Abstract：
Hyperinflammation triggered by SARS-CoV-2 is a major cause of disease severity, with activated macrophages implicated in this response. OP-101, a hydroxyl-polyamidoamine dendrimer-N-acetylcysteine conjugate that specifically targets activated macrophages, improves outcomes in preclinical models of systemic inflammation and neuroinflammation. In this multicenter, randomized, double-blind, placebo-controlled, adaptive phase 2a trial, we evaluated safety and preliminary efficacy of OP-101 in patients with severe COVID-19. Twenty-four patients classified as having severe COVID-19 with a baseline World Health Organization seven-point ordinal scale of ≥5 were randomized to receive a single intravenous dose of placebo (n = 7 patients) or OP-101 at 2 (n = 6), 4 (n = 6), or 8 mg/kg (n = 5 patients). All study participants received standard of care, including corticosteroids. OP-101 at 4 mg/kg was better than placebo at decreasing inflammatory markers; OP-101 at 4 and 8 mg/kg was better than placebo at reducing neurological injury markers, (neurofilament light chain and glial fibrillary acidic protein). Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% (95% CI: 29%, 96%) for placebo and 18% (95% CI: 4%, 43%; P = 0.021) for the pooled OP-101 treatment arms. At 60 days, 3 of 7 patients given placebo and 14 of 17 OP-101-treated patients were surviving. No drug-related adverse events were reported. These data show that OP-101 was well tolerated and may have potential to treat systemic inflammation and neuronal injury, reducing morbidity and mortality in hospitalized patients with severe COVID-19.
摘要：
由SARS-CoV-2引发的过度炎症是疾病严重程度的主要原因，激活的巨噬细胞参与了这种反应。OP-101，一种羟基聚酰胺胺树状聚合物-N-乙酰半胱氨酸缀合物，特异性靶向活化的巨噬细胞，改善全身炎症和神经炎症的临床前模型的结局.在这个多中心，随机化，双盲,安慰剂对照,适应阶段2a试验，我们评估了OP-101在重症COVID-19患者中的安全性和初步疗效。24名被归类为重度COVID-19且基线世界卫生组织七点序数量表≥5的患者被随机分配接受单次静脉给药安慰剂(n=7名患者)或OP-101(n=6)，4（n=6），或8mg/kg（n=5名患者）。所有研究参与者都接受了标准护理，包括皮质类固醇.4mg/kg的OP-101在降低炎症标志物方面优于安慰剂；4和8mg/kg的OP-101在降低神经损伤标志物方面优于安慰剂，（神经丝轻链和神经胶质原纤维酸性蛋白）。治疗后30天和60天机械通气或死亡的复合结局的风险为71%(95%CI:29%,安慰剂为96％）和18％（95％CI：4％，43%；P=0.021），用于合并的OP-101治疗组。在60天，给予安慰剂的7例患者中有3例存活，接受OP-101治疗的17例患者中有14例存活。未报告与药物相关的不良事件。这些数据表明，OP-101具有良好的耐受性，可能具有治疗全身性炎症和神经元损伤的潜力。降低重症COVID-19住院患者的发病率和死亡率。
