A Phase 2 Trial of Leflunomide for the Treatment of COVID‐19 in Patients with Solid Tumors and Hematologic Malignancies

Novel interventions are urgently needed to address the COVID-19 pandemic, especially for highrisk populations. Leflunomide is a dihydroorotate dehydrogenase (DHODH) inhibitor, impacting pyrimidine synthesis for DNA and RNA production, and has been in use for over 20 years for treatment of autoimmune diseases such as rheumatoid arthritis and lupus with an excellent safety profile [1, 2]. It has known anti-viral activity and has been applied against cytomegalovirus (CMV) and polyoma BK virus infections in immunocompromised hosts [3, 4]. Leflunomide is orally available and exhibits hepatic clearance and a long elimination half-life. In vitro and in vivo experiments conducted in Wuhan, China demonstrated DHODH inhibitors have activity against COVID-19, including teriflunomide, the active metabolite of leflunomide [5]. Moreover, our preliminary data at City of Hope also suggest that leflunomide significantly arrests viral RNA replication in cancer cells infected with a naturally-occurring RNA virus (reovirus) and impairs ex vivo IL-6 expression in virally infected peripheral blood mononuclear cells (PBMCs).