Letermovir (Prevymis) was shown to be non-inferior to valganciclovir (Valcyte), the standard of care, in a clinical trial of cytomegalovirus (CMV) prophylaxis in high-risk kidney transplant patients, the researchers reported.
In a phase III study of 589 patients randomized 1:1 to receive both drugs up to 200 days post-transplant, the 1-year prevalence of CMV disease was not significantly different in the letermovir group compared to the valganciclovir group (10.4 % vs 11.8%, adjusted difference -1.4%, 95% CI -6.5% to 3.8%), reported Ajit Limaye, MD, of the University of Washington Medicine in Seattle, and colleagues.
The rate of myelosuppression (leukopenia or neutropenia) at 28 weeks was significantly lower with letermovir than with valganciclovir (26% vs 64%, P<0.001), the researchers reported in JAMA.
Additionally, fewer participants in the letermovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%) than in the letermovir group. valganciclovir, the researchers said.
“Cytomegalovirus disease is a leading cause of morbidity and mortality among kidney transplant recipients,” wrote Limaye and colleagues. “The incidence is highest in the subset of CMV seronegative kidney transplant recipients who receive an organ from a CMV seropositive donor, which comprises approximately 20% of all kidney transplant recipients.”
The standard prophylaxis, valganciclovir, has important limitations, however, the researchers noted. It requires dose adjustments and patients have been known to develop resistance. In addition, valganciclovir commonly causes myelosuppression, particularly leukopenia and neutropenia, which may lead to discontinuation or require dose reductions of immunosuppressants.
“Letermovir is an antiviral active against CMV with no associated myelotoxicity, does not require dose adjustment for renal insufficiency, has a unique mechanism of action as an inhibitor of the CMV DNA terminase complex, and is not associated with cross-resistance to other anti-CMV agents,” the study authors said.
Letermovir has its limitations, however, Limaye and colleagues noted. Unlike valganciclovir, it has no activity against herpes simplex virus (HSV) or varicella zoster virus (VZV). And as a moderate inhibitor of cytochrome P3450 3A, it has the potential to interact with other drugs.
Letermovir was approved by the FDA in 2017 for CMV prophylaxis in CMV seropositive adult hematopoietic cell transplant recipients and has been widely adopted in this population. The drug’s maker, Merck, announced today that the FDA has also approved letermovir for CMV prophylaxis in adult high-risk kidney transplant recipients, based on the results of the ongoing study.
In an editorial accompanying the study, Zoe Raglow, MD, and Daniel R. Kaul, MD, both of the University of Michigan Medical School in Ann Arbor, said another limitation of letermovir is its cost. “Cost will certainly be a factor, because the average daily cost of letermovir (about $250 per day) is more than 20 times that of generic valganciclovir, making it one of the most expensive routine post-transplant drugs,” they wrote.
However, Raglow and Kaul said the findings presented by Limaye’s group are “changing practice” and that clinicians will need to weigh letermovir’s limitations and benefits when considering which patients are most likely to benefit. “Letermovir may be more cost-effective when used among patients with baseline leukopenia or who develop leukopenia while on valganciclovir treatment,” the editorialists suggested.
The Phase III double-blind, double-dummy study included the highest-risk adult patients: CMV seronegative kidney transplant recipients who received an organ from a CMV seropositive donor. Most were white (84%) and male (71%).
The letermovir group received oral letermovir 480 mg daily, aciclovir 400 mg twice daily (as prophylaxis for HSV and VZV), and a valganciclovir placebo. The valganciclovir group received 900 mg of oral valganciclovir daily with placebo for letermovir and aciclovir. Aciclovir has no activity against CMV, the researchers noted.
The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through week 52 posttransplant, with a prespecified noninferiority difference of 10%. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.
Secondary outcomes included CMV disease through week 28 and time to onset of CMV disease. No participants in the letermovir group developed CMV disease through week 28 compared with five participants who received valganciclovir. Time to onset of CMV disease was comparable between groups (HR 0.90, 95% CI 0.56-1.47).
Study limitations, the team said, included that myelotoxicity was assessed as leukopenia or neutropenia, but valganciclovir can also cause anemia and thrombocytopenia. In addition, no cost analysis was performed, although cost is an important consideration with letermovir.
Additionally, the study lacked diversity, the authors said, although CMV disease risk was not linked to gender, race or ethnicity. Finally, the long-term outcomes of CMV disease have not been formally evaluated. “However, because CMV disease was comparable between groups, there is no reason to expect differences in long-term outcomes with letermovir versus valganciclovir,” the researchers said.
The study was funded by Merck Sharp & Dohme.
Limaye reported relationships with Merck, Moderna, NobelPharma, Takeda, AiCuris, Vera, AlloVir and GSK; other coauthors reported relationships with industry, including employment with Merck.
Kaul has reported financial relationships with Takeda, NobelPharma and Medscape; Raglow has disclosed no conflicts of interest.
Reference source: Limaye AP, et al “Letermovir vs valganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients: A randomized clinical trial” JAMA 2023; DOI: 10.1001/jama.2023.9106.
Source reference: Raglow Z, Kaul DR “A new antiviral option for cytomegalovirus prevention after kidney transplantation” JAMA 2023; DOI:10.1001/jama.2023.9100.
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