medwireNews: Preliminary results from two studies suggest that the interleukin (IL)-1 receptor antagonist anakinra may warrant further investigation for the treatment of COVID-19.
Explaining the rationale behind this approach, the authors of the first study say that a “subgroup of patients with COVID-19 show hyperinflammatory symptoms that resemble the cytokine storm after chimeric antigen receptor T-cell treatment or in patients with macrophage activation syndrome,” and cytokine blockers such as anakinra “are effective treatments for these disorders.”
Giulio Cavalli (Vita-Salute San Raffaele University, Milan, Italy) and colleagues add that “anakinra has a remarkable record of safety and a short half-life, which allows prompt discontinuation, and it is therefore suitable for use in critically ill patients.”
In their retrospective single-center study, Cavalli et al found that the 21-day survival rate was 90% for the 29 adult patients with COVID-19, moderate-to-severe acute respiratory distress syndrome, and hyperinflammation who were treated with high-dose intravenous anakinra (5 mg/kg twice daily) alongside noninvasive ventilation and the center’s standard treatment at the time of twice-daily hydroxychloroquine 200 mg, lopinavir 400 mg, and ritonavir 100 mg.
This was significantly higher than the 56% 21-day survival rate for the 16 patients who also had hyperinflammation but were treated prior to the introduction of anakinra treatment for this subgroup and therefore received noninvasive ventilation and standard treatment only.
Moreover, patients treated with high-dose anakinra experienced “prompt reductions” in C-reactive protein (CRP) levels, whereas those in the control group had “persistent or recurrent increases,” say the researchers in The Lancet Rheumatology.
Noting that anakinra is currently used at a dose of 100 mg/day subcutaneously for the treatment of a range of inflammatory disorders, Cavalli et al say that “[h]igh-dose intravenous anakinra […] was assessed based on the hypothesis that increased dosing might be needed to suppress COVID-19-related hyperinflammation.” They report that seven patients received the 100 mg/day subcutaneous dose but this treatment was discontinued due to “a paucity of meaningful clinical or anti-inflammatory effects.”
The researchers say that anakinra was “well tolerated in all patients,” and conclude that the agent “deserves consideration among anti-inflammatory treatments for COVID-19.”
They caution, however, that “[t]he uncontrolled nature of our study mandates caution in interpretation of findings, and validation is absolutely required in a controlled setting.”
And commenting on the results to the press, statistician Kevin McConway (The Open University, Milton Keynes, UK) said that the study is “interesting,” but “there are problems with interpreting its findings” for a number of reasons, including its uncontrolled design and single-center setting. He also pointed out that the proportion of patients who did not require mechanical ventilation did not significantly differ in the anakinra and control groups (72 vs 50%), and therefore “not all the results from this small study were positive for anakinra.”
In the second study, Achille Aouba (CHU Caen, France) and colleagues outline the experience of nine patients with moderate-to-severe COVID-19 pneumonia and elevated CRP levels who were treated with a lower dose of subcutaneous anakinra (100 mg twice daily on day 1–3, followed by 100 mg/day from day 4–10).
As reported in a letter to the Annals of the Rheumatic Diseases, eight patients “showed good clinical [and] biological outcomes” with a reduction in CRP levels from day 1 to 11, while the ninth experienced acute respiratory failure after the first anakinra dose, leading to premature discontinuation and admission to the intensive care unit. This outcome was not considered to be related to anakinra treatment.
Noting that all nine patients were alive at the 11-day follow-up, Aouba et al say that “this promising, preliminary proof-of-concept study with empirical anakinra doses should encourage and help larger prospective controlled studies to confirm these outcomes and to determine the optimal treatment dosage.”
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Lancet Rheumatol 2020; doi:10.1016/S2665-9913(20)30127-2
Ann Rheum Dis 2020; doi:10.1136/annrheumdis-2020-217706