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

Updated: Jan 23, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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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. [236] As of August 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-6 inhibitors (eg, tocilizumab, sarilumab), except in a clinical trial. [237] Average wholesale price for 400 mg of tocilizumab is approximately $2765.

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. Preliminary results for sarilumab have also been reported.

The EMPACTA trial (n = 389) found nonventilated hospitalized patients who received tocilizumab 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 in the first 2 days of ICU admission (12% vs 19.3% respectively). However, there was no difference in incidence of death from any cause between the 2 groups. [248]

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. [240]   

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.  

Results from the BACC Bay trial (n = 243) found tocilizumab was not effective in preventing intubation or death in 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. [241]  

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. [242]  

A variety of observational and open-label trials have reported mixed results. 

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. [243] 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. [244]

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 [95% CI 0.33, 0.90]) and improved status on the ordinal outcome scale (odds ratio per one-level increase: 0.59 [0.36, 0.95]). 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). [245]

A small case among 29 solid organ transplant (SOT) recipients who received tocilizumab compared outcomes with 88 matched SOT controls who did not received tocilizumab. Mortality at 90 days was significantly higher for those who received tocilizumab (41%) compared with those who did not (20%; p = 0.03). Larger trials are needed to determine if there are subsets of patients who may benefit from tocilizumab. [246]

An observational study in New Jersey showed an improved survival rate among patients who received tocilizumab. Among 547 ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend toward an improved survival rate of 54% who received tocilizumab compared with 44% who did not receive the therapy and a propensity adjusted hazard ratio of 0.76. [247]

A retrospective, observational cohort study in tertiary care centers in Bologna, Reggio Emilia, and Modena, Italy, between February 21 and March 24, 2020, concluded that tocilizumab may reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia. Of 1351 patients admitted, 544 (40%) had severe COVID-19 pneumonia and were included in the study. Fifty-seven (16%) of 365 patients in the standard care group needed mechanical ventilation compared with 33 (18%) of 179 patients treated with tocilizumab (P = 0.41; 16 [18%] of 88 patients treated IV and 17 [19%] of 91 patients treated SC). Seventy-three (20%) patients in the standard care group died, compared with 13 (7%; < 0.0001) patients treated with tocilizumab (6 [7%] treated IV and 7 [8%] treated SC). [249]

Another Italian open-labeled, randomized study conducted from March 31 to June 11, 2020 was halted after enrolling 126 patients with COVID-19 pneumonia. In this trial of hospitalized patients, the interim analysis did not show tocilizumab reduced severe respiratory symptoms, intensive care, or death compared with standard care. [250]  

An open-label trial conducted in 9 university hospitals in France between March 31 to April 18, 2020 treated 64 patients with moderate-to-severe COVID-19 with tocilizumab. Compared with 67 patient receiving usual care alone (ie, antibiotics, antivirals, corticosteroids, vasopressor support, and anticoagulants), tocilizumab-treated patients did not reduce did not reduce the WHO-CPS scores lower than 5 at Day 4. At day 14, 12% fewer patients needed noninvasive ventilation or mechanical ventilation died in the tocilizumab group compared with the usual care group. However, there was no difference in death at day 28 between tocilizumab and usual care. [251]

An open label, non-controlled, non–peer reviewed study was conducted in China in 21 patients with severe respiratory symptoms related to COVID-19. All had a confirmatory diagnosis of SARS-CoV-2 infection. The patients in the trial had a mean age of 56.8 years (18 of 21 were male). Although all patients met enrollment criteria of (1) respiratory rate of 30 breaths/min or more, (2) SpO2 of 93% or less, and (3) PaO2/FiO2 of 300 mm Hg or less, only two of the patients required invasive ventilation. The other 19 patients received various forms of oxygen delivery, including nasal cannula, mask, high-flow oxygen, and noninvasive ventilation. All patients received standard of care, including lopinavir and methylprednisolone. Patients received a single dose of 400 mg tocilizumab via intravenous infusion. In general, the patients improved with lower oxygen requirements, lymphocyte counts returned to normal, and 19 patients were discharged with a mean of 15.5 days after tocilizumab treatment. The authors concluded that tocilizumab was an effective treatment in patients with severe COVID-19. [252]

A retrospective review of 25 patients with confirmed severe COVID-19 who received tocilizumab plus investigational antivirals showed patients who received tocilizumab experienced a decline in inflammatory markers, radiological improvement, and reduced ventilatory support requirements. The authors acknowledged the study’s limitations and the need for adequately powered randomized controlled trials of tocilizumab. [253]

Another clinical phase 3 trial (COV-AID) with IL-6 inhibitors (ie, tocilizumab, siltuximab), an IL-1 inhibitor (ie, anakinra), or combining an IL-6 inhibitor with anakinra is ongoing. [254]

An anti-interleukin-6 receptor monoclonal antibody (TZLS-501; Tiziana Life Sciences and Novimmune) is currently under development. [255]

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