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

Background: Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains.

Methods: Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs).

Results: From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57-75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses.

Conclusions: Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified.

Clinical trials registration: NCT01611974.

Keywords: cytomegalovirus; foscarnet; ganciclovir; maribavir; transplantation.

Figure 1.

Patient disposition. Abbreviations: BID, twice daily; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; ITT, intent-to-treat. ^aA total of 14 patients were randomized in the study, despite not meeting 1 or more protocol eligibility criteria. See text for details. ^bA clinically significant medical or surgical condition that could have interfered with the administration of the study drug or the interpretation of study results, or compromised the safety or well-being of the patient. ^cAccording to the study design, treatment could be stopped if the patient achieved confirmed undetectable levels of CMV DNA, indicating successful treatment. Patients achieving undetectable CMV DNA levels could also be maintained on study treatment at the discretion of the investigator.

Figure 2.

Kaplan-Meier plots for (A) time to confirmed undetectable plasma CMV DNA at any time during the study and (B) time from confirmed undetectable plasma CMV DNA to CMV recurrence. Abbreviations: CMV, cytomegalovirus; DNA, deoxyribonucleic acid.