Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model.
Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model.
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DOI：
10.1016/j.trsl.2019.12.002
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发表时间：
2020-04
期刊：
影响因子：
--
通讯作者：
Plemper RK
中科院分区：
文献类型：
--
作者：
Toots M;Yoon JJ;Hart M;Natchus MG;Painter GR;Plemper RK
季节性流感病毒在世界范围内造成重大发病率和死亡率，尤其威胁老年人和免疫功能低下的人。两类流感疗法在当前的疾病管理中占主导地位，但两者都受到预先存在或迅速出现的病毒耐药性的影响。我们最近报道了一种新型核糖核苷类似物临床候选药物 EIDD-2801，它在雪貂和人类气道上皮培养物中具有强大的抗病毒功效，并且具有防止病毒逃逸的高屏障。在这项研究中，我们建立了针对雪貂中大流行性和季节性甲型流感病毒 (IAV) 株的基本 EIDD-2801 功效范例，可用于告知暴露目标和治疗方案。基于降低病毒滴度、减轻临床症状以及降低上呼吸道和下呼吸道组织中的病毒负荷，每日两次的EIDD-2801针对季节性和流行性IAV的最低有效口服剂量浓度分别为2.3和7 mg/kg体重。开始有效治疗的最后时机是雪貂感染后 36 小时。以 12 小时间隔给药，三剂 7 mg/kg 剂量的 EIDD-2801 足以针对大流行 IAV 获得最大治疗效果，并显着缩短临床症状消退的时间。感染大流行性 IAV 并按照最低有效的 EIDD-2801 方案进行治疗的雪貂在鼻腔灌洗液中表现出明显较少的脱落病毒和炎症细胞浸润，但在恢复后出现了强烈的体液抗病毒反应，这与媒介物治疗的动物没有区别。这些结果为人类疾病相关流感动物模型中EIDD-2801的临床测试提供了实验基础。
Seasonal influenza viruses cause major morbidity and mortality worldwide, threatening in particular older adults and the immunocompromised. Two classes of influenza therapeutics dominate current disease management, but both are compromised by pre-existing or rapidly emerging viral resistance. We have recently reported a novel ribonucleoside analog clinical candidate, EIDD-2801, that combines potent antiviral efficacy in ferrets and human airway epithelium cultures with a high barrier against viral escape. In this study, we established fundamental EIDD-2801 efficacy paradigms against pandemic and seasonal influenza A virus (IAV) strains in ferrets that can be used to inform exposure targets and treatment regimens. Based on reduction of shed virus titers, alleviation of clinical signs, and lowered virus burden in upper and lower respiratory tract tissues, lowest efficacious oral dose concentrations of EIDD-2801, given twice daily, were 2.3 and 7 mg/kg of body weight against seasonal and pandemic IAVs, respectively. The latest opportunity for initiation of efficacious treatment was 36 hours after infection of ferrets. Administered in 12-hour intervals, three 7 mg/kg doses of EIDD-2801 were sufficient for maximal therapeutic benefit against a pandemic IAV and significantly shortened the time to resolution of clinical signs. Ferrets infected with pandemic IAV and treated following the minimally efficacious EIDD-2801 regimen demonstrated significantly less shed virus and inflammatory cellular infiltrates in nasal lavages, but mounted a robust humoral antiviral response after recovery that was indistinguishable from that of vehicle-treated animals. These results provide an experimental basis in a human disease-relevant influenza animal model for clinical testing of EIDD-2801.
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影响因子：
3.7
作者：
Huang SS;Banner D;Fang Y;Ng DC;Kanagasabai T;Kelvin DJ;Kelvin AA
通讯作者：
Kelvin AA
DOI：
10.1073/pnas.1811345115
发表时间：
2018-11-06
影响因子：
11.1
作者：
Goldhill DH;Te Velthuis AJW;Fletcher RA;Langat P;Zambon M;Lackenby A;Barclay WS
通讯作者：
Barclay WS
DOI：
10.15585/mmwr.mm6722a4
发表时间：
2018-06-08
期刊：
MMWR. Morbidity and mortality weekly report
影响因子：
--
作者：
Garten R;Blanton L;Elal AIA;Alabi N;Barnes J;Biggerstaff M;Brammer L;Budd AP;Burns E;Cummings CN;Davis T;Garg S;Gubareva L;Jang Y;Kniss K;Kramer N;Lindstrom S;Mustaquim D;O'Halloran A;Sessions W;Taylor C;Xu X;Dugan VG;Fry AM;Wentworth DE;Katz J;Jernigan D
通讯作者：
Jernigan D
影响因子：
6.4
作者：
Checkmahomed, Liva;M'hamdi, Zeineb;Boivin, Guy
通讯作者：
Boivin, Guy
影响因子：
120.7
作者：
Dharan, Nila J.;Gubareva, Larisa V.;Fry, Alicia M.
通讯作者：
Fry, Alicia M.