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

Clinical Pharmacology in Drug Development, 2021 · DOI: 10.1002/cpdd.795 · Published: March 1, 2021

Simple Explanation

This research investigates a new drug, MW189, designed to reduce inflammation in the brain. The study aimed to determine if MW189 is safe and how the body processes it. Healthy volunteers were given single and multiple doses of MW189, and their safety, tolerability, and how their bodies processed the drug were monitored. The effects of MW189 on inflammatory markers were also measured. The study found that MW189 was generally safe and well-tolerated. It also demonstrated potential to modulate inflammatory responses, suggesting it warrants further investigation for treating acute brain injuries.

Study Duration

Not specified

Participants

Healthy adult volunteers

Evidence Level

Level 1, Phase 1 clinical trials (SAD, MAD, Endotoxin study)

Key Findings

1
MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with infusion-site reactions being the most common adverse event.
2
Pharmacokinetic analysis showed dose-proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation.
3
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.

Research Summary

This study reports the first clinical experience with MW189, a novel CNS-penetrant small molecule that selectively suppresses injury- and disease-induced glial proinflammatory cytokine overproduction. The phase 1a SAD and phase 1b MAD trials demonstrated that single and multiple intravenous doses of MW189 in healthy adult volunteers were well tolerated, with no clinical or laboratory safety signals of potential clinical concern. The PK analyses of MW189 showed approximately linear kinetics, dose proportionality, no significant accumulation after multiple doses, a sufficiently long half-life for twice-daily dosing, and steady state achieved by dose 3 for all dosing cohorts.

Practical Implications

Further development for brain injuries

The safety, PK properties, and pharmacodynamic effects of MW189 support further development for treating patients with acute brain injuries like TBI or hemorrhagic stroke.

Optimizing Intravenous Delivery

The infusion-related adverse events suggest a need to optimize the method of intravenous drug delivery in future studies.

Twice-Daily Dosing

The PK parameters support a twice-daily intravenous dosing regimen in future clinical studies, which is relevant for practical application.

Study Limitations

1
The pilot endotoxin study was not powered for efficacy, but was designed as an initial screen in humans.
2
Infusion-related reactions such as pain in extremity, infusion-site pain, or mild phlebitis, were observed as a primary TEAE-related safety issue.
3
Healthy young adult subjects is not feasible, as cytokine levels are constitutively low in the absence of an inflammatory trigger, and these basal physiological levels of cytokines are not suppressed by MW189.

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