Safety, tolerability and pharmacokinetic profile of recombinant human tissue kallikrein, DM199, after intravenous and subcutaneous administration in healthy volunteers

Abstract

<p class="abstract"><strong>Background:</strong> DM199 is a recombinant form of human tissue kallikrein (KLK1) that is being developed for ischemia-related diseases such as acute ischemic stroke. KLK1 is an important serine protease that promotes vasodilation and microcirculation in multiple tissues. Preclinical stroke studies demonstrate that KLK1 treatment promotes vasodilation, angiogenesis, prevents inflammation, and cerebral cell death<span lang="EN-IN">. </span></p><p class="abstract"><strong>Methods:</strong> The safety and tolerability, as well as the pharmacokinetic profile of DM199 was investigated in a Phase 1B clinical trial following an intravenously (IV) or subcutaneous (SC) administration. Part A was a single ascending IV infusion of DM199 and Part B involved a single IV infusion and single SC dose in two different groups<span lang="EN-IN">.</span></p><p class="abstract"><strong>Results:</strong> For both routes of administration, DM199 was found to be safe and well tolerated at all doses given, albeit the PK profile differed between routes with respect to the time to maximum concentration and plasma half-life. Importantly, DM199 did not influence blood coagulation parameters, suggesting it could be safely used with other stroke treatments like tPA<span lang="EN-IN">. </span></p><p class="abstract"><strong>Conclusions:</strong> Together, these results support the design of future studies to test the efficacy of DM199 in ischemic related diseases including in acute ischemic stroke (AIS).</p>

Human urinary kallidinogenase in acute ischemic stroke: A single‐arm, multicenter, phase IV study (RESK study)

“…Thus, these events, especially BP reduction, should be alert and focused on in clinical practice. However, a small number (15.47%) of patients experienced drug‐related AEs, and among them, only 2.82% (incidence of 1.58%) were definitely drug‐related, which was similar to the results of DM199 21 . Unexpectedly, the study reported 3 unexpected events with high frequency.…”

“…However, a small number (15.47%) of patients experienced drug‐related AEs, and among them, only 2.82% (incidence of 1.58%) were definitely drug‐related, which was similar to the results of DM199. 21 Unexpectedly, the study reported 3 unexpected events with high frequency. However, no severe unexpected AEs occurred.…”

Human tissue kallikrein in the treatment of acute ischemic stroke

“…In a recently published phase I clinical trial investigating the safety and pharmacokinetic (PK) profile of DM199 showed positive results. 108 DM199 was safe and well tolerated when administered by either subcutaneous injection or intravenous infusion. This study successfully identified a dose of DM199 that generated plasma concentrations similar to that of the standard intravenous dose of uKLK1 used in China (0.15 PNAU 109 ).…”

“…DM199 treatment had no effect on blood coagulation times, which suggests that it could also be safely administered to patients who have previously received tPA treatment. 108 DM199 has the same amino acid sequence, biochemical activity and pathophysiological effects as uKLK1 but requires no human tissue and is significantly more convenient to produce. Results from the DM199 clinical trial suggest a safer and more convenient administration profile for AIS patients in the hospital and at home given its superior PK profile.…”