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Interleukin-1 Inhibitors

Last Updated: October 19, 2021

Endogenous interleukin (IL)-1 is elevated in patients with COVID-19.1,2 In addition, SARS-CoV-2 infection causes epithelial damage that leads to the release of IL-1 beta, which recruits inflammatory cells and induces the release of IL-1 beta in monocytes. This in turn leads to the release of more IL-1 to recruit and activate additional innate immune cells. Drugs that block the IL-1 receptor (e.g., anakinra) or drugs that block IL-1 signaling (e.g., canakinumab) can potentially interrupt this autoinflammatory loop. These drugs are being investigated as potential treatments for COVID-19.

Anakinra is a recombinant human IL-1 receptor antagonist. It is approved by the Food and Drug Administration (FDA) to treat rheumatoid arthritis and cryopyrin-associated periodic syndromes, specifically neonatal-onset multisystem inflammatory disease.3 It is used off-label to treat severe chimeric antigen receptor T cell-mediated cytokine release syndrome and macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis.

Canakinumab is a human monoclonal antibody that targets the beta subunit of IL-1 and is approved by the FDA for the treatment of systemic juvenile idiopathic arthritis and Still’s disease.

Recommendations

  • There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of anakinra for the treatment of COVID-19.
  • The Panel recommends against the use of canakinumab for the treatment of COVID-19, except in a clinical trial (BIIa).

Rationale

In the SAVE-MORE trial, 594 hospitalized patients who had moderate or severe COVID-19 pneumonia and plasma-soluble urokinase plasminogen activator receptor (suPAR) levels ≥6 ng/mL were randomized to receive either anakinra or placebo. The study found that patients who received anakinra had a lower risk of clinical progression of COVID-19 than those who received placebo.4 CORIMUNO-ANA-1, a randomized controlled trial that compared the use of anakinra to usual care in 116 hospitalized patients who were hypoxemic but did not require high-flow oxygen or ventilation, was stopped early for futility.5 REMAP-CAP, an open-label, adaptive platform, randomized controlled trial that evaluated several immunomodulators in patients with COVID-19 who required organ support, found that anakinra was not effective in reducing the combined endpoint of in-hospital mortality and days of organ support.6 Although the SAVE-MORE study suggests that suPAR levels could be used in risk stratification to identify populations that could benefit from IL-1 inhibition, the laboratory assay that is used to assess suPAR levels is not currently available in many countries, including the United States. After reviewing the results of the studies discussed above and taking into consideration the fact that suPAR assays are not widely available to guide the use of anakinra, the Panel has concluded that there is insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19 in hospitalized patients.

Finally, CAN-COVID, a randomized controlled trial that evaluated canakinumab in hospitalized patients with COVID-19 who were hypoxemic but did not require ventilatory support, reported that the use of canakinumab did not improve the likelihood of survival without invasive mechanical ventilation.7 Because of these results, the Panel recommends against the use of canakinumab for the treatment of COVID-19, except in a clinical trial (BIIa).

Clinical Data for COVID-19

SAVE-MORE

SAVE-MORE was a randomized controlled trial in 594 hospitalized patients with moderate or severe COVID-19 pneumonia and plasma suPAR levels ≥6 ng/mL. Patients who required noninvasive or invasive mechanical ventilation were excluded from the study. Patients were randomized 2:1 to receive anakinra 100 mg subcutaneously once daily for 10 days or placebo. The primary endpoint was clinical status at Day 28 on the 11-point World Health Organization Clinical Progression Scale (WHO-CPS).4

Results

  • Patients who were randomized to receive anakinra had a lower odds of progression of COVID-19 on the WHO-CPS (OR 0.36; 95% CI, 0.26–0.50; P < 0.0001).
  • The secondary endpoints also favored anakinra, including the absolute decrease in WHO-CPS scores from baseline at Days 14 and 28, the absolute decrease in Sequential Organ Failure Assessment scores from baseline at Day 7, the median time to hospital discharge, and the median duration of intensive care unit (ICU) stays.
  • A smaller proportion of patients in the anakinra arm experienced secondary infections, including ventilator-associated pneumonias, than in the placebo arm (8.4% vs. 15.9%; P = 0.01)
  • Twenty-eight-day mortality was lower among patients who received anakinra than those who received placebo (3.2% vs. 6.9%; HR 0.45; 95% CI, 0.21–0.98; P = 0.045).

Limitations

  • The laboratory assay that is used to assess suPAR levels is not currently available in many countries, including the United States.

REMAP-CAP

The REMAP-CAP trial is an open-label, adaptive platform trial in which eligible participants are randomized to several domains, including the Immune Modulation Therapy domain, which consists of two IL-6 inhibitors, anakinra, interferon beta-1a, and a control group. Participants are eligible for enrollment if they are within 24 hours of receiving respiratory or cardiovascular organ support in the ICU and they have suspected or microbiologically confirmed COVID-19.

Anakinra 300 mg was given intravenously (IV) as a loading dose, followed by anakinra 100 mg IV every 6 hours for 14 days until patients were either free from invasive mechanical ventilation for >24 hours or discharged from the ICU. The primary outcome was measured using an ordinal scale that included a composite of in-hospital mortality and duration of respiratory and cardiovascular organ support at 21 days; all deaths up to 90 days were assigned the worst outcome. The trial used a Bayesian design that allowed the authors to compare nonconcurrently randomized interventions across time periods.6

Results

  • Of the 2,274 participants who were randomized to one of the arms in the Immune Modulation Therapy domain, 365 individuals were assigned to receive anakinra and included in the analysis, 406 were assigned to the usual care (control) arm, 943 were assigned to receive tocilizumab, and 483 were assigned to receive sarilumab.
  • Of those assigned to receive anakinra, 37% were receiving invasive mechanical ventilation at study entry compared with 32% of patients in the other arms. The other patients received oxygen through a high-flow nasal cannula or noninvasive ventilation, with a few exceptions.
  • The median number of organ support-free days was similar for patients who received anakinra and those who received usual care (0 days [IQR 1–15 days] vs. 0 days [IQR -1 to 15 days]). The aOR for organ support-free days was 0.99 for anakinra (95% CrI, 0.74–1.35), with a 46.6% posterior probability of superiority to control. Sixty percent of those who were assigned to receive anakinra survived compared to 63% of those who were assigned to the control arm, with a 43.6% posterior probability that anakinra was superior to usual care.
  • The risk of experiencing serious adverse events was similar between the arms.

Limitations

  • Patients were not randomized contemporaneously to receive anakinra or usual care; the treatment effect was estimated from an overarching model that mostly included patients who were randomized to receive an IL-6 inhibitor (tocilizumab or sarilumab) or usual care, and patients who were randomized to receive an IL-6 inhibitor or anakinra. Thus, the estimate of the treatment effect is not fully protected by randomization.
  • This study had an open-label design.

CORIMUNO-ANA-1

The CORIMUNO-ANA-1 trial randomized 116 hospitalized patients with COVID-19 pneumonia 1:1 to receive either usual care plus anakinra (200 mg IV twice a day on Days 1–3, 100 mg IV twice on Day 4, and 100 mg IV once on Day 5) or usual care alone. Patients were eligible for enrollment if they had laboratory-confirmed SARS-CoV-2 infection with COVID-19 pneumonia and they required >3 L/min of supplemental oxygen. Patients who required high-flow oxygen, ventilation, or ICU admission were excluded. The two coprimary outcomes were the proportion of patients who had died or who needed noninvasive or invasive mechanical ventilation by Day 4 (score of >5 on the WHO-CPS) and the proportion who survived without the need for noninvasive or invasive mechanical ventilation (including high-flow oxygen) by Day 14.5

Results

  • There was no difference between the anakinra plus usual care arm and the usual care alone arm in the two coprimary outcomes: by Day 4, 36% of patients in the anakinra arm had died or required high-flow oxygen or ventilation compared with 38% in the usual care arm (90% CrI, -17.1 to 12.0, posterior probability of benefit 61%). By Day 14, 47% of patients in the anakinra arm had died or required noninvasive or invasive mechanical ventilation compared to 51% in the usual care arm (median HR 0.97; 90% CrI, 0.62–1.52; posterior probability of benefit 55%).
  • Fifty-two percent of patients received corticosteroids at study entry.
  • Serious adverse events occurred in 46% of patients in the anakinra arm compared to 38% in the usual care arm; 11 of 59 patients (18.6%) in the anakinra arm experienced bacterial or fungal infections compared to 4 of 55 patients (7.3%) who received usual care.

Limitations

  • The limitations of this study include the small sample size, narrow eligibility criteria, and the fact that many patients did not receive current standard-of-care therapy (e.g., corticosteroids, remdesivir).

CAN-COVID

CAN-COVID was a double-blind, placebo-controlled randomized trial of 454 hospitalized patients with COVID-19 who were hypoxemic but not mechanically ventilated and had elevated C-reactive protein (≥20 mg/L) or ferritin (≥600 micrograms/L) levels. Patients were randomized 1:1 to receive a single dose of IV canakinumab (450 mg for a body weight of 40 kg to <60 kg, 600 mg for 60–80 kg, and 750 mg for >80 kg) or placebo. The primary outcome was survival without the need for invasive mechanical ventilation from Days 3 through 29.7

Results

  • There was no statistical difference between the canakinumab arm and placebo arm in the proportion of patients who survived without invasive mechanical ventilation (88.8% vs. 85.7%; P = 0.29).
  • The number of COVID-19-related deaths at 4 weeks was similar for the two arms (11 of 223 patients [4.9%] in the canakinumab arm vs. 16 of 222 patients [7.2%] in the placebo arm; OR 0.67; 95% CI, 0.30–1.50).
  • Forty-one percent of patients in the canakinumab arm and 32% in the placebo arm received dexamethasone.
  • Serious adverse events occurred in 16% of patients who received canakinumab and in 20.6% of patients who received placebo.

Limitations

  • The use of corticosteroids was unbalanced in this study, with more patients receiving dexamethasone at baseline in the canakinumab arm than in the placebo arm.
  • More patients received dexamethasone after the trial was underway in the placebo arm than in the canakinumab arm (22.5% vs. 14.5%), and more patients received tocilizumab in the placebo arm than in the canakinumab arm (8.8% vs. 2.2%).

Other small cohort studies, case-control studies, and case series have reported mixed findings with regard to improvement in outcomes among patients who received anakinra for the treatment of COVID-19.8-11 The clinical implication of these findings is uncertain due to small sample sizes and unmeasured confounding factors. Therefore, these studies did not substantially influence the Panel’s current recommendations for using IL-1 inhibitors.

Clinical Trials

See ClinicalTrials.gov for a list of clinical trials that are evaluating anakinra and canakinumab for the treatment of COVID-19.

Adverse Effects

Headache, nausea, vomiting, and liver enzyme elevations can occur with both anakinra and canakinumab.

Anakinra was not associated with any significant safety concerns when used in clinical trials for the treatment of sepsis.12-14 Increased rates of infection were reported with prolonged anakinra use in combination with tumor necrosis factor-alpha blockade, but not with short-term use.15

Considerations in Pregnancy

The data on using IL-1 inhibitors to treat COVID-19 in pregnant patients are currently limited. The American College of Rheumatology recommends against the use of anakinra during pregnancy.16 Unintentional first-trimester exposure to anakinra is unlikely to be harmful, given the minimal transfer of monoclonal antibodies across the placenta early in pregnancy.17

Considerations in Children

Anakinra has been used in the treatment of severely ill children with rheumatologic conditions, including MAS. The data on the use of anakinra in pediatric patients with acute respiratory distress syndrome or sepsis are limited. Anakinra is rarely used to treat pediatric patients with acute COVID-19, and it has been used in approximately 10% of cases of multisystem inflammatory syndrome in children (MIS-C).18,19 Anakinra is often included in institutional protocols for the treatment of MIS-C in the United States, and it is mentioned as an option for second-line therapy for refractory MIS-C in national consensus guidelines.20-22 However, robust data on the effectiveness of anakinra for the treatment of MIS-C are not currently available. Data on using canakinumab in pediatric patients are limited to use in patients with periodic fever syndromes and systemic juvenile idiopathic arthritis. There are no data on its use in pediatric patients with acute COVID-19 or MIS-C. The Panel recommends consulting with a multidisciplinary team when using immunomodulating therapy (which may include anakinra) in children with MIS-C (AIII).

References

  1. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior Phase III trial. Crit Care Med. 2016;44(2):275-281. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26584195.
  2. Monteagudo LA, Boothby A, Gertner E. Continuous intravenous anakinra infusion to calm the cytokine storm in macrophage activation syndrome. ACR Open Rheumatol. 2020;2(5):276-282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32267081.
  3. Anakinra (Kineret) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf.
  4. Kyriazopoulou E, Poulakou G, Milionis H, et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34480127.
  5. CORIMUNO-19 Collaborative Group. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet Respir Med. 2021;9(3):295-304. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33493450.
  6. The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2.
  7. Caricchio R, Abbate A, Gordeev I, et al. Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in patients hospitalized with severe COVID-19: a randomized clinical trial. JAMA. 2021;326(3):230-239. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34283183.
  8. Aouba A, Baldolli A, Geffray L, et al. Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series. Ann Rheum Dis. 2020;79(10):1381-1382. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32376597.
  9. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325-e331. Available at: https://pubmed.ncbi.nlm.nih.gov/32501454/.
  10. Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2(7):e393-e400.. Available at: https://pubmed.ncbi.nlm.nih.gov/32835245/.
  11. Kooistra EJ, Waalders NJB, Grondman I, et al. Anakinra treatment in critically ill COVID-19 patients: a prospective cohort study. Crit Care. 2020;24(1):688. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33302991.
  12. Fisher CJ, Jr., Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271(23):1836-1843. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8196140.
  13. Fisher CJ, Jr., Slotman GJ, Opal SM, et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med. 1994;22(1):12-21. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8124953.
  14. Opal SM, Fisher CJ Jr, Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a Phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 1997;25(7):1115-1124. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9233735.
  15. Winthrop KL, Mariette X, Silva JT, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors). Clin Microbiol Infect. 2018;24 Suppl 2:S21-S40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29447987.
  16. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020;72(4):529-556. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32090480.
  17. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-part II: analgesics and other drugs used in rheumatology practice. Rheumatology (Oxford). 2016;55(9):1698-1702. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26750125.
  18. Gotzinger F, Santiago-Garcia B, Noguera-Julian A, et al. COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study. Lancet Child Adolesc Health. 2020;4(9):653-661. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32593339.
  19. Derespina KR, Kaushik S, Plichta A, et al. Clinical manifestations and outcomes of critically ill children and adolescents with coronavirus disease 2019 in New York City. J Pediatr. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32681989.
  20. Dove ML, Jaggi P, Kelleman M, et al. Multisystem inflammatory syndrome in children: survey of protocols for early hospital evaluation and management. J Pediatr. 2021;229:33-40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33075369.
  21. Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19: version 2. Arthritis Rheumatol. 2021;73(4):e13-e29.. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33277976.
  22. Harwood R, Allin B, Jones CE, et al. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process. Lancet Child Adolesc Health. 2021;5(2):133-141. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32956615.