Antiviral Activity of TMC353121, a Respiratory Syncytial Virus (RSV) Fusion Inhibitor, in a Non-Human Primate Model

BackgroundThe study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI).MethodsAfrican green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n=15; Group 1: prophylactic arm [Px50], 0.033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 24 hours pre-infection to 10 days; Group 2: therapeutic arm [Tx50], 0.033mg/mL TMC353121 from 24 hours postinfection to 8 days; Group 3: control [Vh1] vehicle, 24 hours post-infection to 8 days). Study 2 evaluated the prophylactic efficacy of TMC353121 at target plasma levels of 5 and 500 ng/mL (n=12; Group 1: prophylactic 5 arm [Px5], 0.0033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 72 hours pre-infection to 14 days; Group 2: prophylactic 500 arm [Px500], 0.33 mg/mL TMC353121; Group 3:control [Vh2] vehicle, 14 days). Bronchoalveolar lavage fluid and plasma were collected every 2 days from day 1 postinfection for pharmacokinetics and safety analysis.FindingsTMC353121 showed a dose-dependent antiviral activity, varying from 1log10 reduction of peak viral load to complete inhibition of the RSV replication. Complete inhibition of RSV shedding was observed for a relatively low plasma exposure (0.39 μg/mL) and was associated with a dose-dependent reduction in INFγ, IL6 and MIP1α. TMC353121 administered as CI for 16 days was generally well-tolerated.ConclusionTMC353121 exerted dose-dependent antiviral effect ranging from full inhibition to absence of antiviral activity, in a preclinical model highly permissive for RSV replication. No new safety findings emerged from the study.

研究背景：本研究在一种病毒脱落模式与人类相似的临床前非人灵长类攻毒模型中，评估了呼吸道合胞病毒（RSV）融合抑制剂TMC353121经连续输注（CI）后的抗病毒活性。

研究方法：两项研究均通过连续输注方式给予非洲绿猴TMC353121。研究1评估了靶血浆浓度为50 ng/mL的TMC353121的预防与治疗效果（n=15；组1：预防性给药组[Px50]，给药浓度0.033 mg/mL TMC353121，流速2.5 mL/kg/h，给药时间为感染前24小时至感染后10天；组2：治疗性给药组[Tx50]，给药浓度0.033 mg/mL TMC353121，给药时间为感染后24小时至感染后8天；组3：对照组[Vh1]，给予赋形剂，给药时间为感染后24小时至8天）。研究2评估了靶血浆浓度分别为5 ng/mL与500 ng/mL的TMC353121的预防效果（n=12；组1：预防性给药5组[Px5]，给药浓度0.0033 mg/mL TMC353121，流速2.5 mL/kg/h，给药时间为感染前72小时至感染后14天；组2：预防性给药500组[Px500]，给药浓度0.33 mg/mL TMC353121；组3：对照组[Vh2]，给予赋形剂，给药周期为14天）。自感染后第1天起，每2天采集支气管肺泡灌洗液与血浆，用于药代动力学与安全性分析。

研究结果：TMC353121呈现出剂量依赖性的抗病毒活性，其效应范围从病毒载量峰值降低1log₁₀到完全抑制RSV复制不等。在相对较低的血浆暴露量（0.39 μg/mL）下即可观察到RSV脱落完全被抑制，且该效应伴随干扰素γ（INFγ）、白细胞介素6（IL6）与巨噬细胞炎性蛋白1α（MIP1α）的剂量依赖性降低。连续输注给药16天的TMC353121整体耐受性良好。

研究结论：在RSV复制高度易感的临床前模型中，TMC353121展现出剂量依赖性的抗病毒效应，效应范围从完全抑制到无抗病毒活性。本研究未发现新的安全性相关发现。