Reporting on a Phase 1 Trial of a Drug to Suppress Inflammation in the Brain
Inflammation following injury in the brain causes much of the subsequent lasting damage. Further, chronic inflammation in the brain is an important aspect of the development of neurodegenerative disease. Judging from the direction of present research in the Alzheimer's community, it might be the most important mechanism driving these conditions. This may or may not be largely a matter of senescent cells in the brain; senolytic drugs have shown considerable promise in reversing pathology in animal models by destroying senescent supporting cells such as microglia and astrocytes. There are other ways in which the immune system can fall into a state of chronic inflammation beyond cellular senescence, however. Thus drugs that sabotage specific mechanisms of inflammation in the brain are under development at various stages; the ideal situation is not a blanket suppression, as inflammation is a necessary activity, but rather prevention of excessive or chronic inflammation.
Despite advances in our understanding of cellular and molecular neuroinflammatory mechanisms underlying adverse outcomes following injury, approved therapeutics that target this pathological process are lacking. 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 this medical need, we developed a small-molecule drug candidate, MW01-6-189WH, hereafter called MW189. MW189 was developed as a selective suppressor of injury- and disease-induced glial proinflammatory cytokine overproduction associated with destructive glial inflammation/synaptic dysfunction cycles, and their long-term neurotoxic effects.
MW189 is efficacious in vivo in animal models of acute brain injury, in which upregulation of proinflammatory molecules is implicated in disease progression. By attenuating the inflammatory responses of overstimulated glia, MW189 may limit the pathological progression and neurocognitive dysfunction that complicate a variety of central nervous system disturbances.
We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics 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
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.
An alternative approach would be to use montelukast orally. Works quite well as a brain anti inflammatory.
Off patent and cheap. 10mg/ day.
Hello, is there any senolytic in development to clear senescent cells in the brain ?