Background:Granulocyte/macrophage-colony stimulating factor (GM-CSF) is a cytokine both vital to lung homeostasis and important in regulating inflammation and autoimmunity1,2,3 that has been implicated in the pathogenesis of respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.4-6 Mavrilimumab is a human anti GM-CSF receptor α monoclonal antibody capable of blocking GM-CSF signaling and downregulating the inflammatory process.Objectives:To evaluate the effect of mavrilimumab on clinical outcomes in patients hospitalized with severe COVID-19 pneumonia and systemic hyperinflammation.Methods:This on-going, global, randomized, double-blind, placebo-controlled seamless transition Phase 2/3 trial was designed to evaluate the efficacy and safety of mavrilimumab in adults hospitalized with severe COVID-19 pneumonia and hyperinflammation. The Phase 2 portion comprised two groups: Cohort 1 patients requiring supplemental oxygen therapy without mechanical ventilation (to maintain SpO2 ≥92%) and Cohort 2 patients requiring mechanical ventilation, initiated ≤48 hours before randomization. Here, we report results for Phase 2, Cohort 1: 116 patients with severe COVID- 19 pneumonia and hyperinflammation from USA, Brazil, Chile, Peru, and South Africa; randomized 1:1:1 to receive a single intravenous administration of mavrilimumab (10 or 6 mg/kg) or placebo. The primary efficacy endpoint was proportion of patients alive and free of mechanical ventilation at Day 29. Secondary endpoints included [1] time to 2-point clinical improvement (National Institute of Allergy and Infectious Diseases COVID-19 ordinal scale), [2] time to return to room air, and [3] mortality, all measured through Day 29. The prespecified evidentiary standard was a 2-sided α of 0.2 (not adjusted for multiplicity).Results:Baseline demographics were balanced among the intervention groups; patients were racially diverse (43% non-white), had a mean age of 57 years, and 49% were obese (BMI ≥ 30). All patients received the local standard of care: 96% received corticosteroids (including dexamethasone) and 29% received remdesivir. No differences in outcomes were observed between the 10 mg/kg and 6 mg/kg mavrilimumab arms. Results for these groups are presented together. Mavrilimumab recipients had a reduced requirement for mechanical ventilation and improved survival: at day 29, the proportion of patients alive and free of mechanical ventilation was 12.3 percentage points higher with mavrilimumab (86.7% of patients) than placebo (74.4% of patients) (Primary endpoint; p=0.1224). Mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death through Day 29 (Hazard Ratio (HR) = 0.35; p=0.0175). Day 29 mortality was 12.5 percentage points lower in mavrilimumab recipients (8%) compared to placebo (20.5%) (p=0.0718). Mavrilimumab recipients had a 61% reduction in the risk of death through Day 29 (HR= 0.39; p=0.0726). Adverse events occurred less frequently in mavrilimumab recipients compared to placebo, including secondary infections and thrombotic events (known complications of COVID-19). Thrombotic events occurred only in the placebo arm (5/40 [12.5%]).Conclusion:In a global, diverse population of patients with severe COVID-19 pneumonia and hyperinflammation receiving supplemental oxygen therapy, corticosteroids, and remdesivir, a single infusion of mavrilimumab reduced progression to mechanical ventilation and improved survival. Results indicate mavrilimumab, a potent inhibitor of GM-CSF signaling, may have added clinical benefit on top of the current standard therapy for COVID-19. Of potential importance is that this treatment strategy is mechanistically independent of the specific virus or viral variant.References:[1]Trapnell, Nat Rev Dis Pri, 2019[2]Wicks, Nat Rev Immunology, 2015[3]Hamilton, Exp Rev Clin Immunol, 2015[4]De Luca, Lancet Rheumatol, 2020[5]Cremer, Lancet Rheumatol, 2021[6]Zhou, Nature, 2020Disclosure of Interests:Lara Pupim Employee of: Kiniksa, Shareholder of: Kiniksa, Tisha S. Wang Consultant of: Partner Therapeutics; steering committee for Kinevant BREATHE clinical trial, Kristin Hudock: None declared, Joshua Denson: None declared, Nyda Fourie: None declared, Luis Hercilla Vasquez: None declared, Kleber Luz: None declared, Mohammad Madjid Grant/research support from: Kiniksa, Kirsten McHarry: None declared, José Francisco Saraiva: None declared, Eduardo Tobar: None declared, Teresa Zhou Employee of: Kiniksa, Shareholder of: Kiniksa, Manoj Samant Employee of: Kiniksa, Shareholder of: Kiniksa, Joseph Pirrello Employee of: Kiniksa, Shareholder of: Kiniksa, Fang Fang Employee of: Kiniksa, Shareholder of: Kiniksa, John F. Paolini Employee of: Kiniksa, Shareholder of: Kiniksa, Arian Pano Employee of: Kiniksa, Shareholder of: Kiniksa, Bruce C. Trapnell: None declared
LB0001 MAVRILIMUMAB IMPROVES OUTCOMES IN PHASE 2 TRIAL IN NON-MECHANICALLY-VENTILATED PATIENTS WITH SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPERINFLAMMATION