A first‐in‐human study of KMRC011, a potential treatment for acute radiation syndrome,to explore tolerability,pharmacokinetics, and pharmacodynamics

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.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Toll‐like receptor 5 (TLR5) can be a target for acute radiation syndrome (ARS), and KMRC011 is a novel TLR5 agonist being developed as a treatment for ARS. In animal models of irradiation, TLR5 agonists showed radioprotective and radiomitigative effect, and granulocyte colony‐stimulating factor (G‐CSF) and interleukin‐6 (IL‐6) have been proposed as efficacy biomarkers for TLR5 agonists. For further development, properties of KMRC011 including tolerability in humans need to be evaluated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does KMRC011, a novel TLR5 agonist, show acceptable safety profiles and clinically meaningful changes in efficacy biomarkers in healthy humans?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A single intramuscular administration of KMRC011 was tolerated in healthy humans. In addition, KMRC011 exerted TLR5 agonist‐like activities by increasing the levels of serum G‐CSF and IL‐6. As a result, KMRC011 demonstrates acceptable tolerability and preliminary activity in humans as well as animal models, and thus, KMRC011 may have the potential for a treatment for ARS.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our first‐in‐human study provided new clinical pharmacology information, such as safety and pharmacodynamics (PDs) of KMRC011 in humans. These findings are expected to be integrated with previous animal PD data, translate animal efficacy to humans, and ultimately contribute to the drug approval under the Animal Rule.