From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).
N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197.
Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.
We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.
In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.
Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).
巴洛沙韦马波西利是一种流感帽依赖性内切酶的选择性抑制剂。它在甲型和乙型流感病毒感染的临床前模型中表现出治疗活性，包括对当前抗病毒药物耐药的菌株。
我们进行了两项随机、双盲、对照试验，涉及急性单纯性流感的健康门诊患者。在进行了剂量范围（10 至 40 毫克）安慰剂对照试验后，我们在 2016-2017 季节期间对 12 至 64 岁的患者进行了单剂量、基于体重的巴洛沙韦（40 或 80 毫克）的安慰剂和奥司他韦对照试验。奥司他韦的剂量为每日两次 75 毫克，共 5 天。主要疗效终点是意向治疗感染人群中流感症状缓解的时间。
在第 2 阶段试验中，与安慰剂组相比，巴洛沙韦组流感症状缓解的中位时间缩短了 23.4 至 28.2 小时（P<0.05）。在第 3 阶段试验中，意向治疗感染人群包括 1064 名患者；每组 84.8%至 88.1%的患者感染甲型（H3N2）流感。症状缓解的中位时间为 53.7 小时（95%置信区间[CI]，49.5 至 58.5），与安慰剂组的 80.2 小时（95%CI，72.6 至 87.1）相比（P<0.001）。巴洛沙韦和奥司他韦的症状缓解时间相似。与安慰剂或奥司他韦相比，巴洛沙韦在治疗开始后 1 天病毒载量降低幅度更大。20.7%的巴洛沙韦治疗组、24.6%的安慰剂治疗组和 24.8%的奥司他韦治疗组报告了不良事件。在第 2 阶段试验和第 3 阶段试验中，分别有 2.2%和 9.7%的巴洛沙韦治疗组出现聚合酶酸性蛋白变体 I38T/M/F 取代，这些取代导致对巴洛沙韦的敏感性降低。
单剂量巴洛沙韦无明显安全性问题，在缓解流感症状方面优于安慰剂，在开始试验治疗后 1 天降低病毒载量方面优于奥司他韦和安慰剂，在治疗后观察到对巴洛沙韦敏感性降低的证据。（由盐野义公司资助；日本药品临床试验信息中央机构编号，153090，CAPSTONE-1 临床试验.gov 编号，NCT02954354 ）。
