Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Korea.
Clin Transl Sci. 2021 Nov;14(6):2161-2170. doi: 10.1111/cts.13073. Epub 2021 Jun 10.
KMRC011 is a novel Toll-like receptor 5 agonist under development as a treatment for acute radiation syndrome (ARS). The aim of this first-in-human study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of a single intramuscular dose of KMRC011 in healthy subjects. A randomized, single-blind, placebo-controlled, single dose-escalation study was conducted with the starting dose of 5 μg. Eight (4 only for 5 μg cohort) subjects per cohort were randomly assigned to KMRC011 or placebo in a 3:1 ratio. Dose-limiting toxicity (DLT) was assessed throughout the study. Serum concentrations of KMRC011, granulocyte colony-stimulating factor (G-CSF), and interleukin-6 (IL-6) were measured up to 48 h postdose. Based on safety review, the dose of KMRC011 escalated up to 20 μg, and consequently, a total of 4 dose levels (5, 10, 15, and 20 μg) were explored. The most common adverse event was injection site reaction, showing no dose-related trend. Three DLTs (2 cases of hepatic enzyme increased and 1 of pyrexia) were observed; 1 in the 15 μg cohort and 2 in the 20 μg cohort. A developed method could not detect any KMRC011 in serum. KMRC011 15 μg and 20 μg showed significant increases of G-CSF, IL-6, and absolute neutrophil counts, compared with the placebo. A single intramuscular administration of KMRC011 ranging from 5 to 15 μg was tolerated in healthy subjects. Doses of KMRC011 equal to or greater than 15 μg exerted TLR5 agonist-like activities by increasing serum G-CSF and IL-6. It suggests that KMRC011 has the potential for a treatment for ARS.
KMRC011 是一种新型 Toll 样受体 5 激动剂，正在开发用于治疗急性辐射综合征 (ARS)。这项首次人体研究的目的是研究健康受试者单次肌内注射 KMRC011 的耐受性、药代动力学和药效学。这项研究采用随机、单盲、安慰剂对照、单剂量递增设计，起始剂量为 5μg。每个递增剂量组有 8 名（仅 5μg 组有 4 名）受试者，按 3:1 的比例随机分配至 KMRC011 或安慰剂组。在整个研究过程中评估剂量限制性毒性（DLT）。在给药后 48 小时内测量 KMRC011、粒细胞集落刺激因子 (G-CSF) 和白细胞介素-6 (IL-6) 的血清浓度。基于安全性审查，KMRC011 剂量递增至 20μg，因此共探索了 4 个剂量水平（5、10、15 和 20μg）。最常见的不良事件是注射部位反应，无剂量相关性趋势。观察到 3 例 DLT（2 例肝酶升高，1 例发热）；1 例发生在 15μg 组，2 例发生在 20μg 组。开发的方法无法检测到任何 KMRC011 血清浓度。与安慰剂相比，KMRC011 15μg 和 20μg 可显著增加 G-CSF、IL-6 和绝对中性粒细胞计数。健康受试者单次肌内注射 KMRC011 剂量为 5 至 15μg 可耐受。KMRC011 剂量等于或大于 15μg 可通过增加血清 G-CSF 和 IL-6 发挥 TLR5 激动剂样作用。这表明 KMRC011 有治疗 ARS 的潜力。
