Evaluation of Intranasal TLR2/6 agonist INNA-051: Safety, Tolerability and Proof of Pharmacology

F. Mercuri, Scott White, Hayley A McQuilten, Charlotte Lemech, Stephan Mynhardt, Rana Hari, Ping Zhang, Nicole Kruger, Grant Mclachlan, Bruce.E Miller, Nicholas P. West, R. Tal-Singer, Christophe Demaison
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Abstract

Local priming of the innate immune system with a TLR2/6 agonist may reduce morbidity and mortality associated with viral respiratory tract infections, particularly for the elderly and those with chronic diseases.To understand the potential of prophylactic treatment with a TLR2/6 agonist as an enhancer of innate immunity pathways leading to accelerated respiratory virus clearance from the upper airways.Two randomized, double-blind, placebo-controlled clinical trials were conducted in healthy adult participants. The first dose-escalation study assessed safety, tolerability and mechanistic biomarkers following single and repeated intranasal administrations of INNA-051. The second was an Influenza A viral challenge study assessing the impact of treatment on host defence biomarkers and viral load.INNA-051 was well tolerated in both studies, with no dose-limiting toxicities identified. Mechanistic biomarkers assessed in both studies demonstrated the expected engagement of pharmacology, including innate immune pathways. There were lower than anticipated rates of infection. Post hoc analysis conducted in laboratory-confirmed infected participants with low or no antibody titre against the challenge virus showed INNA-051 treatment led to significantly shorter duration of infection and increased expression of genes and pathways associated with host defence responses against influenza.The safety and pharmacology profile of INNA-051 confirms preclinical studies. INNA-051 increased expression of genes and pathways associated with host defence responses against influenza and was associated with shorter duration of infection. These studies support further clinical assessment in the context of natural viral respiratory tract infections in individuals at increased risk of severe illness.
鼻内 TLR2/6 激动剂 INNA-051 的评估:安全性、耐受性和药理学证明
为了了解TLR2/6激动剂作为先天性免疫途径的增强剂,可加速上呼吸道呼吸道病毒清除的预防性治疗潜力,我们在健康成人参与者中开展了两项随机、双盲、安慰剂对照临床试验。第一项剂量递增研究评估了INNA-051单次和多次鼻内给药后的安全性、耐受性和机理生物标志物。第二项是甲型流感病毒挑战研究,评估治疗对宿主防御生物标志物和病毒载量的影响。在这两项研究中,INNA-051的耐受性良好,未发现剂量限制性毒性。两项研究中评估的机理生物标志物都显示了预期的药理作用,包括先天性免疫途径。感染率低于预期。对实验室确诊的感染者进行的事后分析表明,INNA-051治疗可显著缩短感染持续时间,并增加与宿主防御流感反应相关的基因和通路的表达。INNA-051增加了与宿主防御流感反应相关的基因和通路的表达,并缩短了感染持续时间。这些研究支持在自然病毒性呼吸道感染情况下对重症风险增加的个体进行进一步临床评估。
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