Skip to main content

Interleukin-6 Inhibitors

Last Updated: August 27, 2020

Interleukin (IL)-6 is a pleiotropic, pro-inflammatory cytokine produced by a variety of cell types, including lymphocytes, monocytes, and fibroblasts. Infection by the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) induces a dose-dependent production of IL-6 from bronchial epithelial cells.1 COVID-19-associated systemic inflammation and hypoxic respiratory failure can be associated with heightened cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein (CRP), D-dimer, and ferritin.2-4 It is hypothesized that modulating the levels of IL-6 or its effects may alter the course of disease.

There are two classes of Food and Drug Administration (FDA)-approved IL-6 inhibitors: anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) and anti-IL-6 monoclonal antibodies (siltuximab). These classes of drugs have been evaluated for the management of patients with COVID-19 who have systemic inflammation. The COVID-19 Treatment Guidelines Panel’s (the Panel’s) recommendations and clinical data to date are described below.

Recommendation

  • The Panel recommends against the use of anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) or anti-IL-6 monoclonal antibody (siltuximab) for the treatment of COVID-19, except in a clinical trial (BI).

Rationale

Preliminary, unpublished data from randomized, controlled trials failed to demonstrate efficacy of sarilumab or tocilizumab in patients with COVID-19. There are only limited, unpublished data describing the efficacy of siltuximab in patients with COVID-19.11

Anti-Interleukin-6 Receptor Monoclonal Antibodies

Sarilumab

Sarilumab is a recombinant humanized anti-IL-6 receptor monoclonal antibody that is approved by the FDA for use in patients with rheumatoid arthritis. It is available as a subcutaneous (SQ) formulation and is not approved for the treatment of cytokine release syndrome (CRS). A placebo-controlled clinical trial is evaluating the use of an intravenous (IV) formulation of sarilumab administered as a single dose for COVID-19.

Clinical Data for COVID-19

Press Release: July 2, 2020: The efficacy and safety of sarilumab 400 mg IV and sarilumab 200 mg IV versus placebo was evaluated in patients hospitalized with COVID-19 in an adaptive Phase 2 and 3, randomized (2:2:1), double-blind, placebo-controlled trial (ClinicalTrials.gov Identifier NCT04315298). Randomization was stratified by severity of illness (i.e., severe, critical, multisystem organ dysfunction) and use of systemic corticosteroids for COVID-19. The Phase 2 component of the trial verified that sarilumab (at either dose) reduced CRP levels. The primary outcome for Phase 3 of the trial was change on a seven-point ordinal scale, and this phase was modified to focus on the dose of sarilumab 400 mg among the patients in the critically ill group. During the conduct of the trial, there were numerous amendments that increased the sample size and modified the dosing strategies being studied, and multiple interim analyses were performed. Ultimately, the trial findings to date do not support a clinical benefit of sarilumab for any of the disease severity subgroups or dosing strategies studied. Additional detail (as would be included in a published manuscript) is required to fully evaluate the implications of these study findings.5

Adverse Effects

The primary lab abnormalities that have been reported with sarilumab treatment are transient and/or reversible elevations in liver enzymes that appear to be dose dependent and rare occurrences of neutropenia and thrombocytopenia. Risk for serious infections (e.g., tuberculosis [TB], bacterial or fungal infections) and bowel perforation have been reported only with long-term use of sarilumab.

Considerations in Pregnancy

There are insufficient data to determine whether there is a drug-associated risk for major birth defects or miscarriage. Monoclonal antibodies are actively transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in utero in the exposed fetus.

Drug Availability

The SQ formulation of sarilumab is not approved for the treatment of CRS. The IV formulation is not approved by the FDA, but it is being studied in a clinical trial of hospitalized patients with COVID-19. A list of current clinical trials is available at ClinicalTrials.gov.

Tocilizumab

Tocilizumab is a recombinant humanized anti-IL-6 receptor monoclonal antibody that is approved by the FDA for use in patients with rheumatologic disorders and CRS induced by chimeric antigen receptor T cell (CAR-T) therapy. Tocilizumab can be dosed for IV or SQ injection. For CRS, the IV formulation should be used.6

Clinical Data for COVID-19

Press Release: July 29, 2020: In the industry-sponsored Phase 3 COVACTA trial (ClinicalTrials.gov Identifier NCT04320615), 450 adults hospitalized with severe COVID-19-related pneumonia were randomized to receive tocilizumab or placebo. The trial failed to meet its primary endpoint or several key secondary endpoints. The primary outcome was improved clinical status, which was measured using a seven-point ordinal scale to assess clinical status based on the need for intensive care and/or ventilator use and the requirement for supplemental oxygen over a 4-week period. Key secondary outcomes included 4-week mortality. Differences in the primary outcome between the tocilizumab and placebo groups were not statistically significant (OR 1.19; 95% CI, 0.81–1.76; P = 0.36). At Week 4, mortality rates did not differ between the tocilizumab and placebo groups (19.7% vs. 19.4%; difference of 0.3%; 95% CI, -7.6% to 8.2%; P = 0.94). The difference in median number of ventilator-free days between the tocilizumab and placebo groups did not reach statistical significance (22 days for tocilizumab group vs. 16.5 days for placebo group; difference of 5.5 days; 95% CI, -2.8 to 13.0 days; P = 0.32). Infection rates at Week 4 were 38.3% in the tocilizumab group and 40.6% in the placebo group; serious infection rates were 21.0% and 25.9% in the tocilizumab and placebo groups, respectively.7

Published Study

Sixty-three adult patients hospitalized with COVID-19 were enrolled in a prospective, open-label study of tocilizumab for severe COVID-19. Criteria for inclusion in the study were polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; pulmonary involvement, assessed either by oxygen saturation (SaO2) <93% on room air or PaO2/FiO2 ratio <300 mm Hg; and at least three of the following:

  • CRP >10 times normal values,
  • Ferritin >1,000 ng/mL,
  • D-dimer >10 times normal values, or
  • Lactate dehydrogenase >2 times the upper limit of normal.

The patients’ mean age was 62.6 years and most of the patients (88%) were male; 39.7% of the patients were febrile, and 95.7% had bilateral pulmonary infiltrates. Five patients were on mechanical ventilation at baseline. All patients received off-label antiretroviral protease inhibitors. Patients received either tocilizumab (8 mg/kg) IV or tocilizumab (324 mg) SQ; within 24 hours after this initial dose of tocilizumab, a second dose was administered to 52 of the 63 patients. Following administration of tocilizumab, fevers resolved in all but one patient, and CRP, ferritin, and D-dimer levels declined. The mean PaO2/FiO2 ratio of the patients increased between admission (152 +/- 53 mm Hg) and Day 7 of hospitalization (284 +/- 116 mm Hg). No moderate or severe adverse events attributable to tocilizumab were reported. The overall mortality rate was 11% (7 of 63 patients). No details were provided regarding the rate of secondary infections after tocilizumab use. The authors report an association between earlier use of tocilizumab and reduced mortality; however, interpretation of this result is limited because the study results did not describe a comparison group or specify an a priori comparison.8

Clinical Trials

See ClinicalTrials.gov for ongoing trials that are evaluating the use of tocilizumab for the treatment of COVID-19.

Adverse Effects

The primary laboratory abnormalities reported with tocilizumab treatment are elevated liver enzyme levels that appear to be dose dependent. Neutropenia or thrombocytopenia are uncommon. Additional adverse effects, such as risk for serious infections (e.g., TB, bacterial or fungal infections) and bowel perforation, have been reported only in the context of continuous dosing of tocilizumab.

Considerations in Pregnancy

There are insufficient data to determine whether there is a drug-associated risk for major birth defects or miscarriage. Monoclonal antibodies are actively transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in utero in the exposed fetus.

Considerations in Children

In children, tocilizumab is frequently used for CRS following CAR-T therapy9 and it is occasionally used for macrophage activation syndrome.10 Pediatric data for its use in acute respiratory distress syndrome/sepsis are limited.

Drug Availability

Procuring IV tocilizumab may be a challenge at some hospitals in the United States.

Anti-Interleukin-6 Monoclonal Antibody

Siltuximab

Siltuximab is a recombinant human-mouse chimeric monoclonal antibody that binds IL-6 and is approved by the FDA for use in patients with Castleman’s disease. Siltuximab prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors, inhibiting IL-6 signaling. Siltuximab is dosed as an IV infusion.

Clinical Data for COVID-19

There are limited, unpublished data describing the efficacy of siltuximab in patients with COVID-19.11 There are no data describing clinical experiences using siltuximab for patients with other novel coronavirus infections (i.e., severe acute respiratory syndrome [SARS], Middle East respiratory syndrome [MERS]).

Clinical Trials

See ClinicalTrials.gov for a list of current clinical trials for siltuximab and COVID-19.

Adverse Effects

The primary adverse effects reported for siltuximab have been related to rash. Additional adverse effects (e.g., serious bacterial infections) have been reported only with long-term dosing of siltuximab once every 3 weeks.

Considerations in Pregnancy

There are insufficient data to determine whether there is a drug-associated risk for major birth defects or miscarriage. Monoclonal antibodies are transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in utero in the exposed fetus.

Drug Availability

Procuring siltuximab may be a challenge at some hospitals in the United States.

References

  1. Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-3048. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19004938.
  2. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32171076.
  3. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31986264.
  4. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32176772.
  5. Sanofi. Sanofi and Regeneron provide update on Kevzara® (sarilumab) Phase 3 U.S. trial in COVID-19 patients. 2020. Available at: https://www.sanofi.com/en/media-room/press-releases/2020/2020-07-02-22-30-00. Accessed August 10, 2020.
  6. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943-947. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29622697.
  7. Roche. Roche provides an update on the Phase III COVACTA trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 associated pneumonia. 2020. Available at: https://www.roche.com/investors/updates/inv-update-2020-07-29.htm. Accessed August 10, 2020.
  8. Sciascia S, Apra F, Baffa A, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol. 2020;38(3):529-532. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32359035.
  9. Gardner RA, Ceppi F, Rivers J, et al. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood. 2019;134(24):2149-2158. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31697826.
  10. Yokota S, Itoh Y, Morio T, Sumitomo N, Daimaru K, Minota S. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis under treatment with tocilizumab. J Rheumatol. 2015;42(4):712-722. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25684767.
  11. Gritti G, Raimondi F, Ripamonti D, et al. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv. 2020. Available at: https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v1.