Anti-Granulocyte-Macrophage Colony-Stimulating Factor Monoclonal Antibody Gimsilumab for COVID-19 Pneumonia: A Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).

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

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.

Occult Colonic Perforation in a Patient With Coronavirus Disease 2019 After Interleukin-6 Receptor Antagonist Therapy.

BACKGROUND: Interleukin-6 blockade (IL-6) has become a focus of therapeutic investigation for the coronavirus disease 2019 (COVID-19). METHODS: We report a case of a 34-year-old with COVID-19 pneumonia receiving an IL-6 receptor antagonist (IL-6Ra) who developed spontaneous colonic perforation. This perforation occurred despite a benign abdominal exam and in the absence of other known risk factors associated with colonic perforation. RESULTS: Examination of the colon by electron microscopy revealed numerous intact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions abutting the microvilli of the colonic mucosa. Multiplex immunofluorescent staining revealed the presence of the SARS-CoV-2 spike protein on the brush borders of colonic enterocytes that expressed angiotensin-converting enzyme 2. However, no viral particles were observed within the enterocytes to suggest direct viral injury as the cause of colonic perforation. CONCLUSIONS: These data and absence of known risk factors for spontaneous colonic perforation implicate IL-6Ra therapy as the potential mediator of colonic injury in this case. Furthermore, this report provides the first in situ visual evidence of the virus in the colon of a patient presenting with colonic perforation adding to growing evidence that intact infectious virus can be present in the stool.

Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies.

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.