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.
The ACTT-2 results were recently published in New England Journal of Medicine. (More formal NIAID and Emory press releases are here and here.)
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 Schinazi’s lab, Christina Gavegnano had shown that JAK inhibitors had both anti-inflammatory and antiviral properties in the context of HIV — a project she started as a graduate student in 2010. JAK refers to Janus kinases, which regulate inflammatory signals in immune cells.
“Our team was working on this for 10 years for HIV,” Gavegnano says. “There was a huge amount of data that we garnered, showing how this drug class works on chronic inflammation and why.”
For years, Schinazi had tried to convince Eli Lilly to study its JAK inhibitor baricitinib against HIV, thinking that it could reduce inflammation associated with the persistence of the HIV reservoir. At the time, the approach was considered high risk because it might reactivate other dormant viruses and bacteria, he says.
Gavegnano’s preclinical data facilitated the initiation of a large NIH-sponsored study, overseen by infectious disease specialist Vince Marconi. This study demonstrated the safety of a related drug, the JAK inhibitor ruxolitinib, in people infected with HIV.
Then came the COVID-19 pandemic. Talking with collaborators in Hong Kong early in 2020, Schinazi hypothesized that something similar was happening with SARS-CoV-2 as with HIV – despite differences between the viruses and how quickly they weaken the body.
“It was the inflammation in the lungs and lack of oxygen that eventually killed people, not the virus itself,” he says.
When an artificial intelligence-based analysis was published in February in The Lancet, highlighting baricitinib as a potential COVID-19 treatment, Schinazi was surprised, but his group quickly mobilized. A researcher at Lilly called him the next day. After consulting Schinazi, Marconi submitted a proposal to Lilly for a randomized, placebo-controlled trial of baricitinib for hospitalized patients with COVID-19.
At the time, Marconi was also having regular discussions with his trainee, physician-scientist Boghuma Titanji. She had come to Schinazi’s lab to work on HIV and cardiovascular disease, and she found herself caring for severely ill COVID-19 patients at the Atlanta VA Medical Center.
In particular, one patient was on a ventilator in intensive care, and had not responded to other medications. Since no other effective drug was available, they decided to try baricitinib on a “compassionate use” basis. Since the drug was already FDA-approved for rheumatoid arthritis, and thus readily available, the VA team agreed: why not give it a shot? Titanji first tried baricitinib with this patient, under the supervision of Marconi and infectious disease division director Monica Farley, then serving as attending. The man’s recovery a few days later was encouraging.
“I don’t think we would have kept going, if we didn’t have the confidence from our experience with those first few patients,” Titanji says.
With the VA team, Titanji was able to gather information on the drug’s safety and possible efficacy with 14 additional patients. However, when it comes to clinical research, there are limits on the rewards exploratory studies can provide. Most COVID-19 clinical studies have been too small to provide guidance on treatment, according to FDA analyses. To tell physicians what makes a difference in mortality, or getting people out of the hospital more quickly, large multi-center randomized trials are needed.
Schinazi’s industry connections and Marconi’s past experience with HIV clinical trials proved instrumental in expanding the trial to a much bigger group.
“We broke speed records in getting all the parties aligned,” Schinazi says.
After convincing Lilly that a larger trial was warranted, Marconi and Schinazi pushed for baricitinib’s inclusion in a nationwide clinical trial – part of a platform trial, ACTT, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Several of their Emory colleagues contributed to getting the proposal over the finish line, including Nadine Rouphael and David Stephens, co-chair of NIAID’s Infectious Diseases Clinical Research Consortium. Shortly thereafter, Marconi and Schinazi were also able to work with Lilly to launch a separate randomized placebo-controlled trial.
“I think those pre-existing relationships and collaborations that we had, going back several years, are what made this possible,” Marconi says.
“We need to develop innovative new ideas, but it’s also really important to do big clinical trials so that we can come to a rigorous conclusion,” says infectious disease specialist Aneesh Mehta, who led Emory’s part of the study of the antiviral drug remdesivir for NIAID. “Emory is a place where it’s possible to strike that balance.”
Initial results for the second large scale trial, a test of baricitinib and remdesivir together, were presented in October, showing that the combination was associated with a shortened recovery time – particularly in some groups of patients.
Patients who received baricitinib plus remdesivir had a median recovery time of 7 days, as compared with 8 days among those who received remdesivir alone. Those requiring high-flow oxygen or non-invasive ventilation at the beginning of their hospitalization recovered 8 days faster (18 days versus 10).
Although the ACTT-2 study was not designed to assess mortality as a primary outcome, mortality by day 28 was about 35 percent less with baricitinib plus remdesivir compared to remdesivir (5.1 percent versus 7.8 percent). In addition, among ACTT-2 patients who were not already on a ventilator, the baricitinib plus remdesivir combination reduced the likelihood of progression to ventilation or death – at a level that was statistically significant (22.6 percent compared to 29.3 percent).
Another encouraging finding: despite concerns about how baricitinib might suppress immunity or lead to blood clots, the rate of adverse events was significantly less in the baricitinib group.
The Emory investigators say that evidence for barictinib’s efficacy is now strong enough to compare it against the anti-inflammatory steroid dexamethasone, which is used for many non-COVID-19 disorders. ACTT-4, a multi-center head-to-head comparison of baricitinib and dexamethasone in COVID-19, evaluating both drugs in combination with remdesivir, began in November. The trial is enrolling hospitalized adults with COVID-19 who require supplemental oxygen.
Additional Emory resource: podcast interview with Marconi, with transcript
Other publications on baricitinib include: European Science Advances paper, observational clinical studies from Spain and Italy, and a recently published Yerkes non-human primate Cell paper
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