Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study

Abstract

In this multicenter, dose-ranging study of maribavir for the treatment of cytomegalovirus (CMV) infections deemed refractory or resistant to current antivirals, 67% of patients achieved clearance of CMV viremia within 6 weeks, with responses maintained for up to 24 weeks.

New advances in the management of cytomegalovirus in allogeneic haemopoietic stem cell transplantation

“…Maribavir is a novel benzimidazole antiviral agent that is highly potent against CMV, including ganciclovir‐resistant strains . It directly targets the CMV protein kinase UL97 to inhibit effectively viral replication and encapsulation, with mutations in UL97 and UL27 resulting in resistance . Further advantages with maribavir are the availability of an oral formulation and the appreciable lack of either myelotoxicity or nephrotoxicity .…”

“…Testing for CMV resistance may be indicated when recurrence of viraemia occurs after initial viral clearance or with failure to achieve >1 log10 decrease in CMV viral load after more than or equal to 2 weeks of full dose antiviral treatment. 18 For patients failing antiviral therapy, potential causes include virus mutation leading to antiviral pharmacological resistance or low therapeutic antiviral levels due to underdosing, increased metabolism and/or increased excretion. In the case of oral antivirals, reduced patient compliance or poor absorption particularly if GVHD is present should be considered.…”

“…18 The most commonly reported side-effects include metallic taste disturbance and headache. 18 In a small case series, maribavir was successful in clearing CMV virus in treatment refractory CMV disease, however, the development of maribavir resistance in one patient while on treatment is a concern. 28 A large, randomised phase III study of 681 HSCT recipients comparing prophylactic strategies of maribavir to placebo failed to reach the primary end-point of preventing CMV disease at 6 months (4% maribavir vs 5% placebo).…”

Treatment and Prevention of CMV Disease in Transplant Recipients: Current Knowledge and Future Perspectives

“…A possible explanation for the lack of efficacy observed in these phase 3 trials was the maribavir dose selected (100 mg twice daily). In fact, limited data from the use of maribavir under individual emergency investigational new drug applications and data from 2 more recent phase 2 trials (one for the treatment of refractory or resistant CMV infections in HSCT or solid‐organ transplant recipients and the other for the preemptive therapy of CMV viremia in HSCT and solid‐organ transplant recipients) suggest that higher doses of maribavir may have a role in the treatment or prevention of CMV infection, including patients who have a CMV infection refractory or resistant to currently available drugs. Based on these data, 2 phase 3 trials of maribavir 400 mg twice daily are underway …”

An explanation for posttransplant late‐onset disease associated with CMV prophylaxis

“…It is as if the immune system is making a poor contribution to the control of CMV, so on‐going replication in the presence of ganciclovir or foscarnet selects for resistance against one or both of these drugs. The problem is common enough to allow substantial numbers of patients to be available for a phase 2 randomised controlled trial of maribavir, with a phase 3 trial currently following up the encouraging results seen so far (NCT02931539).…”