A Phase 1C, Open Label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of DM199 Administered Intravenously with a Polyvinyl Chloride Bag in Adult Healthy Subjects and Adults Recently Taking Angiotensin-Converting Enzyme Inhibitors

Abstract

This small phase 1C, open-label, single ascending dose study evaluated the safety, tolerability, and pharmacokinetics (PKs) of DM199, a recombinant form of human tissue kallikrein-1 (KLK1). A small sample size of both healthy subjects and hypertensive adults recently taking angiotensin-converting enzyme inhibitors was studied. KLK1 has a known role in vasodilation and blood flow regulation, with potential implications for treatment of acute ischemic stroke (AIS) by focally enhancing cerebral perfusion. A total of 12 subjects were enrolled; 9 healthy subjects received escalating doses of DM199 (0.1-0.5 µg/kg), while 3 hypertensive subjects received the maximum tolerated dose of 0.5 µg/kg. Safety assessments indicated that DM199 was well tolerated, with mild adverse events reported, such as headache and flushing. No infusion-related hypotensive events occurred, and all subjects completed the study without significant clinical issues. The study was performed following prior PK analyses revealing that DM199 exposure was greater when administered with polyvinyl chloride infusion materials compared with polyolefin infusion materials. This study supports a revised dosing strategy for DM199 in the ongoing ReMEDy2 trial for AIS and highlights the need for careful consideration of the risk-benefit profile in the clinical context of AIS treatment.

Keywords: ACE inhibitors; DM199; pharmacokinetics; phase 1C clinical trial; safety; tolerability.

Figure 1

Mean plasma concentrations of DM199 baseline versus time in Part A. Mean plasma concentrations of DM199 (ng/mL) are plotted against time (hours) up to 48 hours post‐administration. Three groups in Part A are represented: DM199 0.1 µg/kg (black), DM199 0.25 µg/kg (red), and DM199 0.5 µg/kg (blue). Data points represent mean values at each time point.

Figure 2

Mean plasma concentrations of DM199 baseline versus time in Part B. Mean plasma concentrations of DM199 (ng/mL) are plotted against time (hours) up to 48 hours post‐administration for the DM199 0.5 µg/kg dose group (blue). Data points represent mean values at each time point.