Letermovir safety and efficacy for cytomegalovirus prophylaxis in adult Japanese kidney transplant recipients: a multicenter, open-label, noncomparative Phase 3 study.

BACKGROUND: Letermovir is approved for cytomegalovirus (CMV) prophylaxis in adult allogeneic hematopoietic cell transplantation recipients worldwide and is also approved in the United States for CMV prophylaxis in adult high-risk (D+/R-) kidney transplant recipients (KTRs). The safety and efficacy of letermovir for CMV prophylaxis in adult Japanese KTRs are reported here. METHODS: In this Phase 3, single-arm, open-label study, adult Japanese KTRs with CMV serostatuses D+/R-, D+/R+, and D-/R+ received letermovir 480 mg daily orally within 7 days post-transplant through Week 28. Participants were followed through Week 52. The primary objective was to evaluate letermovir safety and tolerability. Efficacy was a secondary objective, measured by CMV disease, CMV disease or infection requiring intervention, and quantifiable CMV DNAemia. All CMV disease cases were confirmed by an independent adjudication committee. RESULTS: Among 22 participants (12 were D+/R-) who received letermovir prophylaxis, 20 (90.9%) experienced ≥ 1 AE through Week 28. Most AEs were mild to moderate in severity; no deaths were reported. During the prophylaxis period through Week 28, one transient case of quantifiable CMV DNAemia was detected, but no CMV disease or infection requiring intervention was reported. Through Week 52, four D+/R- participants met the endpoint of CMV disease or infection requiring intervention, of whom two had committee-confirmed CMV syndrome; all recovered with CMV therapy. A total of 5 participants had quantifiable CMV DNAemia through Week 52. CONCLUSION: Letermovir was generally well tolerated, and the data support its use for the prevention of CMV disease/infection in adult Japanese KTRs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04129398.

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

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.