For COVID-19, many researchers around the world have tried to repurpose drugs for other indications, often unsuccessfully. New clinical trial results show that baricitinib, developed by Eli Lilly and approved for rheumatoid arthritis, can speed recovery and may reduce mortality in some groups of hospitalized COVID-19 patients.
How did this study, sponsored by the National Institute of Allergy and Infectious Diseases, come together? In part, through decade-long groundwork laid by investigators at Emory, and their collaborations with others.
For several years, drug hunter and virologist Raymond Schinazi and his team had been investigating a class of medications called JAK inhibitors, as an option for tamping down chronic inflammation in HIV infection. Schinazi was one of the first at Emory to investigate the use of anti-inflammatory agents for herpesviruses and HIV in combination with antiviral drugs. He believed that these viruses “hit and run,” leaving behind inflammation, even if they later go into hiding and seem to disappear.
In the race to halt the COVID-19 pandemic, researchers at Yerkes National Primate Research Center of Emory University share two important findings from their latest peer-reviewed, published study in Cell.
Rhesus monkeys are a valid animal model for COVID-19 studies because the way they experience and respond to the virus has comparable similarities to the way the virus affects humans, the researchers say. And baricitinib, an anti-inflammatory medication that is FDA-approved for rheumatoid arthritis, is remarkably effective in reducing the lung inflammation COVID-19 causes when the medication is started early after infection.
The study results have immediate and important implications for treating patients with COVID-19. Baricitinib will be compared against the steroid dexamethasone in a NIAID-sponsored clinical trial called ACTT-4 (Adaptive COVID-19 Treatment Trial), which started in November.
Mirko Paiardini, PhD, a researcher in Yerkes’ Microbiology and Immunology division, and his team selected rhesus macaques as the animal model because they expected the monkeys would mimic the disease course in humans, including the virus traveling to the upper and lower airways, and causing high levels of inflammation in the lungs. The team randomized eight rhesus macaques into two groups – a control and a treatment group; the animals in the treatment group received baricitinib.
“Our results showed the medication reduced inflammation, decreased inflammatory cells in the lungs and, ultimately, limited the virus’ internal path of destruction,” Paiardini says. “Remarkably, the animals we treated with baricitinib rapidly suppressed the processes responsible for inducing lung inflammation, thus elevating baricitinib for consideration as a frontline treatment for COVID-19 and providing insights on the way the drug works and its effectiveness.”
The FDA recently granted baricitinib emergency use authorization in combination with remdesivir based on the results of the ACTT-2 findings. “Our study was under way concurrently and, now, solidifies the importance of baricitinib in treating COVID-19,” Paiardini adds.
Co-senior author Raymond Schinazi, PhD, DSc, inventor of the most commonly used HIV/AIDS drugs to prevent progression of the disease and death, says: “Our study shows the mechanisms of action are consistent across studies with monkeys and clinical trials with humans. This means the nonhuman primate model can provide enough therapeutic insights to properly test anti-inflammatory and other COVID-19 therapies for safety and effectiveness.”
Schinazi is the Frances Winship Walters Professor of Pediatrics at Emory University School of Medicine and is affiliated with Yerkes.
“Ray and his group have been investigating the potential of anti-inflammatory drugs, such as baricitinib, for years in the context of another infection, HIV, in which inflammation is a key cause of sickness and death,” Paiardini says. “Our laboratories have collaborated for years to test therapeutics in the nonhuman primate model of HIV infection, thus placing us in a unique position when COVID-19 hit the U.S. to focus our combined expertise and efforts to halt the virus. It took only a phone call between the two of us to switch gears, begin work to create a reliable and robust monkey model of COVID-19 at Yerkes and test the potential of drugs to block inflammation.”
Tim Hoang, first author and Emory doctoral student in the Immunology and Molecular Pathogenesis Program, says: “It was exciting to be at the forefront of the response to COVID-19 and to be part of this research team that involved collaboration from Yerkes and Emory infectious disease experts, geneticists, chemists, pathologists and veterinarians.”
Co-first author and Emory postdoctoral fellow Maria Pino, PhD, emphasizes: “We knew Yerkes was uniquely suited to conduct this study because of the research and veterinary expertise, specialized facilities and animal colony, and our team’s commitment to providing better treatment options for people who have COVID-19.”
The research team plans to conduct further studies to better understand the inflammation the virus causes and to develop more targeted approached to mitigate the damage COVID-19 leaves behind.
Steven Bosinger, PhD, co-senior author, and his research team conducted the genomic analyses that helped unravel the process by which baricitinib reduces inflammation. “One of the most exciting aspects of this project was the speed genomics brought to the collaborative research,” says Bosinger. “Eight months ago, we began using genomics to accelerate the drug screening process in order to identify treatable, molecular signatures of disease between humans and model organisms, such as the monkeys in this study, In addition to determining the effectiveness of baricitinib, this study highlights Emory researchers’ commitment to improving human health and, in this case, saving human lives.”
Bosinger is assistant professor, Department of Pathology & Laboratory Medicine, Emory School of Medicine (SOM) and Emory Vaccine Center (EVC); director, Yerkes Nonhuman Primate Genomics Core and a researcher in Yerkes’ Division of Microbiology and Immunology.
Some of the others on the Emory research team include: Arun Boddapati (co-first author), Elise Viox, Thomas Vanderford, PhD, Rebecca Levit, MD, Rafick Sékaly, PhD, Susan Ribeiro, PhD, Guido Silvestri, MD, Anne Piantadosi, MD, PhD, Sanjeev Gumber, BVSc, MVSc, PhD, DACVP, Sherrie Jean, DVM, DACLAM, and Jenny Wood, DVM, DACLAM. Jacob Estes, PhD, at Oregon Health & Science University also collaborated.
Paiardini says, “So many colleagues had a key role in this study. First authors Tim and Maria as well as Yerkes veterinary and animal care personnel who worked non-stop for months on this project. This truly has been a collaborative effort at Emory University to help improve lives worldwide.”
This study was funded by the National Institutes of Health, Emory University’s COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant, Yerkes’ base grant, which included support for the center’s Coronavirus Pilot Research Project grants, and Fast Grants.
Grant amounts (direct + indirect) are:
NIH R37AI141258, $836,452/yr (2018-23)
NIH R01AI116379, $783,714/yr (2015-20 + 2021 NCE)
NIH P51 OD011132, $10,540,602/yr (2016-20)
U24 AI120134 $681,214/yr (2020-2025)
S10OD026799 $985,030/yr (2019-2020)
Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant, $150,000/1 yr
Fast Grants #2144, $100,000/1 yr
Note: Only a portion of the NIH grant funding was applied to the study reported in this news release.
GeneticistÂ Sampath Prahalad and the familiesÂ he works with wereÂ part of this recent PNAS paper, which probesÂ genetic risk factors for systemic juvenile idiopathic arthritis.
There are several subtypes of juvenile arthritis, and sJIA (systemic juvenile idiopathic arthritis) sounds especially painful because of its inflammatory symptoms: daily spiking fever and skin rashes in addition to joint pain.
The international team of investigators assembled what they report as the largest collectionÂ of sJIA patients (close to 1000) and identified HLA-DRB1*11 as a genetic risk factor for sJIA.
When a child is just learning to play sports, swim or even simply get dressed on her own, it can be heartbreaking to see that she is already being affected by symptoms of arthritis: swelling, limping, and/or restricted range of motion.
A challenge in this area is determining what makes juvenile idiopathic arthritis both different from other autoimmune diseases such as lupus or type I diabetes and what makes the disease appear early in life, decades before adult-onset rheumatoid arthritis usually appears.
Determining genetic and other risk factors for the disease can help increase understanding of the mechanisms of disease, leading to better treatments, and knowing how the cheap oakley disease develops can improve diagnosis. On this second point, we asked Prahalad two questions about his work:
What proportion of patients come to you because there is a suspected genetic connection?
Most come because of symptoms of rheumatic disease. I would estimate about 20 percent of our referrals come because of a mild symptom or abnormal lab test plus a family cheap oakley sunglasses history of autoimmunity, which prompts the PCP to seek a rheumatology evaluation. Less than 2 percent come purely for a family history of autoimmunity where they are concerned the child also has it.
Under what circumstances would a doctor seek to determine a genetic risk score for a child?
We know that twins, siblings and children of individuals with an autoimmune disease have a higher risk of the condition. So a genetic risk score could help identify those at risk for closer follow up or further evaluation. Conceivably in a child with symptoms suspicious for an autoimmune disease but not definitive, a genetic risk score could help increase the probability of being able to diagnose a specific condition.
Prahalad and colleagues published a paper in the June issue of Arthritis & Rheumatism investigating the applicability of a genetic risk score for JIA involving variations in four genes. In their study looking at 155 children with JIA and 684 controls, individuals with a risk score in the top fifth have odds of childhood-onset disease 12 times of those in the bottom fifth.
A key passage from the discussion of the Arthritis & Rheumatism paper indicates that genetic factors specific for childhood onset remain to be found.
Studying children has the advantage of focusing more on the influence of genetic factors compared to the influence of environmental factors, such as smoking. Notably, the magnitude and direction of the association between childhood-onset RA [rheumatoid arthritis] and TNFAIP3, STAT4, and PTPN22 variants were similar to those observed in RA. The observation that the selected variants did not have an elevated OR in childhood-onset RA as compared to RA suggests that there are other variants still to be investigated that may influence the risk of childhood-onset RA.
Prahalad says he wants to find out whether genetic http://www.gooakley.com/ factors contributing to childhood onset are simply cumulatively more intense, and thus drive the appearance of the disease earlier, or whether they are active in a childhood-specific context.
Notably, many of the genetic risk factors identified so far are shared with other autoimmune diseases. A recent Nature Genetics paper, which Prahalad contributed to, used a customized â€œImmunochipâ€ to find several new risk factors for JIA.
Non-genetic risk factors: At the retreat, Mina Rohani Pichavant, a researcher working with Prahalad, had a poster discussing her preliminary data on the types of microorganisms found in the intestines of JIA patients. Previous studies in adults with rheumatoid arthritis have shown a link between intestinal bugs and disease risk, but this area of research is new for JIA. There are also connections between gum disease and JIA.