Letermovir可预防造血细胞移植后巨细胞病毒感染

一项针对已接受同种异体造血细胞移植的成年患者的小型短期Ⅱ期临床试验显示，letermovir可预防巨细胞病毒（CMV）感染。这项研究发表在《新英格兰医学杂志》5月8日在线版上（N. Engl. J. Med. 2014 May 8 [doi:10.1056/NEJMoa1309533]）。

德克萨斯大学M.D. Anderson癌症中心的Roy F. Chemaly博士报告称，这种强效抗CMV药物具有靶向作用于病毒末端酶亚单位pUL56的新作用机制，其疗效随着剂量增加而加强。在这项由药企资助的研究中，该药的安全性特征与安慰剂相当，没有发生与其他抗CMV药物相关的血液或肾脏毒性。

研究者称，巨细胞病毒被letermovir完全阻断，并且未发生与其他抗CMV药物相关的血液或肾脏毒性。

结果显示，治疗结束时，240 mg组的病毒学失败率（6%）显著低于120 mg组（19%）和60 mg组（21%）；所有3个letermovir组的病毒学失败率均显著低于安慰剂组（36%）。研究者发现，letermovir组和安慰剂组分别有15例和5例患者在治疗开始时已存在活动性、隐匿性CMV感染，而在之前的病毒血症检测中没有发现。排除这些患者的事后分析显示，240 mg组的病毒学失败率为0%，120 mg组为6%，60 mg组为15%，而安慰剂组为24%。在18个月内，研究者在9家德国移植中心和10家美国移植中心评价了3种日剂量letermovir相对于安慰剂的疗效和安全性。所有患者均在近期接受了同种异体造血细胞移植，供者为匹配的亲属或非亲属，并且CMV病毒血症检测结果为阴性。这些患者被随机分组，接受60 mg（n=33）、120 mg（n=31）或240 mg（n=34）letermovir或匹配安慰剂（n=33）治疗12周。

在可能与治疗相关的不良事件发生率（17% vs. 33%）以及严重不良事件发生率（31% vs. 36%）方面，letermovir组均低于安慰剂组。安慰剂组患者的停药率是Letermovir组患者的2倍（58% vs. 26%）。没有观察到肾脏或血液毒性的征象，移植物抗宿主病发生率在所有4组中无显著差异。值得一提的是，letermovir组中性粒细胞减少发生率与安慰剂组几乎相同（7% vs. 6%），远低于文献报告的其他抗CMV药物的中性粒细胞减少发生率（可高达58%）。

研究者补充道：“本项研究的结果与此前一项针对少量实体器官移植受者的Ⅱ期概念验证研究一致。”

这项研究是由letermovir的生产商AiCuris资助的。Chemaly博士报告称接受了AiCuris、Chimerix、ViroPharma、葛兰素史克和吉利德等公司提供的资助，并接受了阿斯利康和默克提供的个人酬金；他的同事报告称与多家药企有联系。

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By: MARY ANN MOON, Oncology Practice Digital Network

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

VITALS

Major finding: 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%).

Data source: An international randomized double-blind phase II clinical trial comparing three doses of prophylactic letermovir against placebo for the prevention of CMV infection in 131 adults who had undergone hematopoietic-cell transplantation.

Disclosures: 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.

 

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.

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.