First-in-Human Studies of MW01-6-189WH, a Brain-Penetrant, Antineuroinflammatory Small-Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Studies in Healthy Adult Volunteers

Abstract

MW01-6-189WH (MW189) is a novel central nervous system-penetrant small-molecule drug candidate that selectively attenuates stressor-induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose-proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low-dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF-α and higher levels of the anti-inflammatory cytokine IL-10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury.

Keywords: brain injury; cytokine; neuroinflammation; pharmacodynamics; pharmacokinetics; phase 1.

Conflict of interest statement

L.V.E. and D.M.W. are inventors on the patents covering MW189. L.V.E. is a scientific founder of ImmunoChem Therapeutics, LLC, a Northwestern spin‐out formed to commercialize MW189. Northwestern University and the University of Kentucky might benefit if MW189 is successful commercially. J.T.G. is supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K23NS085049.

© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Chemical structure of MW189. 6‐Phenyl‐4‐(pyridin‐4‐yl)‐3‐(4‐(pyrimidin‐2‐yl)piperazin‐1‐yl)pyridazine (CAS #886208‐76‐0) has an empirical formula of C23H21N7 and a molecular weight of 395.47.

Figure 2

MW189 plasma concentration‐time profiles and dose‐proportional increases in exposure following single ascending doses of MW189. Four escalating doses (0.025, 0.05, 0.10, 0.25 mg/kg) of MW189 were administered as a single intravenous infusion. (A) The mean ± SD concentrations (ng/mL) of MW189 versus time after the dosing (hours) are plotted on a log‐linear scale. The inset graph shows an expansion of the data for the first 4 hours after dosing, plotted on a linear scale. (B) The mean ± SEM of Cmax (maximum observed concentration) and AUC0‐inf (area under the concentration‐time curve from time zero to infinity [extrapolated]) parameters are plotted versus increasing single doses of MW189. Linear regression analyses are consistent with dose proportionality.

Figure 3

MW189 plasma concentration‐time profiles following multiple ascending doses of MW189. Four escalating doses (0.075, 0.15, 0.25, and 0.30 mg/kg) of MW189 were administered by intravenous infusion every 12 hours over 5 days. The mean concentrations (ng/mL) of MW189 versus time after the dosing (hours) are plotted on a log‐linear scale.

Figure 4

Plasma cytokine levels following endotoxin challenge and MW189 administration. Healthy adult male volunteers were administered a single intravenous dose of MW189 (0.25 mg/kg) or matched placebo, followed immediately by a single intravenous injection of low‐dose endotoxin (LPS, 2 ng/kg) to induce increases in plasma cytokine levels. Blood was collected over a 12‐hour period after the LPS challenge, and plasma cytokines were measured by ELISA (8 MW189, 8 placebo). Mean ± SEM plasma levels (pg/mL) are shown for (A) IL‐10 and (B) TNF‐α. Note that MW189 treatment increases the anti‐inflammatory cytokine IL‐10 level and decreases the proinflammatory cytokine TNF‐α level compared with placebo treatment. The inset graph in (B) shows an expansion of the data for the last 4 times (4, 6, 8, and 12 hours). *Statistically significant difference between MW189 and placebo groups.