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Baricitinib Significantly Reduces Death in Severe COVID-19

Baricitinib (Olumiant, Eli Lilly), an oral immunomodulatory agent usually used to treat rheumatoid arthritis (RA), reduces mortality in hospitalised patients with severe COVID-19, according to latest results from the landmark RECOVERY trial. The results are published as a preprint.

This once-daily treatment is seen as additive to existing treatments in severe COVID-19, notably dexamethasone and tocilizumab.

"Adding baricitinib on top of other drugs [that also dampen down the over-active immune response], based on the best evidence to date, is beneficial," said Sir Martin Landray, professor of medicine and epidemiology, University of Oxford, and joint chief investigator of the RECOVERY trial. He pointed out that "we did not know that before today".

Reduced Mortality by 13%

Baricitinib was found to reduce mortality by 13% compared to patients receiving usual care. Speaking at a briefing at London’s Science Media Centre, Landray remarked that: "This opens up the possibility of using combinations of anti-inflammatory drugs to further drive down the risk of death for some of the sickest patients."

Patients were also more likely to be discharged within 28 days.

"This was a small finding but it was statistically significant. Also, those patients who are not on mechanical ventilation at the beginning, which was most, were less likely to be put on mechanical ventilation if they received baricitinib."

There was no evidence of increased death rates due to anything other than COVID-19 (for example thrombosis or infection) in patients on baricitinib compared to usual care, added Landray.

The investigators also combined results with those of other studies that looked at baricitinib in severe COVID-19 and found a reduction in death of around one-fifth. Landray pointed out that this represented, a "clear and consistent benefit regardless of age and level of respiratory support".

He highlighted that these results suggested that clinicians now had "a suite of drugs that tackle the immune system in different ways, for use alone or in combination".

Co-chief investigator of RECOVERY, Sir Peter Hornby, professor of emerging infectious diseases, Oxford University, explained that baricitinib had been approved for use in RA for a number of years. In RA, there are some safety concerns, including immune suppression which could lead to other infections such as tuberculosis, as well as concerns around blood clots. "However, this is in long-term use while use in our study was short course [10 days]," he reassured.

Health and Social Care Secretary, Sajid Javid said: "This is promising news from the government-funded RECOVERY trial...A big thank you to all of the researchers, doctors and volunteers involved in this work. Our medical and scientific experts will now consider the results before any decisions are made on next steps."

Professor Patrick Chinnery, clinical director at the Medical Research Council, said: "These new results from RECOVERY show that even more patient lives can be saved by targeting the immune system in a specific way, adding to the benefits already shown with dexamethasone."

Study Details

The RECOVERY trial currently involves 178 hospitals across the whole of the UK for over 2 years with over 47,000 patients, making it the largest COVID-19 treatments trial globally.

Baricitinib is the fourth treatment that the RECOVERY trial has shown can improve mortality in COVID-19 patients, and is a Janus kinase (JAK) inhibitor that interferes with the interleukin-6 inflammatory pathway.

The trial randomised 8156 patients to either usual standard of care or usual standard of care plus baricitinib 4 mg once-daily by mouth for 10 days, or until discharge if sooner.

At randomisation, 95% of patients were receiving a corticosteroid such as dexamethasone, 23% were receiving tocilizumab, and 20% were receiving the anti-viral drug remdesivir. Two-thirds (68%) of patients were receiving oxygen and one quarter (27%) were receiving additional respiratory support. Average patient age was 58 years.

Mortality at 28-days comprised the primary outcome (intention-to-treat analysis), but results were combined in a meta-analysis with all other previous randomised controlled trials of baricitinib or other JAK inhibitors in patients hospitalised with COVID-19.

Results Consistent Across Different Age Groups

Baricitinib significantly reduced deaths, reported Landray, with 513 (12%) deaths within 28 days in patients on baricitinib compared with 546 (14%) patients on usual care only.

"This is a reduction of 13% or one-eighth, [age-adjusted rate ratio 0.87, 95% confidence interval [CI] 0.77 to 0.98; P=0.026]," he said, adding that "this is a similar proportional reduction in risk to the effect we saw with tocilizumab a year ago".

Of particular interest, he highlighted was that "this result was consistent across the wide range of people we studied, young or old, men or women, but also by level of respiratory support on top of the steroids and even among those patients also getting tocilizumab [or remdisivir]."

Other trials have been smaller. "RECOVERY has two to three times the amount of information as all the other studies put together," said Landray. "Other studies have perhaps seen even bigger benefit so whether this was chance or careful selection of patients or other reasons, it is difficult to tell. But if you look at all the studies together it appears that the JAK inhibitors, particularly baricitinib, reduce the risk of dying in the first 28 days by about 20%."

"The benefit seen can be on top of multiple other treatments or if these other treatments can’t be used then it can be used alone, further reducing the risk of death in these patients," Landray pointed out. "This drug is just as effective as tocilizumab, the effect size is similar."

Drug Combinations Best Way to Treat Severe COVID

Landray pointed out that in the beginning they never thought there would be one miracle drug that would treat COVID-19, but that there will probably be multiple drugs.

"If they could each reduce death by one fifth then we could use multiple drugs in combination and quite soon reduce the risk of mortality by around a half, and in a sense that is what we are seeing now."

He also said that, as COVID-19 became endemic, there would continue to be a substantial number of deaths, even if that spread out over time, so it was still necessary to continue to investigate more drugs that reduce death and reduce the need for ventilators further.

There remains an open question about the impact of short courses of treatment in the most severe state of COVID-19 on longer term recovery of COVID-19, including for example hospital admission, impact with respect to GPs managing breathlessness, and fatigue.

"We will know this information in due course because we have permission to link to hospital data and also to general practice records… this means we can look at what happens to these people not just at one month as per the results so far, but at 6 months or 12 months. People ask if a short course of tocilizumab, for example, reduces breathlessness, reduces readmissions to hospital in the long-term."

There are also implications for availability of these drugs on a global and local level.

"If only one lot of drugs is available and there’s a difficulty in the supply chain, particularly in low-and middle-income countries, then there’s a problem," said Landray. "In fact, even in a high-income country more choice is important. If Omicron had turned out to be anything like the previous variants we wondered if we would have had enough drug."

Hornby added that these new baricitinib data would be a big step towards marketing approval for baracitinib in COVID-19 versus emergency use authorisation.

A manuscript providing further details on these results has been submitted to medRxiv and will be submitted to a peer-reviewed medical journal shortly.

Lead Image Credit: Getty Images