that showed baricitinib in combination with remdesivir reduced time to recovery and improved clinical outcomes for patients with COVID-19 infection compared with remdesivir. This finding was part of additional efficacy and safety data from the Adaptive COVID-19 Treatment Trial (ACTT-2) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), which was presented on October 8th  by John Beigel, M.D., associate director for clinical research in the Division of Microbiology and Infectious Diseases at NIAID. These data were presented at a special International Society for Influenza and other Respiratory Virus Diseases Antiviral Group (isirv-AVG) Virtual Conference on ‘Therapeutics for COVID-19.’ The largest benefits were observed in patients requiring supplemental oxygen (grade 5 on the eight-point ordinal scale) and those who required high-flow oxygen/non-invasive ventilation (grade 6) at baseline.

The new data provide a better understanding of the improved clinical outcomes in hospitalized adults with COVID-19 infection who received baricitinib, including data for mortality. As previously reported, ACTT-2 achieved the primary endpoint, demonstrating that the overall patient population treated with baricitinib in combination with remdesivir improved their median time to recovery from 8 to 7 days in comparison to remdesivir, a 12.5% improvement (incidence rate ratio: 1.16; 95% CI: 1.01, 1.32; p=0.04). Recovery was defined as the participant being well enough for hospital discharge, meaning the participant either no longer required supplemental oxygen or ongoing medical care in the hospital, or was no longer hospitalized at Day 29. The study also met a pre-specified secondary endpoint. Using the ordinal scale that ranged from recovered to death, the odds of improvement in clinical status at Day 15 were 30% greater in patients being treated with baricitinib in combination with remdesivir compared with remdesivir (odds ratio 1.3; 95% CI: 1.0, 1.6; p=0.04).

A numerical decrease in death (35%) through Day 29 was observed in patients treated with baricitinib plus remdesivir compared to remdesivir in the overall population (5.1% vs. 7.8%, respectively; hazard ratio: 0.65; 95% CI: 0.39, 1.08; p=0.09). The reduction in mortality was more pronounced for patients receiving oxygen, as mortality at Day 29 was 60% lower and 43% lower for the OS5 and OS6 subgroups respectively. No new safety signals were observed for baricitinib-treated patients in this study. NIAID authors are working to have the full analysis completed and a peer-reviewed manuscript will be made available soon.

“We are very pleased to learn that baricitinib in combination with remdesivir has demonstrated further positive results and clinical improvement in hospitalized patients with COVID-19,” says Dr. Doron Sagman, vice president, R&D and Medical Affairs, Eli Lilly Canada. “We look forward to learning more about the potential role for baricitnib to treat hospitalized patients with COVID-19 through the full data analysis.”

Lilly is continuing conversations with the U.S. Food and Drug Administration (FDA) around the potential for Emergency Use Authorization (EUA) of baricitinib as a treatment for hospitalized patients with COVID-19, and will explore similar measures with other regulatory agencies, including Health Canada. Baricitinib has not been approved by the FDA, or any regulatory agency, to treat COVID-19; the efficacy and safety of baricitinib for the treatment of COVID-19 has not been established.

About Lilly’s COVID-19 Efforts
Lilly is bringing the full force of its scientific and medical expertise to attack the coronavirus pandemic around the world. Existing Lilly medicines are now being studied to understand their potential in treating complications of COVID-19, and the company is collaborating with two partner companies to discover novel antibody treatments for COVID-19. Lilly intends to test both single antibody therapy as well as combinations of antibodies (sometimes known as antibody cocktails) as potential therapeutics for COVID-19.

About OLUMIANT®
OLUMIANT is a once-daily, oral Janus Kinase (JAK) inhibitor. In Canada, OLUMIANT (baricitinib), in combination with methotrexate (MTX), is indicated for reducing the signs and symptoms of moderate- to severe rheumatoid arthritis (RA) in adult patients who have responded inadequately to one or more disease-modifying anti-rheumatic drugs (DMARDs). OLUMIANT can be used as a monotherapy in cases of intolerance to MTX.1

There are four known JAK enzymes: JAK1, JAK2, JAK3 and TYK2. JAK-dependent cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases.2 OLUMIANT has greater inhibitory potency at JAK1, JAK2 and TYK2 relative to JAK3; however, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.

About Lilly Canada
Eli Lilly and Company is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by Colonel Eli Lilly, who was committed to creating high quality medicines that meet people’s needs, and today we remain true to that mission in all our work. Lilly employees work to discover and bring life-changing medicines to people who need them, improve the understanding and management of disease, and contribute to our communities through philanthropy and volunteerism.

Eli Lilly Canada was established in 1938, the result of a research collaboration with scientists at the University of Toronto, which eventually produced the world’s first commercially available insulin. Our work focuses on oncology, diabetes, autoimmunity, neurodegeneration, and pain. To learn more about Lilly Canada, please visit us at www.lilly.ca.

For our perspective on issues in healthcare and innovation, follow us on twitter @LillyPadCA and @LillyMedicalCA.

About Incyte
Incyte is a Wilmington, Delaware-based, global biopharmaceutical company focused on finding solutions for serious unmet medical needs through the discovery, development and commercialization of proprietary therapeutics. For additional information on Incyte, please visit Incyte.com and follow @Incyte.

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about OLUMIANT (baricitinib) as a potential treatment for patients with COVID-19 and as a treatment for patients with rheumatoid arthritis, and reflects Lilly’s and Incyte’s current beliefs. This press release also contains a forward-looking statement about Lilly’s potential antibody treatments for COVID-19. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. Among other things, there can be no guarantee that OLUMIANT will receive additional regulatory approvals or continue to be commercially successful, or that potential antibody treatments will be safe and effective. For further discussion of these and other risks and uncertainties, see Lilly’s and Incyte’s most recent respective Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly and Incyte undertake no duty to update forward-looking statements to reflect events after the date of this release.

References

1

Olumiant Product Monograph, 2020. 

2

Walker JG and Smith MD. J Rheumatol. 2005;32;1650-1653.

SOURCE Eli Lilly Canada Inc.

For further information: Media Contact: Samira Rehman, Rehman_Samira@lilly.com, 647-617-1994

Related Links

http://www.lilly.ca

Baricitinib treatment resolves lower airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

Highlights

  • SARS-CoV-2 infected RMs mimic signatures of inflammation seen in COVID-19 patients
  • Baricitinib suppresses production of pro-inflammatory cytokines in lung macrophages
  • Baricitinib limits recruitment of neutrophils to the lung and NETosis
  • Baricitinib preserves innate antiviral and SARS-CoV-2-specific T-cell responses

Summary

SARS-CoV-2 induced hypercytokinemia and inflammation are critically associated with COVID-19 disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type-I IFN antiviral responses and SARS-CoV-2-specific T-cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib treated animals had a rapid and remarkably potent suppression of lung macrophages production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.

Learn More:

  • What is Olumiant? – Lilly
    • Olumiant is a once-daily pill to treat adults with moderately to severely active rheumatoid arthritis (RA) who have tried at least one other medicine called a tumor necrosis factor (TNF) antagonist, such as Humira® (adalimumab), Enbrel® (etanercept), and Remicade® (infliximab), that did not work well or could not be tolerated.
  • Arthritis drug ‘cuts elderly Covid-19 deaths by two-thirds’, say researchers – raising hopes that it will save the most vulnerable – Daily Mail
    • Daily drug reduces deaths by 71 per cent in those with moderate or severe illness Drug baricitinib, marketed as Olumiant, has only been available for three years. Medics hope the arthritis drug could help save most vulnerable to coronavirus. An arthritis drug has been found to cut deaths in patients admitted to hospital with Covid-19 by a remarkable two-thirds – giving medics a powerful new weapon in their armoury against the disease. The daily pill, first earmarked as a potential Covid game-changer by a British firm, reduces deaths by 71 per cent in those with moderate or severe illness, researchers say. Importantly, it works in the elderly, raising hopes that it will save the most vulnerable. Its artificial intelligence program predicted baricitinib would ‘reduce the ability of the virus to infect lung cells’. Now the idea has been validated with pan-European researchers, led by Sweden’s Karolinska Institute, reporting baricitinib slashes death rates in those admitted to hospital with the disease by two-thirds. Last night NHS cancer specialist Professor Justin Stebbing, of Imperial College London, predicted that baricitinib would help save thousands of lives. He said: ‘The history of treatments for Covid has not left many drugs standing. What has been left standing is two British-discovered drugs.’ The other is the steroid dexamethasone, found to cut the risk of death in severely ill Covid patients by 33 per cent. The results, in the journal Science Advances, come from patients hospitalised with Covid-19 pneumonia at two hospitals, in Italy and Spain.
    • Professor Volker Lauschke, of the Karolinska, who led the study, said: ‘These results are especially encouraging seeing as the study included a large cohort of elderly patients, a group often excluded.’

Reprinted for educational purposes and social benefit, not for profit.