Anakinra in COVID-19: A step closer to the cure

Published:November 10, 2021DOI:https://doi.org/10.1016/j.ejim.2021.11.005
      Acute respiratory distress syndrome and cytokine release syndrome are the major complications of coronavirus disease 2019 (COVID-19) associated with increased mortality risk [
      • Grasselli G.
      • Zangrillo A.
      • Zanella A.
      • Antonelli M.
      • Cabrini L.
      • Castelli A.
      • et al.
      Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy.
      ]. Apart from dexamethasone and probably tocilizumab in critically ill patients, there are no well-established effective therapies to treat SARS-CoV-2 infection [
      • Lamontagne F.
      • Agoritsas T.
      • Macdonald H.
      • Leo Y.S.
      • Diaz J.
      • Agarwal A.
      • et al.
      A living WHO guideline on drugs for covid-19.
      ,
      • Gupta S.
      • Leaf D.E.
      Tocilizumab in COVID-19: some clarity amid controversy.
      ]. Considering the noticed shortage of intensive care unit (ICU) beds and consequently the increased burden in medical wards [
      • Remuzzi A.
      • Remuzzi G.
      COVID-19 and Italy: what next?.
      ], identifying additional therapeutic modalities to improve adverse outcomes and prevent ICU admission and death in this population remains a public health emergency.
      In this setting, anakinra has been proved an appealing therapeutic option for the management of coronavirus disease 2019 (COVID-19) [
      • Barkas F.
      • Ntekouan S.F.
      • Kosmidou M.
      • Liberopoulos E.
      • Liontos A.
      • Milionis H.
      Anakinra in hospitalized non-intubated patients with coronavirus disease 2019: a systematic review and meta-analysis.
      ]. A meta-analysis of four observational studies (n = 184) provided early evidence indicating that the administration of anakinra was safe and could be associated with a clinical benefit in patients with COVID-19 [
      • Pasin L.
      • Cavalli G.
      • Navalesi P.
      • Sella N.
      • Landoni G.
      • Yavorovskiy A.G.
      • et al.
      Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies.
      ]. This argument was further strengthened by a subsequent meta-analysis with a larger sample (9 cohorts; n = 1119) which demonstrated that anakinra reduced both the need for invasive mechanical ventilation (IMV) and mortality risk of hospitalized non-intubated patients with COVID-19 without increasing the risk of adverse effects (Fig. 1) [
      • Barkas F.
      • Ntekouan S.F.
      • Kosmidou M.
      • Liberopoulos E.
      • Liontos A.
      • Milionis H.
      Anakinra in hospitalized non-intubated patients with coronavirus disease 2019: a systematic review and meta-analysis.
      ]. This notion has been recently confirmed by SAVE-MORE, a double blinded, placebo-controlled, randomized trial [
      • Kyriazopoulou E.
      • Poulakou G.
      • Milionis H.
      • Metallidis S.
      • Adamis G.
      • Tsiakos K.
      • 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.
      ]. SAVE-MORE evaluated the efficacy and safety of anakinra in 594 patients with COVID-19 at risk of progressing to respiratory failure, as identified by plasma soluble urokinase plasminogen activator receptor (suPAR) ≥6 ng/ml [
      • Kyriazopoulou E.
      • Poulakou G.
      • Milionis H.
      • Metallidis S.
      • Adamis G.
      • Tsiakos K.
      • 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.
      ]. Based on the assessment of 11-point World Health Organization Clinical Progression Scale (WHO CPS) at day 28, anakinra was associated with a better clinical outcome compared with placebo (odds ratio, OR: 0.36; 95% confidence interval, CI: 0.26–0.50, p <0.001) [
      • Kyriazopoulou E.
      • Poulakou G.
      • Milionis H.
      • Metallidis S.
      • Adamis G.
      • Tsiakos K.
      • 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.
      ]. Moreover, treatment with anakinra resulted in a reduced 28-day mortality risk and a non-significant reduction of intubation risk (Fig. 1) [
      • Kyriazopoulou E.
      • Poulakou G.
      • Milionis H.
      • Metallidis S.
      • Adamis G.
      • Tsiakos K.
      • 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.
      ]. SAVE-MORE also confirmed the safety of anakinra in patients with COVID-19, since it did not increase the risk of bloodstream infections or liver dysfunction compared with placebo (Fig. 1) [
      • Kyriazopoulou E.
      • Poulakou G.
      • Milionis H.
      • Metallidis S.
      • Adamis G.
      • Tsiakos K.
      • 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.
      ].
      Fig. 1
      Fig. 1Effect of anakinra on the risk of (A) invasive mechanical ventilation, (B) mortality, (C) bacteremia and (D) liver enzyme increase in non-intubated patients with COVID-19.
      The encouraging results of SAVE-MORE towards the use of anakinra in COVID-19 should be considered within the clinical setting of the study design. Patients with critical COVID-19 and severe respiratory failure (PO2/FiO2 <150) were excluded. This prompts for an early treatment in the initial stages of the disease. Although accumulating evidence indicates that suPAR can reliably be used as a marker of progression to severe respiratory failure or death in patients with COVID-19 [
      • Rovina N.
      • Akinosoglou K.
      • Eugen-Olsen J.
      • Hayek S.
      • Reiser J.
      • Giamarellos-Bourboulis E.J.
      Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia.
      ], its applicability could be problematic if not widely available. To overcome this restriction, commonly inflammatory markers, such as C-reactive protein (CRP) and ferritin, could be enlisted to assess eligible patients to receive the drug [
      • Manson J.J.
      • Crooks C.
      • Naja M.
      • Ledlie A.
      • Goulden B.
      • Liddle T.
      • et al.
      COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study.
      ]. Indeed, a recent patient-level meta-analysis (n = 1185) demonstrated that anakinra was more effective in lowering mortality risk in patients with CRP >100 mg/L (OR: 0.28, 95% CI: 0.17–0.47) or in those with ferritin >1000 ng/ml (OR: 0.36, 95% CI: 0.19–0.69) [

      Kyriazopoulou E., Huet T., Cavalli G., Gori A., Kyprianou M., Pickkers P., et al. Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis. The Lancet Rheumatology. 2021.

      ].
      Tocilizumab, another humanized antibody which blocks the action of circulating IL-6, has been shown to increase survival in patients with COVID-19 [
      • Group R.C.
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ]. U.S. FDA (Food and Drug Administration) has recently issued its emergency use authorization for the treatment of hospitalized adult and pediatric patients (≥2 years of age) treated with systemic corticosteroids and requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation [

      Coronavirus (COVID-19) Update: FDA Authorizes Drug for Treatment of COVID-19. Assessed on 24 June 2021 from https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-treatment-covid-19.

      ]. Considering the results derived from the latest anakinra studies, a question arises as to which of these two immunomodulating agents is superior. Although there is no head-to-head randomized clinical trial (RCT) comparing anakinra with tocilizumab available yet, an analysis of three observational studies (n = 237) indicated that anakinra might be superior to tocilizumab in terms of COVID-19 death prevention, since the former was associated with a decreased mortality risk by 40% (relative risk: 0.60, 95% CI: 0.36–0.98, I2=0%) [
      • Patoulias D.
      • Dimosiari A.
      • Michailidis T.
      Anakinra or tocilizumab for prevention of COVID-19 death? A big dilemma.
      ]. However, the small sample size and design flaws of the included studies comprise notable limitations to reach safe conclusions.
      Considering that vaccination rates fall behind what was expected, encouraging results from RCTs promote continuously testing for efficacious, safe and tolerable therapeutic interventions in COVID-19.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      Dr Barkas, Dr Christaki and Dr Kosmidou report no conflicts of interest associated with the present work. Prof Liberopoulos reports honoraria, grants and non-financial support from AstraZeneca , MSD, Amgen, Sanofi-Aventis, Bayer, Novo-Nordisk, Lilly, Boehringer-Ingelheim, Servier, and Novartis. Prof Milionis reports honoraria and non-financial support from Amgen , Angelini, Bayer, MSD, Pfizer, Sanofi, and Servier

      Acknowledgements

      None.

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