FDA Approves New Indication for Letermovir for Prevention of Cytomegalovirus in Adult Kidney Transplant Recipients

The FDA has approved a new indication for letermovir (Prevymis, Merck) for prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk, defined as a donor who is CMV-seropositive and a recipient who is CMV-seronegative.

Many adults are CMV-seropositive, meaning they have CMV antibodies in their blood. This indicates a previous exposure to, or primary infection with CMV, although individuals with healthy immune systems rarely develop CMV symptoms after initial infection. However, the virus typically remains inactive or latent in the body for life, and CMV-seronegative patients who receive an organ from a CMV-seropositive donor are at high risk of CMV disease after transplantation.

Letermovir is an antiviral agent initially approved in 2017 for the prevention of CMV infection and disease in adult patients who received an allogeneic hematopoietic stem cell transplant and who are CMV-seropositive. It is administered once daily as an oral tablet or as an injection for intravenous infusion.

“Prevymis has been an important addition to the care of high-risk adult CMV-seropositive patients who have received allogeneic stem cell transplants to help prevent CMV infection and disease,” said Elizabeth Rhee, MD, vice president of global clinical development at Merck Research Laboratories, in a press release. “We are delighted that Prevymis is now approved to help prevent CMV disease in adult kidney transplant patients at high risk.”

The new approval was supported by a phase 3, randomized, multicenter, double-blind, active comparator-controlled non-inferiority trial in 589 adult kidney transplant recipients at high risk. Participants were randomized 1:1 to receive either letermovir concomitantly with acyclovir or valganciclovir concomitantly with a placebo to acyclovir.

Letermovir was initiated between day 0 and day 7 post-kidney transplant and continued through week 28 post-transplant. It was administered either orally or intravenously and the dose was the same regardless of the route of administration. Three participants received intravenous letermovir for a mean duration of 1.7 days and participants were monitored through week 52 post-transplant.

The study demonstrated that letermovir was non-inferior to valganciclovir, the current standard of care, for the primary endpoint of incidence of CMV disease through week 52. The proportion of participants with CMV disease was 10% with letermovir and 12% with valganciclovir, meeting the pre-specified non-inferiority margin.

Furthermore, the incidence of CMV was 8% in the letermovir arm versus 11% in the valganciclovir arm. The incidence of CMV end organ disease was 2% vs less than 1%, respectively.

For the purposes of the analyses, participants who discontinued prematurely from the study for any reason or who were missing data at the timepoint were not counted as failures. Before week 52, 32 (11%) participants in the letermovir arm and 28 (9%) in the valganciclovir arm discontinued, and the number of participants with a missing outcome in the week 52 visit window was 24 (8%) in the letermovir arm and 25 (8%) in the valganciclovir arm.

The efficacy was comparable across all subgroups, including those who used or did not use highly cytolytic, anti-lymphocyte immunotherapy during induction, which was a stratification factor at randomization. In an exploratory analysis of the incidence of CMV disease through week 28 post-transplant, the difference between the 2 arms was -1.7%. No subjects in the letermovir group experienced CMV disease through week 28 post-transplant compared with 5 subjects in the valganciclovir group.

The safety of letermovir was also evaluated in the phase 3 trial and adverse events (AEs) were those reported while participants were on study medication or within 2 weeks of completion or discontinuation. Diarrhea was reported in at least 10% of participants in the letermovir arm and at a greater frequency than in the valganciclovir arm.

Furthermore, the study drug was discontinued due to an AE in 4% of the letermovir group and 14% of the valganciclovir group. The most frequently reported AEs leading to study drug discontinuation were neutropenia and leukopenia.

Reference

US FDA Approves New Indication for Merck’s Prevymis (letermovir) for Prevention of Cytomegalovirus (CMV) Disease in High-Risk Adult Kidney Transplant Recipients. News release. Merck. June 6, 2023. Accessed June 6, 2023. https://www.merck.com/news/u-s-fda-approves-new-indication-for-mercks-prevymis-letermovir-for-prevention-of-cytomegalovirus-cmv-disease-in-high-risk-adult-kidney-transplant-recipients/