Letermovir for Prevention of Cytomegalovirus Infection in Chinese Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Phase 3, Open-Label, Single-Arm Trial

Background: Letermovir is a small molecule inhibitor of cytomegalovirus (CMV) DNA replication that acts by inhibiting the viral terminase complex. Letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive (CMV+) allogeneic hematopoietic stem cell transplant (HSCT) recipients. This Phase 3 trial is the first clinical trial conducted to evaluate the efficacy and safety of letermovir for the prevention of CMV infection in CMV+ allogeneic HSCT recipients in China. As no other anti-CMV agents are currently approved for CMV prophylaxis in this population, no comparator was used in the study.

Methods: This was an open-label post-marketing trial (NCT05763823) in adult (≥18 years old) Chinese participants to evaluate the approved doses of letermovir in CMV+ allogeneic HSCT recipients. Participants received letermovir administered orally or intravenously through Week 14 post-transplant, and were followed through Week 24 post-transplant. Participants who developed clinically significant CMV infection (csCMVi; CMV end-organ disease or CMV viremia requiring pre-emptive treatment) discontinued the trial regimen and received anti-CMV treatment. The primary endpoint was the proportion of participants with csCMVi through Week 24 post-transplant. Key secondary endpoints included the proportion of participants with csCMVi through Week 14 post-transplant and safety (including adverse events [AEs]).

Results: A total of 120 participants were enrolled and received letermovir beginning a median of 7 days post-transplant. The majority of participants were male (62.5%), median age was 36 years (range, 18-65), and median weight was 60.55 kg. Among the 98 participants with undetectable CMV DNA at treatment initiation (efficacy-evaluable population), 32 (32.7% [95% confidence interval (CI): 23.5%-42.9%]) had csCMVi through Week 24 post-transplant using the non-completer=failure (NC=F) approach for missing data: 21 participants (21.4%) had csCMVi, while 7 (7.1%) discontinuations and 4 (4.1%) participants with missing outcome were also imputed as failures under this approach. None (0/98) developed CMV end-organ disease through Week 24 post-transplant. Through Week 14 post-transplant, 7 of 98 participants (7.1% [95% CI: 2.9-14.2]) had csCMVi using the NC=F approach for missing data: 1 (1.0%) with csCMVi and 6 (6.1%) with discontinuations. Among the 120 letermovir-treated participants, drug-related AEs were reported in 17 (14.2%) participants and serious AEs (of any cause) in 70 (58.3%) participants through Week 24 post-transplant. A drug-related serious AE of increased blood creatinine was reported in 1 (0.8%) participant, which did not lead to dose change or discontinuation. No study discontinuations due to an AE or treatment-related deaths were reported.

Conclusions: Letermovir was effective for prevention of csCMVi in Chinese adult CMV+HSCT recipients and was generally safe and well tolerated. The results of this trial are consistent with those of the global pivotal Phase 3 trial (NCT02137772; Marty FM, et al. N Engl J Med. 2017;377(25):2433-2444), showing the safety and efficacy of letermovir in reducing the risk of csCMVi in adult CMV+ HSCT recipients.

Guo:MSD China: Current Employment, Current holder of stock options in a privately-held company. Zhao:MSD China: Current Employment, Current holder of stock options in a privately-held company. Badshah:Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.: Current Employment, Current holder of stock options in a privately-held company.