What are the roles of the IL-6 inhibitors tocilizumab (Actemra) and sarilumab (Kevzara) in the treatment of coronavirus disease 2019 (COVID-19)?

Updated: Apr 19, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Answer

Interleukin-6 inhibitors 

IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. [180]  

Tocilizumab has been studied in several phase 3 clinical trials to evaluate the safety and efficacy plus standard of care in hospitalized adults with COVID-19 pneumonia compared to placebo plus standard of care. Average wholesale price of tocilizumab is approximately $5000 for an 800-mg dose. Preliminary results for sarilumab have also been reported.

The Infectious Disease Society of America guidelines recommend tocilizumab in addition to standard of care (ie, steroids) among hospitalized adults with COVID-19 who have elevated markers of systemic inflammation. [27] The NIH guidelines recommend use of tocilizumab (single IV dose of 8 mg/kg, up to 800 mg) in combination with dexamethasone in recently hospitalized patients who are exhibiting rapid respiratory decompensation caused by COVID-19. [181] These recommendations are based on the paucity of evidence from randomized clinical trials to show certainty of mortality reduction. 

The EMPACTA trial found nonventilated hospitalized patients who received tocilizumab (n = 249) in the first 2 days of ICU admission had a lower risk of progression to mechanical ventilation or death by day 28 compared with those not treated with tocilizumab (n = 128) (12% vs 19.3% respectively). The data cutoff for this study was September 30, 2020. In the 7 days before the trial or during the trial, 200 patients in the tocilizumab group (80.3%) and 112 patients in the placebo group (87.5%) received systemic glucocorticoids and 55.4% and 67.2% of the patients received dexamethasone. Antiviral treatment was administered in 196 (78.7%) and 101 (78.9%), respectively, and 52.6% and 58.6% received remdesivir. However, there was no difference in incidence of death from any cause between the 2 groups. [182]

Preliminary results from the REMAP-CAP international adaptive trial evaluated efficacy of tocilizumab 8 mg/kg (n = 353), sarilumab 400 mg (n = 48), or control (n = 402) in critically ill hospitalized adults receiving organ support in intensive care. Hospital mortality at day 21 was 28% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab, and 35.8% (142/397) for control. Of note, corticosteroids became part of the standard of care midway through the trial. Estimates of the treatment effect for patients treated with either tocilizumab or sarilumab and corticosteroids in combination were greater than for any single intervention. [183]   

The US-based trial (n = 194) for sarilumab was stopped in July 2020 after observing positive trends in the primary prespecified analysis group (critical patients on 400 mg who were mechanically ventilated at baseline) did 48), not reach statistical significance and these were countered by negative trends in a subgroup of critical patients who were not mechanically ventilated at baseline.  

The RECOVERY trial assessed use of 4,116 hospitalized adults with COVID-19 infection who received either tocilizumab (n = 2,022) compared with standard of care (n = 2,094) in the UK from April 23, 2020 to January 24, 2021. Among participants, 562 (14%) received invasive mechanical ventilation, 1686 (41%) received non-invasive respiratory support, and 1868 (45%) received no respiratory support other than oxygen. Median C-reactive protein was 143 mg/L and 3385 (82%) patients were receiving systemic corticosteroids at randomization. Preliminary results show 596 (29%) of patients allocated to tocilizumab and 694 (33%) allocated to usual care died within 28 days (p = 0.007). Tocilizumab mortality benefits were clearly seen among those who also received systemic corticosteroids. Patients in the tocilizumab group were more likely to be discharged from the hospital within 28 days (54% vs 47; p < 0.0001). Among those not receiving invasive mechanical ventilation at baseline, patients who received tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (33% vs 38%; p = 0.0005). [184]

Results from early trials produced conflicting results. The dynamic changes and knowledge of treatment that took place during these trials (eg, ventilatory support, medications) and varying degrees of diseases severity causes added dimensions to consider. Several of these initial studies are discussed.

Results from the BACC Bay randomized, double-blind, placebo-controlled trial (n = 243; conducted between April 20 to June 15, 2020) found tocilizumab was not effective in preventing intubation or death in nonventilated hospitalized patients with moderate COVID-19 disease. The researchers point out that the confidence interval for efficacy comparisons were wide, so some benefit or harm is uncertain. Additionally, results of the ACTT-1 trial for remdesivir were release during the trial, so some patients received remdesivir. The RECOVERY trial results for dexamethasone had not been released, so no patients received dexamethasone. Other antiviral or glucocorticoid therapies were permitted. [185]  

Results from the COVACTA randomized controlled phase 3 trial included approximately 38% mechanically ventilated patients. The trial did not meet its primary endpoint of improved clinical status in patients with COVID-19–associated pneumonia or the secondary endpoint of reduced patient mortality. The trial did show a positive trend in time to hospital discharge among patients who received tocilizumab. [186]  

An observational study of 239 consecutive patients with severe COVID-19 was conducted at Yale (New Haven, CT). Patients were treated with a standardized algorithm that included tocilizumab to treat cytokine release syndrome. These early observations showed that, despite a surge of hospitalizations, tocilizumab-treated patients (n = 153) comprised 90% of those with severe disease, but their survival rate was similar to that in patients with nonsevere disease (83% vs 91%; P = 0.11). In tocilizumab-treated patients requiring mechanical ventilation, the survival rate was 75%. Oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor levels increased significantly. [187] Similarly, a small compassionate use study (n = 27) found that a single 400-mg IV dose of tocilizumab reduced inflammation, oxygen requirements, vasopressor support, and mortality. [188]

A study compared outcomes of patients who received tocilizumab (n = 78) with tocilizumab-untreated controls in patients with COVID-19 requiring mechanical ventilation. Tocilizumab was associated with a 45% reduction in hazard of death (hazard ratio, 0.55) and improved status on the ordinal outcome scale (odds ratio per one-level increase, 0.59). Tocilizumab was associated with an increased incidence of superinfections (54% vs 26%; P < 0.001); however, there was no difference in 28-day case fatality rate among tocilizumab-treated patients with superinfection versus those without superinfection (22% vs 15%; P = 0.42). [189]


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