Baricitinib, an oral drug that dampens an overactive immune system and is commonly used by people with rheumatoid arthritis, reduced hospitalized COVID-19 patients’ risk of dying by 13%, investigators of the world’s largest trial of coronavirus treatments announced today. Patients in the study also took other drugs, such as the steroid dexamethasone, that act on the immune system and have already been shown to help against COVID-19. “Adding baricitinib on top of whatever else the doctors are currently prescribing … is beneficial,” says University of Oxford clinical scientist Martin Landray, one of the principal investigators of the United Kingdom’s Recovery trial.
Scientists and doctors welcomed the addition of the pill to the few treatments already shown to help treat severe COVID-19. “The pandemic is far from over, and we will likely have to contend with additional case surges in the future. It is heartening to have more mortality-reducing therapeutic options,” says Emory University virologist Boghuma Titanji, noting that the baricitinib comes in generic versions that low- and middle-income countries can afford.
Baricitinib inhibits enzymes in the Janus kinase (JAK) family, which play an important role in regulating immune responses. Several smaller randomized trials had concluded that baricitinib helped against COVID-19, and it is already being used in some countries to treat severe cases. But some of these trials only included patients that did not receive other drugs targeting the immune system, and the Recovery trial is by far the largest test of the drug yet.
The researchers compared 4148 hospitalized patients who received usual COVID-19 care plus baricitinib with 4008 hospitalized patients who only received the usual care. Of the patients who took baricitinib, 513 people (12%) died within 28 days of randomization versus 546 deaths (14%) in the control group, the researchers write in a preprint. That protective effect is smaller than found in previous trials of the drug. The new result “is likely a better reflection of the actual treatment effect,” says Eric Topol, director of the Scripps Research Translational Institute, because the “finding reflects a more current, real-world background of standard treatments for severe COVID.” A meta-analysis of Recovery and the other eight completed trials that investigated baricitinib or another JAK inhibitor suggests a 20% reduction in deaths, the researchers write.
The COVID-19 treatment landscape has changed dramatically since the Recovery trial announced the first therapy shown to be effective, in June 2020: It found that dexamethasone, a widely available steroid, reduced deaths in ventilated patients by one-third. In February 2021, the Recovery trial announced that tocilizumab, another drug acting on the immune system, further reduced deaths in hospitalized patients taking dexamethasone. Now, baricitinib reduces deaths even further. “This is a drug that is just as effective as tocilizumab,” Landray says. “The effect size is very similar.”
Drugs targeting the virus, rather than the body’s response to it, have also proved their worth. Intravenous antibody treatments given early in disease have been shown to protect some patients against hospitalization. And more recently, oral antivirals from Merck and Pfizer have demonstrated they can cut COVID-19 deaths if given early enough. This week, the World Health Organization (WHO) updated its treatment guidelines to include the first such drug: Merck’s molnupiravir. “As this is a new medicine, there is little safety data,” the agency cautioned, recommending prescribing only for those at highest risk of hospitalization and active monitoring for side effects.
But the rise of the Omicron variant of SARS-CoV-2 has also challenged progress in treating COVID-19. Several antibody treatments are ineffective against this variant, which now dominates infections across the globe. In its recent guideline update, WHO recommended that an antibody cocktail, casirivimab-imdevimab, only be given when a different variant has caused an infection. There are also indications that an antibody therapy called sotrovimab, one of the only antibodies known to work against the Omicron subtype BA.1, has lost some efficacy against the spreading BA.2 subtype of Omicron, says Leif Erik Sander, an immunologist at Charité University Hospital in Berlin. “Still, we are in a much better position now to treat the sick patients we see in the hospital than we were a year ago.”
And other treatments are on the horizon. For instance, after Eli Lilly and Company’s cocktail of the antibodies etesevimab and bamlanivimab was found ineffective against the Omicron variant, the company brought forward a new antibody, bebtelovimab. It received emergency use authorization from the US Food and Drug Administration in February. Dozens of other drug candidates in testing, with results expected within months.
The Recovery trial, which started in March 2020, has so far enrolled more than 47,000 hospitalized patients. Most have been treated at UK clinics, but the trial has expanded to include locations in South Africa, Ghana, Vietnam, Indonesia, and Nepal. In addition to identifying three drugs that treat COVID-19, the study helped rule out several others, including aspirin, the antimalarial hydroxychloroquine, the HIV drug combination lopinavir/ritonavir, and colchicine, an anti-inflammatory drug.
Recovery is still testing molnupiravir, sotrovimab, and the diabetes drug empagliflozin. It is also testing higher doses of corticosteroids such as dexamethasone in the hope that using them alone would work just as well as combining them with more expensive immune-modulating drugs.