Baricitinib for patients with severe COVID-19—time to change the standard of care?

AuthorsAlexander Supadya,c,d and Robert Zeiserb Lancet Respir Med. 2022 Feb 3doi: 10.1016/S2213-2600(22)00021-2 [Epub ahead of print]PMCID: PMC8813061PMID: 35123659

Mortality is high among patients with severe COVID-19 who require invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).12 Therefore, further specific treatment options for these patients are urgently needed.

Early in the COVID-19 pandemic, Janus kinase (JAK) inhibitors were identified as potential therapeutic agents for the treatment of SARS-CoV-2 infections.34 JAK inhibitors, such as ruxolitinib, fedratinib, and baricitinib, have strong anti-inflammatory properties and are already in clinical use for the treatment of graft-versus-host disease, myelofibrosis, and rheumatoid arthritis.567

Two large, randomised, controlled trials have assessed the use of baricitinib in hospitalised patients with COVID-19.89 The Second Adaptive COVID-19 Treatment Trial (ACTT-2)8 showed that administration of baricitinib in combination with remdesivir shortened the time to recovery in hospitalised patients with COVID-19 compared with remdesivir alone. The COV-BARRIER trial9 did not show a significant benefit of baricitinib plus standard of care compared with placebo plus standard of care in the primary endpoint of disease progression by day 28. Nevertheless, although these were only secondary endpoints, 28-day mortality and 60-day mortality were significantly lower in patients who received baricitinib than in those who received placebo.

However, important questions remain, especially regarding the effect of baricitinib in patients with severe COVID-19 who require IMV or even ECMO. In the ACTT-2 trial, only 111 (11%) of 1033 patients were receiving IMV or ECMO at study inclusion; whereas in the primary COV-BARRIER trial, these severely affected patients were excluded.

In The Lancet Respiratory Medicine, E Wesley Ely and colleagues10 report the findings of an exploratory trial that followed the design of the COV-BARRIER trial and aimed to evaluate the efficacy and safety of baricitinib in addition to standard of care in critically ill hospitalised adults with COVID-19 who were receiving IMV or ECMO. Patients were randomly assigned to receive baricitinib 4 mg (n=51) or matched placebo (n=50) once daily for up to 14 days in addition to standard of care. All-cause mortality by day 28 was significantly lower in patients who received baricitinib than in those who received placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31–0·96]; p=0·030); this finding persisted through day 60 (23 events [45%] vs 31 [62%]; HR 0·56 [95% CI 0·33–0·97]; p=0·027). The authors concluded that baricitinib might represent a novel option for the reduction of mortality in patients with COVID-19, even in progressed disease stages (ie, when already receiving IMV or ECMO).

Although the assignment of participants to the treatment groups was randomised and masked, the mortality benefit determined in this exploratory trial should be interpreted with caution. Important baseline data for the assessment of disease severity and comparison of the study cohort with other cohorts were not provided, including duration of IMV and ECMO before study inclusion, ventilator settings, ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, and prognostic scores, such as Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score (SAPS) II, or Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP). Without these supporting data, it cannot be assumed that the study groups were balanced in terms of baseline disease severity and that quality of care was consistent across study locations. Therefore, the results from this study cannot match the level of evidence from a phase 3 randomised, controlled trial with well-defined primary and secondary endpoints, accompanying sample size estimations, and a prespecified statistical analysis plan.

Interestingly, the all-cause mortality by day 60 in the placebo group in this study was high (62%), despite the baseline use of corticosteroids in 44 (88%) of 50 patients in this group.10 A meta-analysis summarising data from more than 50 000 patients with COVID-19 receiving IMV showed a mortality of only 45%, although a large number of these patients were treated without corticosteroids at the beginning of the pandemic.1 Furthermore, by contrast with the findings from this trial, in ACTT-2, in the subgroup of patients receiving IMV or ECMO at baseline, who were randomly assigned to receive baricitinib (n=54) or placebo (n=57) in addition to remdesivir but without corticosteroids, there was no significant difference between the treatment groups with respect to the outcomes of recovery time or survival by day 28.8 These observations contradict the results of the study by Ely and colleagues. At this time, we can only speculate about the reasons for these conflicting results; possible explanations are a potential influence of the concomitant treatment with remdesivir, the effect of corticosteroids, or any other differences between the groups or the treatments they received.

Taken together, we believe that the level of evidence provided by the results from this study is not sufficient to change standard of care and introduce baricitinib into clinical routine for COVID-19 patients with severe respiratory failure. However, the results of this exploratory trial and the data from COV-BARRIER and ACTT-2 reflect clinical equipoise for the addition of baricitinib to standard of care for patients with severe COVID-19 requiring IMV or ECMO, and provide a sound basis for a well-designed phase 3 trial to confirm these findings.

Open in a separate windowCopyright © 2022 Dr Barry Slaven/Science Photo Library

AS reports research grants and lecture fees from CytoSorbents and lecture fees from Abiomed, outside of the submitted work. RZ reports lecture fees from Novartis, Incyte, and Mallinckrodt, outside of the submitted work.

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Arthritis drug reduces mortality in severe COVID-19, huge clinical trial finds

For hospitalized patients already taking other proven COVID-19 drugs, pill further reduces chance of death

Authors: KAI KUPFERSCHMIDT 3 MAR 2022 1:20 PM

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 U.S. 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 U.K. 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.