Letermovir receives FDA approval for CMV prophylaxis after kidney transplant in donor CMV-seropositive/recipient CMV-seronegative patients

In a randomized, phase 3 trial, letermovir demonstrated non-inferiority to valganciclovir for prophylaxis of cytomegalovirus (CMV) disease over 52 weeks among adult CMV-seronegative kidney transplant recipients who had received an organ from a CMV-seropositive donor.1 The positive results led to the United States (US) Food and Drug Administration (FDA) approval of letermovir in June 2023, adding an important treatment option to the care of this high-risk, kidney transplant population.2

Approximately 20% of CMV-seronegative kidney transplant patients receive the organ from a CMV-seropositive donor.1 These patients are associated with an elevated risk of morbidity and mortality.1 Currently, the standard of care (SoC) for preventing CMV among this population is oral valganciclovir administered 900mg daily for 200 days after transplant.1 Nevertheless, this antiviral agent is associated with myelosuppression, especially leukopenia and neutropenia, thus leading to dose interruption or even treatment discontinuation.1 In certain cases, dose reduction of immunosuppressants and the use of granulocyte colony-stimulating factors (G-CSF) are required.1 In addition, dose adjustment of valganciclovir is required among patients with fluctuating renal function after transplant.1

Letermovir is an antiviral medication which is effective against CMV and is not associated with bone marrow suppression.1 Moreover, the drug does not require dosage modifications for kidney impairment and does not exhibit cross-resistance with other anti-CMV agents.1 Letermovir has previously been approved by the US FDA and the European Medicine Agency (EMA) for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic stem cell transplant (HSCT).1 Based on the high efficacy of letermovir in allogenic HSCT patients, it is postulated that letermovir could be a non-inferior alternative to valganciclovir with lower myelotoxicity for kidney transplant patients.1

The safety and efficacy of letermovir among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor were evaluated in a randomized, double-blind, double-dummy, non-inferiority, phase 3 trial.1 A total of 601 patients were enrolled and randomized 1:1 to receive letermovir 480mg orally (PO) daily or valganciclovir 900mg PO daily for up to 200 days after transplant, with matching placebos.1 The primary endpoint was the occurrence of CMV disease through post-transplant week 52.1 Meanwhile, CMV disease through week 28 and the time to onset of CMV disease through week 52 were the secondary outcomes.1 The safety outcome was the rate of leukopenia or neutropenia through week 28.1

The results demonstrated that letermovir was non-inferior to valganciclovir for the prevention of CMV disease through week 52, achieving the rates of CMV disease of 10.4% and 11.8% with a stratum-adjusted difference of -1.4% (95% CI: -6.5% to 3.8%).1 Notably, through week 28, no participants in the letermovir group developed CMV disease, while 5 participants (1.7%) in the valganciclovir arm were diagnosed with the condition.1 The time to onset of CMV disease was similar between the 2 groups (HR=0.90; 95% CI: 0.56-1.47).1

Regarding safety, patients treated with letermovir exhibited a lower rate of leukopenia when compared with valganciclovir (26% vs. 64%), with a significant between-group difference of -37.9% (95% CI: -45.1% to -30.3%; p<0.001).1 In addition, few patients in the letermovir group discontinued treatment due to adverse events (AEs) (4.1% vs. 13.5%) or treatment-emergent adverse events (TEAEs) (2.7% vs. 8.8%) when compared with valganciclovir.1

In summary, among adult kidney transplant recipients who are CMV-seronegative and have received an organ from a CMV-seropositive donor, letermovir demonstrated non-inferiority to valganciclovir in preventing CMV disease through 52 weeks.1 Additionally, it is associated with a lower incidence of leukopenia or neutropenia, thereby supporting its use in this specific high-risk kidney transplant population.1

  1. Limaye AP, et al. Letermovir vs valganciclovir for prophylaxis of cytomegalovirus in high-risk kidney transplant patients: a randomized clinical trial. JAMA. 2023;330(1):33-42.
  2. U.S. FDA Approves New Indication for Merck’s PREVYMIS® (letermovir) for Prevention of Cytomegalovirus (CMV) Disease in High-Risk Adult Kidney Transplant Recipients. Press release MERCK. Available at Accessed July 24, 2023.

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Real-world data confirm effectiveness of letermovir prophylaxis in reducing CMV manifestations in alloHCT recipients

Cytomegalovirus (CMV) infection is a common complication that surfaces in recipients after allogeneic hematopoietic cell transplantation (alloHCT) and may lead to overall detrimental effects on the transplant outcome.1,2 Antiviral prophylaxis (where antivirals are given to all transplant recipients) or preemptive therapies (where antivirals are prescribed only if CMV is detected) are used to counter the risk of CMV infection in alloHCT recipients.3 The success of preemptive therapy depends on early detection, since the early reactivation of CMV in transplant recipients is associated with significant morbidity and mortality.1,2 This leads to the consideration of antiviral prophylaxis, which can effectively prevent early CMV activation.1,2 The mainstay antiviral drugs like valganciclovir, foscarnet, and cidofovir are often associated with a high incidence of toxicity and adverse drug reactions in these patients, propelling the development of novel antivirals.1,2 Letermovir is a relatively novel antiviral drug that targets the deoxyribonucleic acid terminal transferase of CMV and inhibits its maturation.2,4 This medicine was approved by the United States Food and Drug Administration (FDA)  in 2017 as a prophylactic treatment for alloHCT CMV-seropositive recipients, based on the efficacy results of a phase 3 randomized clinical trial.1,2 Letermovir is safe and efficacious with a favorable tolerability profile, but its clinical performance should be persistently monitored in the real-world setting.1,2,5 In the 48th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) held in March 2022, Raval et al. presented the results of a systematic review and meta-analysis of the real-world observational studies on the impact of letermovir as primary prophylaxis in adult alloHCT recipients in a clinical setting.6