Prevymis demonstrates efficacy in phase III study for prevention of cytomegalovirus disease in adults after kidney transplantation.- Merck Inc.,

At 52 weeks following kidney transplant, trial results met the primary endpoint demonstrating that Prevymis was effective and non-inferior to valganciclovir for preventing CMV disease -- 10.4% (n=30) of participants who received Prevymis 5% CI, -6.5, 3.8]). In a pre-specified safety analysis, Prevymis-treated participants had significantly less myelotoxicity, as measured by rates of leukopenia or neutropenia, compared to valganciclovir-treated participants; 26.0% (n=76) versus 64.0% (n=190), (95% CI, -45.1, -30.3; p-value <0.0001)></0.0001)>

The findings from this trial were presented during a late-breaking oral session at the IDWeek Annual Meeting (Abstract # LB2307). Merck plans to submit a supplemental new drug application (sNDA) with these data to the FDA by the end of this year.

Prevymis is a first-in-class antiviral agent that was approved by the FDA in 2017 and is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Prevymis is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations may lead to ergotism. Prevymis is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.

“CMV disease is an important cause of morbidity and mortality in kidney transplant recipients. Valganciclovir has been the most commonly used drug for CMV prophylaxis in this setting, but myelotoxicity (especially neutropenia and leukopenia) is an important limitation of this drug. Myelotoxicities can be difficult to manage in patients who are already receiving complex treatment regimens with other drugs that also have bone marrow suppressive effects,” said Dr. Ajit P. Limaye, director, Solid Organ Transplant Infectious Disease Program at University of Washington School of Medicine. “I was excited to see these trial results that showed that the efficacy of Prevymis for prevention of CMV disease in kidney transplant patients was similar to the current standard of care treatment (valganciclovir), but with significantly less toxicity.”

About the Phase III trial and efficacy results for Prevymis in kidney transplant recipients : The objective of this Phase III, randomized, double-blind, non-inferiority trial was to evaluate Prevymis versus valganciclovir in preventing CMV disease in adult kidney transplant recipients at high risk for CMV disease. In the trial, 601 participants were randomized (1:1) to receive either 480 mg of Prevymis once a day (n=301) or 900 mg of valganciclovir once a day (n=300) within 7 days post-kidney transplant through 28 weeks (~200 days) post-transplant, with follow-up through 52 weeks. The primary endpoint was the proportion of participants with CMV disease adjudicated by an independent committee that was blinded to treatment assignment through Week 52 post-kidney transplant. The median age of participants was 52 years in the Prevymis study group and 51 years in the valganciclovir study group. Participants were stratified by use/non-use of lymphocyte-depleting induction immunotherapy.

At 52 weeks following transplant, 10.4% (n=30) of the Prevymis group had CMV disease versus 11.8% (n=35) of the valganciclovir group (stratum adjusted difference = -1.4, [95% CI, -6.5, 3.8]), meeting non-inferiority for the trial’s primary endpoint. Efficacy was comparable across all subgroups (age, gender, race and geography). For the secondary endpoint of adjudicated CMV disease at 28 weeks following transplant, 0% (n=0) of Prevymis participants and 1.7% (n=5) of valganciclovir participants had CMV disease (stratum adjusted difference = -1.7 [95% CI, -3.4, 0.1]).

Key safety results : Prevymis had a more favorable safety profile compared to valganciclovir, with fewer drug-related adverse events and study drug discontinuations due to adverse events reported in the Prevymis group compared to the valganciclovir group. The incidence of leukopenia (decrease in leukocytes, or white blood cells) and neutropenia (decrease in of neutrophils, the most common type of white blood cell) was lower with Prevymis than with valganciclovir: i.The treatment difference in leukopenia/neutropenia was 38% lower in the Prevymis group versus the valganciclovir group and statistically significant; ii. Neutropenia measured during treatment through week 28 post-transplant (absolute neutrophil count <1000 cells µl) was reported in 4.1% (n="12)" of the prevymis group versus 19.5% (n="58)" of the valganciclovir group (95% ci, -20.7, -10.5); iii. leukopenia and neutropenia leading to discontinuation of study drug during the 28-week treatment phase was reported in 1.0% (n="3)" in the prevymis group and 5.4% (n="16)" in the valganciclovir group, and 1.4% (n="4)" in the prevymis group and 1.7% (n="5)" in the valganciclovir group, respectively.></1000>

Additional safety information from the trial : i. Drug-related adverse events (AEs) were reported in 19.9% (n=58) of Prevymis participants and 35.0% (n=104) of valganciclovir participants through Week 28 post kidney transplant (95% CI, -22.2, -8.0). Serious drug-related AEs were reported in 1.4% (n=4) of Prevymis participants and 5.1% (n=15) of valganciclovir participants (95% CI, -7.0, -0.9); ii. Discontinuations due to an AE: 4.1% (n=12) in the Prevymis group and 13.5% (n=40) in the valganciclovir group (95% CI -14.1, -4.9); iii. Discontinuation due to a serious AE: 2.1% (n=6) of Prevymis participants versus 4.7% (n=14) of valganciclovir participants (95% CI -5.9, 0.3); iv. Discontinuation due to a drug-related AE: 2.7% (n=8) of Prevymis participants versus 8.8% (n=26) of valganciclovir participants (95% CI -10.1, -2.4); v. Discontinuation due to serious drug-related AE: 0.7% (n=2) of Prevymis participants versus 2.4% (n=7) of valganciclovir participants (95% CI -4.2, 0.4); vi. Two participants (0.7%) in the Pevymis group and one participant in the valganciclovir group (0.3%) died (95% CI, -1.3, 2.2).

About the trial evaluating 200 days of therapy with Prevymis in HSCT recipients : Merck recently concluded another Phase III, randomized, double-blind, placebo-controlled trial that evaluated the safety and efficacy of prophylaxis with Prevymis when extended from 100 to 200 days in CMV-seropositive recipients (R+) following an HSCT. This Phase III trial (NCT03930615) evaluated whether extending CMV prophylaxis with Prevymis from 100 days to 200 days post-HSCT resulted in additional benefit compared to placebo in patients at high risk for clinically significant CMV infection (CS-CMVi) beyond 100-days post-HSCT. This trial met its primary endpoint, which was the proportion of participants with CS-CMVi from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT. Merck is planning to present these data at a scientific congress and also plans to submit a sNDA with these data to the FDA by the end of this year.