Visterra Inc, 275 2nd Avenue, Waltham, MA 02451, USA.
Certara, Princeton, NJ, USA.
EBioMedicine. 2019 Feb;40:574-582. doi: 10.1016/j.ebiom.2018.12.051. Epub 2019 Jan 9.
VIS410, a broadly neutralizing monoclonal antibody that binds the hemagglutinin stem of influenza A viruses, was safe and efficacious in a human H1N1 virus challenge study. This study evaluated the safety and tolerability of VIS410 in non-hospitalized adult patients with uncomplicated influenza A.
Patients 18 to 65 years of age with symptom onset within 72 h were randomized 1:1:1 to receive a single intravenous infusion of VIS410 4000 mg, 2000 mg, or placebo. Neuraminidase inhibitor therapy was prohibited. Treatment-emergent adverse events (TEAEs) were evaluated up to 100 days post-infusion. Influenza symptoms were assessed daily for 10 days using the FLU-PRO tool. Nasopharyngeal virus shedding was assessed by quantitative reverse-transcription PCR (qRT-PCR) and viral culture through Day 7.
Of the 150 patients randomized, 148 received study drug, and 138 were confirmed influenza A positive. Median age was 42 years; median time from symptom onset to treatment was 42 h; 93% had influenza A subtype H3N2.
TEAEs, most commonly diarrhea of mild severity, were dose-related, occurring in 55%, 35%, and 24% of the 4000 mg, 2000 mg, and placebo patients, respectively. Two serious adverse events occurred, both in placebo patients.
Baseline FLU-PRO symptom scores were balanced among groups. Mean scores were lower by Days 3 and 4 in the pooled VIS410 treatment group versus placebo (p < 0.023), with a tendency toward faster resolution by Kaplan-Meier analysis.
VIS410 was associated with reduced median nasopharyngeal viral load TCID AUC (days × log TCID/mL) (3.66 pooled VIS410 vs 4.78 placebo, p = 0.08) and in the subset of patients with baseline hemagglutination inhibition (HAI) titer ≤40 (overall, 74% of patients) was significantly reduced vs placebo (4.218 pooled VIS410 vs 6.152 placebo, p = 0.009). Kaplan-Meier estimated time to resolution of viral shedding was reduced (1.9 vs 3.6 days, p = 0.03) in VIS410 treated patients. There was a trend toward greater proportion of culture-negative patients by Day 3 (66.7% vs 51.1%, p = 0.11); when this analysis was limited to the subset of patients with positive baseline cultures, this difference became more pronounced (63.2% vs 42.5%, p = 0.053). No differences were observed in nasopharyngeal influenza qRT-PCR profiles, which represent both live and neutralized virus.
VIS410 was safe and well tolerated in adults with uncomplicated influenza A, with favorable effects on symptom resolution and virus replication.
Clinical Trials: NCT02989194.
This project was funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201500018C.
VIS410 是一种广泛中和的单克隆抗体，可结合甲型流感病毒的血凝素茎，在人类 H1N1 病毒挑战研究中表现出安全性和有效性。本研究评估了 VIS410 在未住院的患有单纯性流感 A 成人患者中的安全性和耐受性。
症状出现后 72 小时内的 18 至 65 岁患者以 1:1:1 的比例随机接受单次静脉输注 VIS410 4000mg、2000mg 或安慰剂。禁止使用神经氨酸酶抑制剂治疗。直至输注后 100 天评估治疗出现的不良事件（TEAEs）。使用 FLU-PRO 工具每天评估流感症状 10 天。通过定量逆转录 PCR（qRT-PCR）和病毒培养评估鼻咽喉病毒脱落，直至第 7 天。
在 150 名随机分组的患者中，148 名接受了研究药物，138 名被确诊为甲型流感阳性。中位年龄为 42 岁；从症状出现到治疗的中位时间为 42 小时；93%的患者为甲型流感亚型 H3N2。
TEAEs，最常见的是轻度腹泻，与剂量有关，分别在 4000mg、2000mg 和安慰剂组中发生 55%、35%和 24%。2 例严重不良事件发生在安慰剂组患者中。
各组基线 FLU-PRO 症状评分均衡。与安慰剂相比，在合并 VIS410 治疗组中，第 3 和第 4 天的平均评分较低（p<0.023），通过 Kaplan-Meier 分析，有更快缓解的趋势。
VIS410 与降低中位鼻咽病毒载量 TCID AUC（天×log TCID/mL）相关（VIS410 为 3.66，安慰剂为 4.78，p=0.08），在基线血凝抑制（HAI）滴度≤40 的患者亚组中（总体上为 74%的患者），与安慰剂相比显著降低（VIS410 为 4.218，安慰剂为 6.152，p=0.009）。Kaplan-Meier 估计病毒脱落的时间缩短（1.9 天与 3.6 天，p=0.03）在 VIS410 治疗的患者中。第 3 天时，培养阴性患者的比例有增加的趋势（66.7%比 51.1%，p=0.11）；当将此分析仅限于基线培养阳性的患者亚组时，这一差异变得更加明显（63.2%比 42.5%，p=0.053）。未观察到鼻咽喉流感 qRT-PCR 谱的差异，这些谱代表活病毒和中和病毒。
VIS410 在患有单纯性流感 A 的成年人中是安全且耐受良好的，对症状缓解和病毒复制有有利影响。
临床试验：NCT02989194。
本项目部分由美国卫生与公众服务部；助理部长办公室为准备和应对工作；生物医学高级研究与发展局（BARDA），根据合同号 HHSO100201500018C 提供资金。
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