First in-human study of drug targeting brain inflammation supports further development

Summary: MW189, a small molecule drug candidate, blocks abnormal inflammation in the brain which contributes to injury and disease-induced neurological impairments.

Source: University of Kentucky

Linda J. Van Eldik, director of the Sanders-Brown Center on Aging at the University of Kentucky, co-authored a paper reporting the first human clinical study of a drug candidate that suppresses injury and disease-induced inflammation of the brain.

The paper was accepted in February by Clinical Pharmacology in Drug Development and the article published online this week. Clinical Pharmacology in Drug Development is an international, peer-reviewed, online publication focused on publishing high-quality clinical studies, especially those presenting first-time in-human study results.

The article explains how acute brain injuries resulting from trauma or cerebrovascular injury, such as traumatic brain injury (TBI) and intracerebral hemorrhage (ICH), are major medical problems that cause substantial mortality and neurologic damage. The authors state in the article, “Although there have been significant advances in the medical management of patients with acute brain injuries, there is a clear and urgent need for interventions that improve neurologic recovery and outcomes.”

To address that need, a small-molecule drug candidate now known as MW189 was developed. MW189 blocks abnormal inflammation in the brain that is known to contribute to injury- and disease-induced neurologic impairments in a number of acute and chronic brain disorders. This study examining MW189 in healthy adult volunteers was performed by a collaborative team from UK, Duke University, and Northwestern University. The work by Van Eldik and the rest of the team is substantial as it is the first time MW189 had been tested in humans. The study was open to healthy men and women between the ages of 18 and 50 years.

The article reports that MW189 was safe and well-tolerated by volunteers, with no clinically significant concerns after either a single dose or multiple administrations of MW189. “This is an important result,” said Van Eldik, “because in order to get future FDA approval of any drug for patients, the drug candidate first has to be tested and shown to be safe in healthy volunteers.” Van Eldik goes on to say “overall, these studies support further development of MW189 for treatment of patients with acute brain injuries such as TBI or hemorrhagic stroke.”

Funding: The study was supported in part by an Alzheimer’s Association Part the Cloud grant.

About this neuroscience research article

Source:
University of Kentucky
Media Contacts:
Hillary Smith – University of Kentucky
Image Source:
The image is in the public domain.

Original Research: Open access
“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”. Linda J. Van Eldik et al.
Clinical Pharmacology in Drug Development doi:10.1002/cpdd.795.

Abstract

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

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.

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