Potential for tocilizumab to treat moderate to severe COVID-19

Simon Collins, HIV i-Base

A study published in PNAS includes encouraging reports from use of the anti-IL-6 monoclonal antibody tocilizumab as treatment for COVID-19 and a press release issued by INSERM two days earlier promises significant results but includes no further details.

The Chinese study ran from 5 to 14 February at a single site in Wuhan and included 21 participants (18 men, 3 women): mean age 56 years (± 16, range 25 to 88). Baseline symptoms included fever (21/21), cough (14/21), phlegm (9/21), fatigue (6/21), tight chest (6/21). Overall, 17/21 were judged severe and 4/21 critical with 9/20 using high flow oxygen, 7/20 using nasal canula, 2/10 using invasive ventilation, 1/21 using non-invasive ventilation and 1/21 using an oxygen mask. [1]

Fever and body temperature returned to normal on day one in all participants. Other symptoms improved within a few days including reductions in CRP (from 75.06 mg/L ± 66.80 before tocilizumab to 2.72 ± 3.60 (day 5), although IL-6 remained very elevated (274.90 ± 414.08 at day 5). Oxygen saturation improved and 15/20 had lowered oxygen intake by day 5.

No serious events were associated with tocilizumab with no reports of elevated transaminase, neutropenia, infection, etc. There were no emerging bacterial, fungal, or viral infections were observed during the treatment.

All participants were discharged within mean 15 days (+/– 5.8, range 10 to 31 days).

Two days earlier, a press release from the French INSERM network reported positive results but only with the most limited results. This is from a multicentre study that randomised 129 participants with moderate to severe COVID-19 pneumonia to open label tocilizumab in addition to standard of care compared to standard of care alone, and that had significantly fewer composite primary endpoints of the need for ventilation or deaths at day 14. [2]

However, although the results have been submitted for publication, further details were not made available in terms of participant responses or the degree of benefit, and the study apparently is still ongoing.

The CORIMUNO-19 study was started on 27 March 2020 to evaluate the efficacy and tolerance of various immune modulators and other treatments in adult patients with severe COVID-19 infection and is still ongoing.

Approximately 30 other studies are planned or ongoing on clinicaltrials.gov. Another dozen studies are using sarilumab and one study in Russia is using olokizumab. [3]

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A new randomised phase 3 study will use tocilizumab plus remdesivir with a control arm using remdesivir alone. The study (called REMDACTA) is due to enrol 450 participants from June but is not yet listed on clinicaltrials.gov. [4]

More than 40 studies of tocilizumab are listed on clincaltrials.gov registry as either ongoing or planned. This includes the large multi-arm UK RECOVERY study that has already enrolled more than 10,500 participants. [5]

POSTSCRIPT to online edition.

Two additional studies also recently reported on tocilizumab for COVID-19.

A retrospective analysis reported better clinical outcomes for 20 participants with severe COVID-19 who received tocilizumab compared to 21 participants receiving standard of care, despite poorer baseline characteristics in the tocilizumab group. [6]

A retrospective analysis of 100 patients at a single site in Brecsia, Italy reported better outcomes for the 43 participants with received tocilizumab vs 57/100 who standard of care. In this study, tocilizumab was given at 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. [7]

However, the large randomised placebo-controled COVACTA study failed to show any benefit from tocilizumab. [8]

References

Xu X et al. Effective treatment of severe COVID-19 patients with tocilizumab. PNAS, DOI: 10.1073/pnas.2005615117. (29 April 2020).
https://www.pnas.org/content/early/2020/04/27/2005615117
INSERM press release. Tocilizumab improves significantly clinical outcomes of patients with moderate or severe COVID-19 pneumonia. (27 April 2020). https://pipelinereview.com/index.php/2020042874458/Antibodies/Tocilizumab-improves-significantly-clinical-outcomes-of-patients-with-moderate-or-severe-COVID-19-pneumonia.html
clinicaltrials.gov. Search results for tocilizumab and COVID-19.
https://clinicaltrials.gov/ct2/results?cond=&term=tocilizumab+covid-19&cntry=&state=&city=&dist=
Roche press release. Roche initiates phase III clinical trial of Actemra/RoActemra plus remdesivir in hospitalised patients with severe COVID-19 pneumonia. (28 May 2020).
https://www.roche.com/media/releases/med-cor-2020-05-28.htm
clinicaltrials.gov. Randomized evaluation of COVID-19 therapy (RECOVERY). NCT04381936.
https://clinicaltrials.gov/ct2/show/NCT04381936
Klopfenstein T et al. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Med Mal Infect. 2020. DOI:10.1016/j.medmal.2020.05.001. (6 May 2020).
https://www.sciencedirect.com/science/article/pii/S0399077X20301293
Toniati P et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020. DOI:10.1016/j.autrev.2020.102568. (3 May 2020).
https://www.sciencedirect.com/science/article/pii/S1568997220301300
Collins S. Tocilizumab fails to meet clinical endpoints in randomised COVACTA study: other studies continue. HTB (9 September 2020).
https://i-base.info/htb/38965