CMX001 to Prevent Cytomegalovirus Disease in Hematopoietic-Cell Transplantation

BackgroundThe use of available antiviral agents for the prevention of cytomegalovirus (CMV) disease is limited by frequent toxic effects and the emergence of resistance. CMX001 has potent in vitro activity against CMV and other double-stranded DNA viruses. We evaluated the safety and anti-CMV activity of CMX001 in patients who had undergone allogeneic hematopoietic-cell transplantation. MethodsFrom December 2009 through June 2011, a total of 230 patients with data that could be evaluated were enrolled in the study. We randomly assigned these adult CMV-seropositive transplant recipients from 27 centers to oral administration of CMX001 or placebo. Patients were assigned in a 3:1 ratio to five sequential study cohorts according to a dose-escalating, double-blind design. Randomization was stratified according to the presence or absence of acute graft-versus-host disease and CMV DNA in plasma. Patients received the study drug after engraftment for 9 to 11 weeks, until week 13 after transplantation. Polymerase-chain-reaction analysis of CMV DNA in plasma was performed weekly. Patients in whom CMV DNA was detected at a level that required treatment discontinued the study drug and received preemptive treatment against CMV infection. The primary end point was a CMV event, defined as CMV disease or a plasma CMV DNA level greater than 200 copies per milliliter when the study drug was discontinued. The analysis was conducted in the intention-to-treat population. ResultsThe incidence of CMV events was significantly lower among patients who received CMX001 at a dose of 100 mg twice weekly than among patients who received placebo (10% vs. 37%; risk difference, -27 percentage points; 95% confidence interval, -42 to -12; P=0.002). Diarrhea was the most common adverse event in patients receiving CMX001 at doses of 200 mg weekly or higher and was dose-limiting at 200 mg twice weekly. Myelosuppression and nephrotoxicity were not observed. ConclusionsTreatment with oral CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of CMV events in recipients of hematopoietic-cell transplants. Diarrhea was dose-limiting in this population at a dose of 200 mg twice weekly. (Funded by Chimerix; CMX001-201 ClinicalTrials.gov number, NCT00942305.) A dose-finding study showed that CMX001 at an oral dose of 100 mg twice weekly, as compared with placebo, reduced the risk of cytomegalovirus events from 37% to 10% among patients who had undergone hematopoietic-cell transplantation. Cytomegalovirus (CMV) infection is a common cause of illness after allogeneic hematopoietic-cell transplantation.(1),(2) CMV seropositivity in transplant recipients is also associated with an increased risk of death after transplantation, despite preemptive and prophylactic strategies with available antiviral agents.(3)-(5) Although valganciclovir is approved for prophylaxis against CMV infection after solid-organ transplantation, its use is limited by myelosuppression, particularly after hematopoietic-cell transplantation.(3),(6)-(8) Thus, there is an unmet need for effective drugs against CMV infection that have a better safety profile. CMX001 is an orally bioavailable lipid acyclic nucleoside phosphonate that is absorbed in the small intestine and transported ...