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Interleukin-6 Inhibitors

Last Updated: June 11, 2020

Recommendation

  • There are insufficient data to recommend either for or against the use of interleukin-6 (IL-6) inhibitors (e.g., sarilumab, siltuximab,tocilizumab) for the treatment of COVID-19.

Rationale

There are insufficient data from clinical trials on the use of IL-6 inhibitors in patients with COVID-19.

Rationale for Use in Patients with COVID-19

IL-6 is a pleiotropic, pro-inflammatory cytokine produced by a variety of cell types, including lymphocytes, monocytes, and fibroblasts. Infection by the related SARS-associated coronavirus induces a dose-dependent production of IL-6 from bronchial epithelial cells.1 Elevations in IL-6 levels may be an important mediator when severe systemic inflammatory responses occur in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. COVID-19-associated systemic inflammation and hypoxic respiratory failure is associated with heightened cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein (CRP), D-dimer, and ferritin.2-4

Sarilumab

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

Clinical Data in COVID-19:

Press Release, April 27, 2020: In a Phase 2/3 clinical trial (ClinicalTrials.gov identifier NCT04315298), hospitalized COVID-19 patients were randomized (2:2:1) to receive sarilumab 400 mg, sarilumab 200 mg, or placebo. Preliminary data were released after an Independent Data Monitoring Committee recommended discontinuing the 200-mg arm and restricting future enrollment to critical patients only. At the time of the interim review of the first 457 participants enrolled, 145 were randomized to receive sarilumab 400 mg, 136 to receive sarilumab 200 mg, and 77 to receive placebo. At study entry, 28% of the patients had severe illness, 49% had critical illness, and 23% had multisystem organ dysfunction.5

Sarilumab decreased CRP, which changed by -79%, -77%, and -21% in the sarilumab 400 mg group, sarilumab 200 mg group, and placebo group, respectively (this is the primary outcome measure of the Phase 2 trial).

At the time of data analysis, the percentage of patients with critical illness (n = 226) who died or were on a ventilator was lower in the sarilumab 400 mg group (28%) than in the sarilumab 200 mg group (46%) and in the placebo group (55%). Comparing mortality alone, the percentage of patients who died also was lower in the sarilumab 400 mg group (23%) than in the sarilumab 200 mg group (36%) and in the placebo group (27%). In contrast to the positive trend in outcomes among patients with critical illness who received sarilumab, the April 27, 2020, press release about the study cited “negative trends” for most outcomes in patients with severe illness who received the drug.

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], other bacterial pathogens) have been reported only in the context of 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 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.

Siltuximab

Siltuximab is a recombinant human-mouse chimeric monoclonal antibody that binds IL-6 and that 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-6R, inhibiting IL-6 signaling. Siltuximab is dosed as an IV infusion.

Clinical Data in COVID-19

There are limited, unpublished data describing the efficacy of siltuximab in patients with COVID-19.6 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.

Clinical Trials

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

Adverse Effects

The primary adverse effects (AEs) reported for siltuximab have been related to rash. Additional AEs, such as serious bacterial infections, have been reported only in the context of long-term dosing of siltuximab once every 3 weeks.

Considerations in Pregnancy

There are insufficient data to determine if 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

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

Tocilizumab

Tocilizumab is a recombinant humanized anti-IL-6R 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.7

Clinical Data for COVID-19

  • Press Release, April 27, 2020: The CORIMUNO-TOCI trial (ClinicalTrials.gov identifier NCT04331808) is an open-label, randomized trial of hospitalized patients with COVID-19 (n = 129 at seven sites in France) who had moderate or severe disease at study entry and who were randomized to receive tocilizumab plus standard of care (n = 65) or standard of care alone (n = 64). Patients received tocilizumab 8 mg/kg on Day 1. If there was no response to the treatment (i.e., no decrease in oxygen requirement), a second infusion of tocilizumab was administered on Day 3. In this preliminary report, the proportion of participants who had died or who needed ventilation (noninvasive or mechanical) was lower in the tocilizumab group than in the standard of care group. Detailed results of the trial have not been reported. The Data and Safety Monitoring Board resigned after the press release was issued.8
  • Published study: Sixty-three hospitalized adult patients 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 (Sa02) <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 level of normal. The patients’ mean age was 62.6 years and most (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 of the patients received off-label antiretroviral protease inhibitors. Patients received either tocilizumab IV (8 mg/kg) or tocilizumab SQ (324 mg); within 24 hours after this initial dose, 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.9

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 AEs, such as risk for serious infections (e.g., TB, other bacterial pathogens), 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 therapy10 and it is occasionally used for MAS.11 Pediatric data for its use in ARDS/sepsis are limited.

Drug Availability

Procuring IV tocilizumab 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. Regeneron and Sanofi provide update on U.S. Phase 2/3 adaptive-designed trial of KEVZARA® (sarilumab) in hospitalized COVID-19 patients [press release]. 2020.
  6. 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.
  7. 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.
  8. Tocilizumab improves significantly clinical outcomes of patients with moderate or severe COVID-19 pneumonia [press release]. 2020.
  9. 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.
  10. 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.
  11. 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.