Letermovir prevented cytomegalovirus infection in a small, short-term phase II clinical trial involving adults who had undergone allogeneic hematopoietic-cell transplantation, according to a report published online May 8 in the New England Journal of Medicine.
The efficacy of the new drug, "a highly potent anti-CMV agent with a novel mechanism of action targeting the viral terminase subunit pUL56," increased with increasing dosage. Its safety profile was comparable to that of placebo in this industry-sponsored study, with none of the hematologic or renal toxicities associated with other anti-CMV drugs, said Dr. Roy F. Chemaly of the University of Texas M.D. Anderson Cancer Center, Houston, and his associates.
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Cytomegalovirus was completely prevented by letermovir with none of the hematologic or renal toxicities associated with other anti-CMV drugs, researchers said.
The investigators tested three daily oral doses of letermovir against placebo at nine transplantation centers in Germany and 10 in the United States over an 18-month period. All the patients had recently received allogeneic transplants from matched related or unrelated donors and had tested negative for CMV viremia. They were randomly assigned to receive 60 mg (33 patients), 120 mg (31 patients), or 240 mg (34 patients) of active drug or matching placebo (33 patients) for 12 weeks.
At the conclusion of treatment, the rate of virologic failure was "markedly" lower in the 240-mg group (6%) than in the 120-mg group (19%) and the 60-mg group (21%); the rate of virologic failure was significantly lower in all three active-treatment groups than in the placebo group (36%). It was discovered that 15 patients given letermovir and 5 given placebo already had active, occult CMV infections at the start of treatment, which had not been detected on viremia testing. When these cases were excluded from a post hoc analysis, rates of virologic failure were 0% with 240-mg letermovir, 6% with 120-mg letermovir, and 15% with 60-mg letermovir, compared with 24% with placebo, the investigators said (N. Engl. J. Med. 2014 May 8 [doi:10.1056/NEJMoa1309533]).
The rate of adverse events considered to be possibly treatment related was lower with letermovir (17%) than with placebo (33%), as was the rate of serious adverse events (31% vs 36%). Patients discontinued the study drug twice as often in the placebo group (58%) as in the active-treatment groups (26%). There was no indication of renal or hematologic toxicity, and the incidence of graft-versus-host disease was similar among the four study groups. In particular, the incidence of neutropenia was nearly identical between letermovir (7%) and placebo (6%) – much lower than the rates as high as 58% reported with other anti-CMV agents, Dr. Chemaly and his associates said.
"These results are consistent with those of a previous phase II proof-of-concept trial involving a small number of recipients of solid-organ transplants," they added.
This study was funded by AiCuris, maker of letermovir. Dr. Chemaly reported receiving grants from AiCuris, Chimerix, ViroPharma, GlaxoSmithKline, and Gilead, and receiving personal fees from Astellas and Merck; his associates reported ties to numerous industry sources.