Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
J Infect Dis. 2022 Jun 15;225(12):2087-2096. doi: 10.1093/infdis/jiaa716.
PC786 is a nebulized nonnucleoside respiratory syncytial virus (RSV) polymerase inhibitor designed to treat RSV, which replicates in the superficial layer of epithelial cells lining the airways.
Fifty-six healthy volunteers inoculated with RSV-A (Memphis 37b) were randomly dosed with either nebulized PC786 (5 mg) or placebo, twice daily for 5 days, from either 12 hours after confirmation of RSV infection or 6 days after virus inoculation. Viral load (VL), disease severity, pharmacokinetics, and safety were assessed until discharge. RSV infection was confirmed by reverse-transcription quantitative polymerase chain reaction with any positive value (intention-to-treat infected [ITT-I] population) or RSV RNA ≥1 log10 plaque-forming unit equivalents (PFUe)/mL (specific intention-to-treat infection [ITT-IS] population) in nasal wash samples.
In the ITT-I population, the mean VL area under the curve (AUC) was lower in the PC786 group than the placebo group (274.1 vs 406.6 log10 PFUe/mL × hour; P = .0359). PC786 showed a trend toward reduction of symptom score and mucous weight. In ITT-IS (post hoc analysis), the latter was statistically significant as well as VL AUC (P = .0126). PC786 showed an early time to maximum plasma concentration, limited systemic exposure, and long half-life and consequently a 2-fold accumulation over the 5-day dosing period. PC786 was well tolerated.
Nebulized PC786 demonstrated a significant antiviral effect against RSV, warranting further clinical study.
ClinicalTrials.gov: NCT03382431; EudraCT: 2017-002563-18.
PC786 是一种雾化的非核苷呼吸道合胞病毒（RSV）聚合酶抑制剂，旨在治疗 RSV，RSV 在气道上皮细胞的浅层复制。
56 名健康志愿者接种 RSV-A（孟菲斯 37b）后，随机接受雾化 PC786（5mg）或安慰剂，每天两次，共 5 天，分别在 RSV 感染后 12 小时或病毒接种后 6 天开始。评估病毒载量（VL）、疾病严重程度、药代动力学和安全性，直至出院。通过逆转录定量聚合酶链反应（RT-qPCR）检测，任何阳性值（意向治疗感染人群 [ITT-I]）或鼻洗液样本中 RSV RNA≥1log10 噬菌斑形成单位等效物（PFUe）/mL（特定意向治疗感染人群 [ITT-IS]）均确认 RSV 感染。
在 ITT-I 人群中，PC786 组的平均 VL 曲线下面积（AUC）低于安慰剂组（274.1 与 406.6 log10 PFUe/mL×小时；P=0.0359）。PC786 组症状评分和黏液重量有降低趋势。在 ITT-IS（事后分析）中，后者以及 VL AUC 也有统计学意义（P=0.0126）。PC786 表现出较早的达峰时间、有限的系统暴露、较长的半衰期，因此在 5 天的给药期间出现 2 倍的蓄积。PC786 耐受性良好。
雾化 PC786 对 RSV 具有显著的抗病毒作用，值得进一步的临床研究。
ClinicalTrials.gov：NCT03382431；EudraCT：2017-002563-18。
