Don’t Write Actemra Off Yet: Roche Drug Found To Be ‘Lifesaving’ In COVID-19

Source : 'Scrip Intelligence'

Patients admitted to intensive care in the UK with severe COVID-19 will receive Roche Holding AG’s Actemra/RoActemra (tocilizumab) after an international trial found the drug could cut the relative risk of death by 8% and time spent in intensive care by 10 days.

The results from the international REMAP-CAP study are a surprise turnaround for the drug, an immunomodulator best known for its use in rheumatoid arthritis treatment, and in quelling cytokine release syndrome (CRS) in CAR-T patients.

Its IL-6 inhibitor anti-inflammatory mechanism had made it a major hope in the early days of the pandemic last year, but its chances were written off after five separate randomized trials, (including Roche's own COVACTA and EMPACTA) all failed to show benefits in mortality.

Another IL-6 inhibitor, Sanofi/Regeneron Pharmaceuticals, Inc.’s Kevzara (sarilumab), was also shown to cut deaths in the study, despite failing in an earlier Phase III trial, but was tested in far fewer patients that tocilizumab. ()

This reversal of fortune is being treated with caution by experts for the meantime, however, given the earlier negative findings and because the study has yet to be peer reviewed.

That has not stopped the UK government hailing the results as another step forward in treating the sickest COVID-19 patients, and will issue guidance to the National Health Service (NHS) on how to use Actemra in this setting.

The results arrive as the UK, Europe and the US are battling with a new high in the number of patients being admitted to hospital, and there are hopes the drugs could help reduce deaths and speed patient recoveries.

The news seemed to catch Roche by surprise, as the findings were much more promising than disappointing results from its own two earlier Phase III studies ()

REMAP-CAP study is being led by Imperial College London and the Intensive Care National Audit & Research Centre (ICNARC) in the UK and University Medical Center Utrecht in Europe. It began investigating treatments for COVID-19 in March 2020, enrolling hospitalized patients with either moderate or severe (requiring ICU care) COVID-19, and uses a Bayesian statistical model to generate results.

The trial has run in parallel with the RECOVERY trial, co-ordinated by academics in Oxford, UK, that showed that dexamethasone can save lives in critically ill COVID-19, and the cheap off-patent steroid is now used worldwide.

REMAP-CAP involved 800 patients hospitalized with COVID-19, who within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control).

The primary outcome was an ordinal scale combining in-hospital mortality and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility.

At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10, 11 and 0 for tocilizumab, sarilumab and control, respectively.

Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control, producing an 8% relative risk reduction for patients on Roche’s drug. While the statistical probability analysis suggests that sarilumab produced even better results, external experts point out that this cohort was much smaller than the tocilizumab and control groups.

All secondary outcomes and analyses also supported efficacy of the IL-6 receptor antagonists.

Given the similarity in design to earlier Phase III trials that failed, such as Roche’s COVACTA, it is not immediately clear why REMAP-CAP produced a much more positive result.

The Imperial researchers believe it was because they looked specifically at severely ill patients, and intervened very early when these patients deteriorated, administering the drugs within 24 hours of them entering intensive care.

Anthony Gordon, chair in anaesthesia and critical care at Imperial College London and a consultant in intensive care medicine, said the results could have immediate implications for the sickest COVID-19 patients.

Commenting on the contrasting results from earlier studies, he said the treatment of patients within 24 hours of ICU admission may have made a crucial difference. “This highlights a potential early window for treatment where the sickest patients may gain the most benefit from immune modulation treatment.”

Also of potential significance was than many of the patients on the trial were also given dexamethasone, after its benefits were made clear from the RECOVERY trial.

Meanwhile, the RECOVERY trial is assessing efficacy of tocilizumab in wider patient groups outside of intensive care settings, and this are still ongoing. It is hoped that the results, expected within weeks, could help provide more solid evidence on Actemra.

It has enrolled more than 2,800 patients to assess tocilizumab, and is studying it versus usual care alone for patients with low oxygen saturations or who need ventilation and have evidence of significant inflammation.

This could answer further questions such as how well the drug works in different types of patients, and whether, if administered earlier, it could reduce the need for patients to require mechanical ventilation.

Commenting on the research for the Science Media Centre, Dr Adam Jacobs, director of biostatistics at Premier Research, said the results were impressive, but he would reserve his full judgement until it had been peer reviewed.

He expressed doubts, however, about the Kevzara data, given that it was based on a smaller sample, but was convinced overall that study results were robust.

While the 8% relative risk reduction was significant, this did not make tocilizumab a ‘miracle cure’. He commented: “If you gave it to 100 people in intensive care with COVID infection, then you would expect eight more of them to survive than would have done otherwise. Or to put it another way, you would save one life for approximately each 12 patients you treat.”

Marius Scholtz, chief medical officer at Roche UK, welcomed the trial results, and praised the “unprecedented collaboration” between academia, the NHS, the UK’s National Institute of Health Research, government and industry.

The guidance from England’s Department of Health and Social Care on how tocilizumab should be used in this setting has not yet been published, but it will be off label in the immediate term.

Roche has not provided any further comment yet on how it might take forward the results. Given that this was not a Roche-sponsored trial, it is not clear whether it will pursue any kind of formal approval for the drug’s use in this setting, which might well require further trials to be undertaken. 

By Andrew McConaghie