Pharmacological and clinical effects of letermovir (Prevymis^®), a novel anti-human cytomegalovirus prophylactic drug

Abstract

Letermovir is an anti-human cytomegalovirus (HCMV) drug with a novel mechanism of action. Virological characterization and sequence analysis of resistant viruses indicate that the viral DNA terminase complex is the target of this compound. Unlike currently marketed anti-HCMV drugs, which act via inhibition of the viral DNA polymerase, the terminase inhibitor interferes with viral DNA cleavage and packaging of monomeric genome units into capsids. Letermovir has potent anti-HCMV activity, with 50% effective concentration of single-digit nanomolar against most clinical HCMV isolates in cell-culture models of infection. Besides its excellent in vitro inhibitory activity against laboratory and clinical HCMV isolates, letermovir exhibits activity against virus strains resistant to the currently approved anti-HCMV drugs. Letermovir is specific for human cytomegalovirus but lacks inhibitory activity against major pathogenic viruses including other Herpesviridae. In a xenograft mouse infection model, the 50% and 90% effective doses of the letermovir were 3 and 8 mg/kg/day, respectively. HCMV infection and disease in recipients of allogeneic hematopoietic stem cell transplant (HSCT) is a serious disease leading to significant morbidity and mortality. In the Phase 3 trial, the preventive effect of clinically significant HCMV infection by oral or intravenous administration of letermovir in allogeneic HSCT patients was confirmed, and letermovir was well tolerated with no suggestions of myelotoxicity or nephrotoxicity.