Maribavir for Treatment of Cytomegalovirus (CMV) Infections Resistant or Refractory to Ganciclovir or Foscarnet in Hematopoietic Stem Cell Transplant (SCT) or Solid Organ Transplant (SOT) Recipients: A Randomized, Dose-Ranging, Double-Blind, Phase 2 Study

Abstract

Background. CMV infection resistant or refractory to standard therapy is associated with substantial morbidity and mortality among transplant recipients. Approved anti-CMV therapies are associated with adverse effects including myelosuppression, nephrotoxicity and electrolyte imbalances. Maribavir (MBV) is active in vitro against CMV strains resistant to other agents. This Phase 2 study (NCT01611974) assessed the safety, tolerability and antiviral activity of MBV for treatment of resistant or refractory CMV infections among SCT and SOT recipients. Methods. SCT/SOT recipients aged ≥12 years with CMV infection (≥1000 DNA copies/mL in blood/plasma) resistant or refractory to (val)ganciclovir or foscarnet were randomized 1:1:1 to receive oral MBV 400, 800 or 1200 mg twice daily (BID), for up to 24 weeks. Primary safety analysis focused on incidence of treatment-emergent adverse events (TEAEs). Primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks' treatment. Secondary endpoints included the proportion of patients with plasma CMV DNA recurrence during the study. Results. From July 2012 to December 2014, 120 patients were randomized (47 SCT, 73 SOT; 40/dose group); median age 55 (range 18–74) years. At baseline, 17/106 (16%) patients had neutropenia (ANC <1000/mm3). Efficacy results are shown in the table. MBV was discontinued due to an AE in 41/120 (34%) patients; 17/41 due to CMV infection. Dysgeusia was the most common TEAE (table) and led to MBV discontinuation in 1 patient. Neutropenia occurred in 12/106 (11%) patients; rates similar across doses. Conclusion. MBV 400–1200 mg BID was effective for treatment of CMV infection resistant/refractory to standard therapy among SCT/SOT recipients. There was no evidence of myelosuppression; data support the safety of MBV administered for up to 24 weeks. Further development of MBV for CMV treatment is warranted. Disclosures. G. Papanicolaou, Shire: Investigator, Research support; F. P. Silveira, Shire: Investigator, Research support. Viropharma: Investigator, Research support; R. Avery, Shire: Investigator, Research support. Astellas: Investigator, Research support. Merck: Investigator, Research support. Chimerix: Investigator, Research support. Oxford Immunotec: Investigator, Research support; A. Wijatyk, Shire: Employee, Salary and Stock; J. J. Wu, Shire: Employee, Salary; M. Boeckh, Merck: Consultant and Investigator, Consulting fee and Research support. Shire: Consultant, Consulting fee. Chimerix: Consultant and Investigator, Consulting fee and Research support. Astellas: Consultant and Investigator, Consulting fee and Research support. Microbiotix: Consultant, Consulting fee. Clinigen: Consultant, Consulting fee; F. M. Marty, Alexion: Scientific Advisor, Consulting fee. Ansun: Investigator, Research support. Astellas: Consultant and Investigator, Consulting fee and Research support. Basilea: Conference speaker, Speaker honorarium. Chimerix: Consultant and Investigator, Consulting fee and Research support. Gilead: Consultant and Investigator, Consulting fee and Research support. GlaxoSmithKline: Consultant and Investigator, Consulting fee and Research grant. LFB, S.A.: Consultant, Consulting fee. Merck: Consultant and Investigator, Consulting fee and Research support. Shire: Consultant and Investigator, Consulting fee and Research support. WHISCON: Investigator, Research support. Pfizer: Course speaker, Speaker honorarium. Fate Therapeutics: Scientific Advisor, Consulting fee; S. Villano, Shire (at time of study): Employee, Salary