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Canakinumab in a subgroup of patients with COVID-19

2020; Elsevier BV; Volume: 2; Issue: 8 Linguagem: Inglês

10.1016/s2665-9913(20)30167-3

2665-9913

Claudio Ucciferri, Antonio Auricchio, Marta Di Nicola, Nicola Potere, Antonio Abbate, Francesco Cipollone, Jacopo Vecchiet, Katia Falasca,

Hematological disorders and diagnostics

In a subgroup of patients, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a hyperinflammatory response that leads to acute respiratory distress syndrome.1Weiss P Murdoch DR Clinical course and mortality risk of severe COVID-19.Lancet. 2020; 395: 1014-1015Summary Full Text Full Text PDF PubMed Scopus (487) Google Scholar SARS coronaviruses have been shown to trigger the inflammasome and the release of interleukin-1β (IL-1β).2Siu K-L Yuen K-S Castano-Rodriguez C et al.Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC.FASEB J. 2019; 33: 8865-8877Crossref PubMed Scopus (383) Google Scholar We did a retrospective analysis of ten patients (nine white men and one white woman) with confirmed SARS-CoV-2 infection, bilateral pneumonia, hyperinflammation (defined as serum C-reactive protein ≥50 mg/L), and respiratory failure (requiring supplemental oxygen without invasive ventilation). These patients were treated with canakinumab, a human monoclonal antibody against IL-1β, administered subcutaneously in a single 300 mg dose, in April, 2020, at the Infectious Disease Clinic of SS. Annunziata Hospital in Chieti, Italy (appendix pp 1–8). All patients also received hydroxychloroquine (200 mg twice daily) and lopinavir–ritonavir (400 mg twice daily of lopinavir and 100 mg twice daily of ritonavir). The patients provided written informed consent for the off-label use of the drugs. The patients' baseline characteristics can be found in the appendix (pp 1, 4). Canakinumab was well tolerated, with no recorded injection site reactions or systemic adverse events. Canakinumab administration was associated with a rapid and significant reduction in serum C-reactive protein at day 1 and day 3 and an improvement in oxygenation, with the PaO2:FiO2 ratio increasing between baseline and day 3 and day 7 after treatment (appendix pp 2, 7–8). At 45 days after hospitalisation, all ten patients were alive and discharged from hospital without physical limitations caused by COVID-19 or the need for oxygen therapy (appendix p 3). Notably, none of the patients developed neutropenia or bacterial sepsis. For an indirect comparison, we selected the first ten patients with confirmed SARS-CoV-2 infection, bilateral pneumonia, hyperinflammation, and respiratory failure (requiring supplemental oxygen without invasive ventilation) who were hospitalised at our centre in March, 2020. These patients received hydroxychloroquine and lopinavir–ritonavir, but not canakinumab. By contrast to the patients treated with canakinumab, the patients not treated with canakinumab showed slower improvements in serum C-reactive protein and PaO2:FiO2 ratio (appendix pp 5, 8). At 45 days after hospitalisation, one patient had died, nine patients had been discharged from hospital, and one of the nine discharged patients required oxygen therapy (appendix p 6). To our knowledge, these data, although preliminary, are the first to describe the use of canakinumab to treat patients with COVID-19. Canakinumab is an IL-1 blocker approved for the treatment of juvenile rheumatoid arthritis and other chronic autoinflammatory syndromes. Cavalli and colleagues3Cavalli 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: e325-e331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar reported on the efficacy of another IL-1 blocker, intravenous anakinra (5 mg/kg twice daily), which also rapidly reduced serum C-reactive protein, improved oxygenation, and, when compared with a matched cohort, was associated with improved survival. Our observations add further evidence to support the central role of IL-1β in the pathophysiology of COVID-19. Although anakinra functions as a receptor antagonist that blocks the activity of both IL-1β and IL-1α, canakinumab selectively blocks the IL-1β that is generated within the inflammasome.4Geleris J Sun Y Platt J et al.Observational study of hydroxychloroquine in hospitalized patients with Covid-19.N Engl J Med. 2020; (published online May 7.)DOI:10.1056/NEJMoa2012410Crossref PubMed Scopus (1212) Google Scholar The rapid improvement in serum inflammatory biomarkers after the administration of canakinumab therefore implicates the IL-1β inflammasome pathway in the pathophysiology of COVID-19. Notwithstanding the many limitations of these initial data, such as the small sample size and the absence of a random comparison, these data represent the first available description of the use of canakinumab to treat COVID-19 and show a rather favourable safety and efficacy profile that would be considered encouraging if compared with other published cohort studies.3Cavalli 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: e325-e331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar, 4Geleris J Sun Y Platt J et al.Observational study of hydroxychloroquine in hospitalized patients with Covid-19.N Engl J Med. 2020; (published online May 7.)DOI:10.1056/NEJMoa2012410Crossref PubMed Scopus (1212) Google Scholar Canakinumab is already commercially available. When tested in patients with cardiovascular disease, a group that is at a particularly high risk for COVID-19-related mortality, canakinumab significantly reduced the incidence of atherothrombotic events and heart failure exacerbations, which is another potential benefit.5Abbate A Toldo S Marchetti C Kron J Van Tassell BW Dinarello CA Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease.Circ Res. 2020; 126: 1260-1280Crossref PubMed Scopus (370) Google Scholar In conclusion, in ten hospitalised adult patients with COVID-19, bilateral pneumonia, hyperinflammation, and respiratory failure who did not require mechanical ventilation, 300 mg of subcutaneous canakinumab was safe, well tolerated, and associated with a rapid reduction in the systemic inflammatory response and an improvement in oxygenation. AAb has received research support from Novartis, Olatec, and Swedish Orphan Biovitrum. All other authors declare no competing interests. We thank all patients who agreed to participate in the study. We thank Novartis International AG for providing us with canakinumab free of charge. Download .pdf (.19 MB) Help with pdf files Supplementary appendix