Tocilizumab trial failure highlights the complexity of COVID-19 inflammation

Negative findings from another tocilizumab trial in COVID-19 patients show there is still a lot to learn about which inflammatory pathway to target, researchers say .

“Maybe blocking IL-6 is not the right way, and it could be that blocking TNF [tumour necrosis factor] will be effective, or blocking IL-1, or one of the other inflammatory mediators,” said Professor Mike Ehrenstein, a clinician researcher in rheumatology at University College London, in an interview with the limbic.

The latest setback, adds to several others in recent weeks relating to the IL-6 inhibitor tocilizumab. Once thought to be a promising therapeutic option for the hyper-inflammatory responses to the COVID-19 virus because of its proven efficacy against cytokine release syndrome (CRS), it has now showing little or no effect in randomised controlled trials (RCTs) in COVID-19 pneumonia.

A new RCT, conducted at seven hospitals in  the U.S., and published in the NEJM, included 243 hospitalised patients who were not receiving mechanical ventilation. Patients received either tocilizumab or placebo, and there was no significant difference between the groups with regard to the risk of intubation or death (Hazard Ratio 0.83). The same was true for the risk of disease worsening (HR 1.11), and there was also no significant difference in the median time to discontinuation of supplemental oxygen.

The authors, led by Dr. John H. Stone, director of clinical rheumatology at Massachusetts General Hospital, expressed disappointment at the trial’s failure to show benefit.

“Our data do not provide support for the concept that early interleukin-6 receptor blockade is an effective treatment strategy in moderately ill patients hospitalised with COVID-19,” they wrote.

The authors did note that the width of the confidence intervals meant they could not completely exclude the possibility of benefit with tocilizumab.

The study joins several others recently published in JAMA Internal Medicine that showed some potential for the IL-6 monoclonal antibody widely used in RA, but falling short of providing conclusive evidence for its use in patients with COVID-19.

One trial conducted in Italy found no effect of tocilizumab on disease progression, while another in France found the potential to reduce ventilatory support but no effect on mortality at 14 or 28 days.

Still, each of these trials has been limited by its size; the largest trial testing tocilizumab in COVID-19 is the RECOVERY trial, taking place in the UK.

Dr Peter Horby, a professor of emerging infectious diseases and global health at Oxford University, is leading that trial, and he said that the existing evidence for tocilizumab remains inconclusive.

The somewhat conflicting results so far, he told the limbic, “make[s] a large definitive trial like RECOVERY all the more important. So we will continue until we get a clear answer from RECOVERY.”

A complicated inflammatory environment

The scientific rationale for testing an IL-6 blocker such as tocilizumab is sound, according to Professor Ehrenstein. He noted that C-reactive protein (CRP) has been shown to be increased in severe cases of COVID-19, which is driven by IL-6. And yet, at least to date, inhibiting this pathway does not appear to have a dramatic effect.

“I think we understand so little about COVID-related inflammation that essentially what people are doing is taking treatments that are already available in the toolbox and trying them out in a sort of educated guesswork-type manner,” he said.

“Sometimes it turns out to be effective and other times not.”

He highlighted the difference between targeted therapies with only one or two applications such as tocilizumab, and steroids, which are used across a number of rheumatic diseases.

Dexamethasone has been approved for use with COVID-19, while the targeted therapies remain a challenge.

“So often in rheumatic diseases we have evidence that a target might be appropriate, and then we try it and sometimes it turns out to be correct other times not,” Professor Ehrenstein said.

“We’re quite used to this experimental approach.”

A recent commentary in JAMA Internal Medicine also questioned the validity of targeting IL-6 in COVID-19 disease, noting that although levels were elevated, the median IL-6 levels in patients with the hyperinflammatory phenotype of ARDS were up to 200-fold higher than levels in patients with severe COVID-19.

Interventions targeting single cytokines in other hyperinflammatory syndromes also had a long history of failure, it noted.

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