Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial

Abstract

Background In patients with COVID-19, granulocyte-macrophage colony stimulating factor (GM-CSF) might be a mediator of the hyperactive inflammatory response associated with respiratory failure and death. We aimed to evaluate whether mavrilimumab, a monoclonal antibody to the GM-CSF receptor, would improve outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation. Methods This investigator-initiated, multicentre, double-blind, randomised trial was done at seven hospitals in the USA. Inclusion required hospitalisation, COVID-19 pneumonia, hypoxaemia, and a C-reactive protein concentration of more than 5 mg/dL. Patients were excluded if they required mechanical ventilation. Patients were randomly assigned (1:1) centrally, with stratification by hospital site, to receive mavrilimumab 6 mg/kg as a single intravenous infusion, or placebo. Participants and all clinical and research personnel were masked to treatment assignment. The primary endpoint was the proportion of patients alive and off supplemental oxygen therapy at day 14. The primary outcome and safety were analysed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov , NCT04399980 , NCT04463004 , and NCT04492514 . Findings Between May 28 and Sept 15, 2020, 40 patients were enrolled and randomly assigned to mavrilimumab (n=21) or placebo (n=19). A trial of 60 patients was planned, but given slow enrolment, the study was stopped early to inform the natural history and potential treatment effect. At day 14, 12 (57%) patients in the mavrilimumab group were alive and off supplemental oxygen therapy compared with nine (47%) patients in the placebo group (odds ratio 1·48 [95% CI 0·43–5·16]; p=0·76). There were no treatment-related deaths, and adverse events were similar between groups. Interpretation There was no significant difference in the proportion of patients alive and off oxygen therapy at day 14, although benefit or harm of mavrilimumab therapy in this patient population remains possible given the wide confidence intervals, and larger trials should be completed. Funding Kiniksa Pharmaceuticals.

Lenzilumab Efficacy and Safety in Newly Hospitalized Covid-19 Subjects: Results From the Live-Air Phase 3 Randomized Double-Blind Placebo-Controlled Trial

“…Mavrilimumab, a monoclonal antibody that acts as a GM-CSF alpha-receptor antagonist demonstrated non-significant trends of 48% improvement in survival without requirement for supplemental oxygen. 27 Otilimab, a monoclonal antibody targeting circulating GM-CSF in ventilated subjects, was reported in a non-peer-reviewed disclosure of results from its phase 2b COVID-19 study (NCT04376684) to not meet its primary endpoint of improvement in the proportion of COVID-19 subjects who were alive and free of respiratory failure 28 days; however, in pre-planned analysis of subjects aged at least 70 years, which comprised 22% of the entire patient population, 65.1% were alive and free of respiratory failure, compared to 45.9% of subjects who received the standard of care. 28 The results of all three trials of GM-CSF antagonism suggest the central role of GM-CSF in CS of COVID-19 that has been recently demonstrated through network analysis of cytokine profiles from COVID-19 subjects.…”

Early treatment with inhaled GM-CSF improves oxygenation and anti-viral immunity in COVID-19 induced lung injury – a randomized clinical trial

“…Indeed, given the known role of GM-CSF in emergency myelopoiesis and CAR-T cell associated cytokine release syndrome 75 , and the observation of increased numbers of GM-CSF producing T cells 31 and higher serum concentrations 45 of GM-CSF in some patients with COVID-19, blockade of systemic GM-CSF or its receptor was also proposed as a strategy to dampen hyperinflammation in severe COVID-19. At least six randomized clinical trials have been launched since the beginning of the pandemic 46 , one of which already reported promising results on a preprint server 76 , while another did not show benefit and was prematurely halted 77 . Major differences in outcome of GM-CSF interventions might depend on timing of intervention, but also on the route of administration.…”

Therapeutic approaches to tackle COVID-19: An overview

“…A possibility of Granulocyte-macrophage colony stimulating factor (GM-CSF) being a hyperinflammatory mediator was also questioned and thus Mavrilimumab, a monoclonal antibody to GM-CSF receptor came into the moonlight for testing the proposed hypothesis. 72 In a prospective cohort study by Giacomo De Luca et al, treatment with Mavrilimumab single intravenous dose (6 mg/kg) showed significant clinical outcomes. Further studies will have to be conducted to confirm the findings and prove the efficacy of this drug.…”