Oral CMX001 100 mg Twice Weekly Reduces Cytomegalovirus Events in Patients Receiving Hematopoietic Cell Transplants
The anti-cytomegalovirus agent CMX001 is an oral lipid acyclic nucleoside phosphonate that is absorbed in the small intestine and transported throughout the body as a phospholipid. It is converted intracellularly to cidofovir diphosphate, but unlike cidofovir, is not a substrate of organic ion transporter 1, is not concentrated in renal proximal tubules, and is unlikely to cause renal toxicity. In a study reported in The New England Journal of Medicine, Francisco M. Marty, MD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and colleagues found that CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of cytomegalovirus (CMV) events in patients receiving hematopoietic cell transplants. Diarrhea was the dose-limiting toxicity.
Study Details
In the study, 230 adult CMV-seropositive transplant recipients were randomly assigned 3:1 to double-blind CMX001 or placebo (n = 59) in five sequential dose-escalated cohorts consisting of CMX001 40 (n = 25), 100 (n = 27), or 200 mg (n = 39) once weekly and 100 (n = 50) and 200 mg (n = 30) twice weekly. Patients received study drug after engraftment for 9 to 11 weeks, until week 13 after transplantation. The primary endpoint was a CMV event, defined as CMV disease or plasma CMV DNA level > 200 copies/mL when the study drug was discontinued.
CMV Event Rates
CMV event rates were 37% in the placebo group vs 52% in the CMX001 40-mg weekly group (P = .23), 22% in the 100-mg weekly group (P = .22), 31% in the 200-mg weekly group (P = .53), 10% in the 100-mg twice weekly group (P = .002), and 23% in the 200-mg twice weekly group (P = .24). Results according to the stratification criteria of presence/absence of acute graft-vs-host disease and plasma CMV DNA at baseline were consistent with those of the primary analysis.
Compared with placebo, rates of positivity for CMV DNA during study drug administration were significantly reduced with 200 mg weekly, 100 mg twice weekly, and 200 mg twice weekly treatment among all patients, with 200 mg twice weekly among patients with detectable CMV DNA at baseline, and with all doses except for 40 mg weekly among patients without detectable CMV DNA at baseline.
Toxicities
In placebo patients and patients in the CMX001 groups receiving 40 mg or 100 mg weekly, plasma CMV DNA levels requiring treatment were the most common reason for discontinuing study treatment, whereas adverse events were the primary reason for discontinuation in the other CMX001 dose groups. Common clinical adverse events were gastrointestinal in nature and similar in the placebo group and the 40-, 100-, and or 200-mg weekly CMX001 groups, except for nausea in the 200-mg group (28% vs 10%). Diarrhea was the dose-limiting toxicity, occurring in 70% of patients in the 200-mg twice weekly group and considered serious in 33%. Diarrhea occurred in 52% of patients in the 100-mg twice weekly group and was considered serious in 10%.
Elevated ALT was more common among patients who received > 200 mg of CMX001 per week than among those receiving lower doses or placebo, but the elevations were not associated with increases in bilirubin or AST. There were no consistent differences in the frequency of anemia, thrombocytopenia, or neutropenia among the dose groups and there was no evidence of increased nephrotoxicity or ocular toxicity with increasing doses of CMX001.
The investigators concluded, “Treatment 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.”
The study was funded by Chimerix.
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