FDA Approves Letermovir (Prevymis) for Preventing CMV in Adult Kidney Transplant Patients


The federal agency gave Merck the nod to use the company's antiviral as prophylaxis for Cytomegalovirus Disease (CMV), postoperatively.

The FDA has approved a new indication for letermovir for prophylaxis of CMV disease in adult kidney transplant recipients at high risk (Donor CMV-seropositive/Recipient CMV-seronegative [D+/R-]). Letermovir is a first-in-class non-nucleoside that inhibits viral replication by specifically targeting the viral terminase complex.

“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, global clinical development, Merck Research Laboratories. "We are delighted that Prevymis is now approved to help prevent CMV disease in adult kidney transplant patients at high risk.”

The FDA’s decision was supported by the pivotal phase 3 data that demonstrated letermovir was non-inferior to valganciclovir, the current standard of care, for the primary endpoint of incidence of CMV disease (CMV end-organ disease or CMV syndrome, confirmed by an independent adjudication committee) through Week 52 post-kidney transplant.

Phase 3 Study Results
Investigators conducted a phase 3, randomized, double-blind non-inferiority trial in order to compare Prevymis to valganciclovir and their abilities to prevent CMV disease among 601 high-risk adult kidney transplant recipients, as was previously reported by Contagion. The patients were randomized to either receive 480 mg of Prevymis once per day or 900 mg of valganciclovir once per day for 7 days post-transplant for 28 weeks with follow-up through 52 weeks, the study authors explained. The median age for the patients was 52 years in the Prevymis group and 51 years in the valganciclovir group, they added.

At 52 weeks post-transplant, 10.4% of the letermovir cohort had CMV vs 11.8% of the valganciclovir group, the investigators reported. They said this finding was consistent across all subgroups such as age, gender, race, and geography. In addition, they reported that after 52 weeks post-transplant, none of the letermovir participants had adjudicated CMV disease compared to 5 patients (1.7 percent) of the valganciclovir group.

Letermovir was approved by the FDA in 2017 for the prophylaxis of CMV infection among adult CMV-seropositive recipients of an allogenic hematopoietic stem cell transplant (HSCT).

In a separate phase 3 study, investigators evaluated 200 days of therapy with letermovir in HSCT recipients at high risk of late clinically significant CMV infection, which met its primary endpoint.

As a result, Merck applied for a separate FDA supplemental application to extend prophylaxis with letermovir to 200 days in certain HSCT recipients. The PDUFA date for this application has been set for September 7.

According to Merck, the recommended dosage for letermovir in high-risk adult kidney transplant recipients is 480 mg administered once daily orally or as an intravenous infusion, initiated as early as Day 0 and up to Day 7 post-kidney transplant and continued through Day 200 post-transplant. If letermovir is co-administered with cyclosporine, the dosage of oral or intravenous letermovir should be decreased to 240 mg once daily.

Letermovir 240 mg and 480 mg tablets may be administered with or without food. Following the completion of letermovir prophylaxis, monitoring for CMV reactivation is recommended. For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of letermovir is required based on renal impairment.

The safety of letermovirin patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown. In patients with CLcr less than 50 mL/min receiving letermovir injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Serum creatinine levels should be closely monitored in these patients.

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