Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series

Development of specific therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is urgently required. Several drugs such as antimalarial and anti-Ebola virus drugs are under investigation for coronavirus disease 2019 (Covid-19). Transmembrane protease serine 2 (TMPRSS2) plays a crucial role for SARS-CoV-2 entry into the cytoplasm [1]. Inhibition of TMPRSS2 protease activity is assumed to prohibit viral entry of SARS-CoV-2. Through high-throughput screening of 1017 existing drugs, a clinically available serine protease inhibitor nafamostat mesylate was identified as a potent inhibitor of Middle East respiratory syndrome coronavirus entry into human epithelial cells [2]. More recently, nafamostat mesylate was shown to inhibit the entry of SARS-CoV-2 into the human epithelial cells at EC50 of ~ 10 nM [3, 4]. Nafamostat mesylate has been clinically used for the treatment of acute pancreatitis and disseminated intravascular coagulation in Japan. By intravenous administration, its blood concentrations are maintained at 30–240 nM, which are sufficient to block the virus entry [3]. An anti-influenza A H1N1 virus drug favipiravir exhibits antiviral activity against other RNA viruses and therefore is expected to have antiviral action against SARS-CoV-2. This drug has been approved in Japan for novel influenza virus disease.