Kinevant – a wholly owned subsidiary of Roivant Sciences – is developing gimsilumab for the treatment and prevention of acute respiratory distress syndrome (ARDS) in patients with COVID-19. ARDS is a serious complication of COVID-19 that necessitates hospitalization and mechanical ventilation or other life support measures. Gimsilumab is an investigational fully human monoclonal antibody targeting granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF is believed to be a master regulator of the cytokine disregulation and myeloid cell lung infiltration that leads to respiratory failure in COVID-19. Roivant has assembled a world-class team of experts in clinical development, COVID-19 disease management, and GM-CSF immunobiology to lead Kinevant’s gimsilumab program.
Kinevant is investigating the effects of gimsilumab in its ongoing pivotal BREATHE study – a clinical trial currently enrolling patients with a confirmed diagnosis of COVID-19 and clinical evidence of acute lung injury or ARDS. Subjects will be randomized 1:1 to receive either gimsilumab or placebo. The primary endpoint of the study is incidence of mortality by Day 43. The study is being conducted with an adaptive design and includes a planned interim analysis.
The COVID-19 clinical course is shown above.1 During the “Active Viral Infection Phase,” the coronavirus attacks cells in the lungs. At this disease stage, doctors may prescribe drugs called antivirals (e.g., remdesivir) that are designed to directly inhibit the virus from replicating. However, many patients progress to the “Excessive Inflammation Phase” in which patients become more sick due to an overactive immune response consisting of cytokine dysregulation and increased tissue-infiltrating inflammatory myeloid cells.2 This leads to acute lung injury, ARDS, and ultimately death. At this disease stage, many doctors choose to prescribe anti-inflammatory agents, which are distinct from antiviral therapeutic mechanisms and may provide synergistic effects when used in combination.
Gimsilumab is one such anti-inflammatory agent and is designed to inhibit GM-CSF, a myeloid cell growth factor and pro-inflammatory cytokine.3 GM-CSF may be a key driver of the COVID-19-induced hyperinflammation, operating upstream of other pro-inflammatory cytokines and chemokines. Emerging data from COVID-19 patients4 and many preclinical studies of COVID-19-related hyperinflammatory disorders5-10 suggest that blocking GM-CSF could reduce the immunopathology caused by COVID-19 in late-stage patients. Gimsilumab has been studied in two Phase 1 trials and has demonstrated a favorable safety and tolerability profile to date.
Gimsilumab is an investigational drug product that has not been approved by the US Food and Drug Administration.
1: Siddiqi HK, Mehra MR. COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal. J Heart Lung Transplant (2020). doi:10.1016/j.healun.2020.03.012
2: Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol (2020). doi:10.1038/s41577-020-0331-4.
3: Hamilton JA. GM-CSF in inflammation. J Exp Med. 217, pii:e20190945 (2020).
4: Zhou Y, Fu B, Zheng X, et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl Sci Rev (2020). doi:10.1093/nsr/nwaa041.
5: Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe. 19, 181-93 (2016).
6: Huang H, Wang S, Jiang T, et al. High levels of circulating GM-CSF+CD4+ T cells are predictive of poor outcomes in sepsis patients: a prospective cohort study. Cell Mol Immunol. 16, 602-610 (2019).
7: Sterner RM, Sakemura R, Cox MJ, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 133, 697-709 (2019).
8: Puljic R, Benediktus E, Plater-Zyberk C, et al. Lipopolysaccharide-induced lung inflammation is inhibited by neutralization of GM-CSF. Eur J Pharmacol. 557, 230-235 (2007).
9: Tugues S, Amorim A, Spath S, et al. Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF-licensed myeloid cells. Sci Transl Med. 10, pii:eaat8410 (2018).
10: Stock AT, Hansen JA, Sleeman MA, McKenzie BS, Wicks IP. GM-CSF Primes Cardiac Inflammation in a Mouse Model of Kawasaki Disease. J Exp Med.
213, 1983-1998 (2016).