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标题: 强生实验性药物可有效治疗呼吸道合胞病毒（RSV）感染 [打印本页]

作者: Biodog 时间: 2015-11-20 22:30
标题: 强生实验性药物可有效治疗呼吸道合胞病毒（RSV）感染

强生旗下Abios BioPharma公司近日宣布，《新英格兰医学杂志》（NEJM）已在线发表其呼吸道合胞病毒（RSV）潜在治疗药物ALS-008176一项IIa期研究的积极数据。

ALS-008176是RSV复制抑制剂ALS-008112的一种口服生物可利用前体药物，ALS-008112是一种胞嘧啶核苷类似物，通过作用于病毒聚合酶抑制RSV复制；即使呼吸道细胞已经被RSV感染，ALS-008176仍能够有效抑制RSV复制。这也意味着，即便在RSV感染的较晚阶段用药，ALS-008716仍能够发挥抗病毒，有望成为RSV感染临床治疗中一种安全有效的药物。强生目前正在住院治疗的RSV感染婴幼儿中调查ALS-008716的疗效和安全性。

在婴幼儿群体中，RSV是导致严重呼吸道疾病的主要原因，同时也是工业化国家患者住院的最常见原因。此次公布的IIa期研究奠定了ALS-008176在健康成人群体中抗病毒作用的人体概念验证，同时也揭示了该药在自然感染患者临床治疗中的潜力。

该IIa期研究是一项随机双盲研究，62例健康志愿者接种RSV之后，随机接受ALS-008716和安慰剂。数据显示，与安慰剂相比，ALS-008716治疗组病毒载量显著降低（病毒载量AUC降低73-88%）、病毒清除率显著更快（1.3-2.3天 vs 7.2天）。此外，在安慰剂组病毒载量达到峰值时，ALS-008716 3个治疗组平均病毒载量低于安慰剂组1000倍以上，同时症状评分及呼吸道分泌物总量显著降低。研究中，未发生严重不良事件（SAEs）、过早停药或临床上显著的治疗相关不良事件。最常见的不良事件为鼻出血、上呼吸道感染、咳嗽。更重要的是，ALS-008716治疗组无一例患者经历病毒反弹或病毒耐药。

呼吸道合胞病毒（RSV）是一种季节性病毒，影响肺部和气道，目前尚无疫苗及指南推荐的抗病毒治疗方案。RSV可通过单克隆抗体予以部分阻击，但其应用仅局限于很少一部分伴有心脏或肺部问题的早产儿或新生儿。据估计，在成人及儿童中，每年约有6400万例RSV感染病例；婴幼儿则几乎100%会在第2岁时发生至少一次RSV感染。在2005年，约3380万婴幼儿发生下呼吸道RSV感染，至少340万例住院治疗，死亡病例在6.6-19.9万例。

Alios BioPharma是一家位于美国加州的生物制药公司，强生在2014年10月耗资17.5亿美元将其收购，获得了一系列潜在的抗病毒感染治疗药物。本月初，强生再次出手，将Novira公司收购，获得了乙肝药物NVR3-778及其他一系列抗病毒药物。

作者: bigben446 时间: 2016-2-18 10:20
【标题】：Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study
【作者】：DeVincenzo, J. P.; McClure, M. W.; Symons, J. A. (...)
【来源】：N Engl J Med, 2015, 373(21), 2048-2058
【摘要】：BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents x hours per milliliter, respectively (P</=0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P</=0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P</=0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).

作者: bigben446 时间: 2016-2-18 10:20
【标题】：Discovery of 4'-chloromethyl-2'-deoxy-3',5'-di-O-isobutyryl-2'-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection
【作者】：Wang, G.; Deval, J.; Hong, J. (...)
【来源】：J Med Chem, 2015, 58(4), 1862-1878
【摘要】：Respiratory syncytial virus (RSV) is a leading pathogen of childhood and is associated with significant morbidity and mortality. To date, ribavirin is the only approved small molecule drug, which has limited use. The only other RSV drug is palivizumab, a monoclonal antibody, which is used for RSV prophylaxis. Clearly, there is an urgent need for small molecule RSV drugs. This article reports the design, synthesis, anti-RSV activity, metabolism, and pharmacokinetics of a series of 4'-substituted cytidine nucleosides. Among tested compounds 4'-chloromethyl-2'-deoxy-2'-fluorocytidine (2c) exhibited the most promising activity in the RSV replicon assay with an EC50 of 0.15 muM. The 5'-triphosphate of 2c (2c-TP) inhibited RSV polymerase with an IC50 of 0.02 muM without appreciable inhibition of human DNA and RNA polymerases at 100 muM. ALS-8176 (71), the 3',5'-di-O-isobutyryl prodrug of 2c, demonstrated good oral bioavailability and a high level of 2c-TP in vivo. Compound 71 is a first-in-class nucleoside RSV polymerase inhibitor that demonstrated excellent anti-RSV efficacy and safety in a phase 2 clinical RSV challenge study.

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