呼吸道合胞病毒挑战研究中口服 GS-5806 的活性。

Oral GS-5806 activity in a respiratory syncytial virus challenge study.

机构信息

From the University of Tennessee School of Medicine (J.P.D., C.S.-W., L.H., E.F., S.M.) and Le Bonheur Children's Hospital, Children's Foundation Research Institute (J.P.D.) - both in Memphis; University of Alabama School of Medicine, Birmingham (R.J.W.); Gilead Sciences, Foster City, CA (R.L.M., R.J., Y.X., S.R., T.O., S.A.L., X.L., S.L.T., S.-L.L., J.W.C.); and Retroscreen Virology, London (R.L.-W.). Address reprint requests to Dr. DeVincenzo at the Children's Foundation Research Institute, Le Bonheur Children's Hospital, Rm. 400R, 50 North Dunlap St., Memphis, TN 38103, or at

出版信息

N Engl J Med. 2014 Aug 21;371(8):711-22. doi: 10.1056/NEJMoa1401184.

DOI:10.1056/NEJMoa1401184

PMID:25140957

Abstract

BACKGROUND

Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists.

METHODS

We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores.

RESULTS

Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P=0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 × hours; P=0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806.

CONCLUSIONS

Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.).

摘要

背景

呼吸道合胞病毒（RSV）是导致婴儿住院的常见原因，并且越来越被认为是导致相当大发病率和死亡率的原因。目前尚无公认的抗病毒治疗方法。

方法

我们对健康成年人进行了一项双盲、安慰剂对照的 GS-5806 研究，这些成年人通过鼻腔接种了 RSV 临床挑战株。参与者被监测了 12 天。在 RSV 感染检测呈阳性或接种后 5 天（以先发生者为准），参与者随机分为 GS-5806 或安慰剂组，共分为七个连续队列。第 1 至 4 个队列接受 50mg GS-5806 的首剂量，然后接下来 4 天每天服用 25mg；第 5 个队列接受 50mg GS-5806 的首剂量，然后接下来 2 天每天服用 25mg；第 6 个队列接受 100mg 剂量；第 7 个队列接受 10mg 的首剂量，然后接下来 4 天每天服用 5mg。第 5、6 和 7 个队列的剂量选择是基于第 1 至 4 个队列的数据进行的中期分析。主要终点是病毒载量的曲线下面积（AUC），评估从首剂量给药到接种后第 12 天。次要终点是黏液重量和症状评分。

结果

在接种 RSV 的第 1 至 4 个队列的 54 名感染者中，与安慰剂相比，GS-5806 治疗可降低病毒载量（校正平均病毒载量，250.7 对 757.7 log10 噬菌斑形成单位等效物 [PFUe] × 每毫升小时；P<0.001），总黏液重量（平均 6.9g 对 15.1g；P=0.03），以及症状评分从基线变化的 AUC（校正平均 AUC，-20.2 对 204.9 × 小时；P=0.005）。第 5、6 和 7 个队列的结果相似。接受 GS-5806 治疗的参与者中，不良事件（包括中性粒细胞计数降低和丙氨酸氨基转移酶水平升高）更为常见。