611. MT1980: translating anti-inflammatory and metabolic mechanisms into new treatment opportunities for schizophrenia

Abstract

Abstract Background Neuroinflammation contributes to the pathophysiology of schizophrenia in up to 50% of patients and is associated with the persistence of negative symptoms, a major unmet clinical need. Inflammatory activation of the kynurenine pathway disrupts dopaminergic and glutamatergic signalling, mechanisms central to negative symptom biology. Elevated inflammatory biomarkers (e.g., IL-6, CRP) and genomic evidence further implicate immune pathways. However anti-inflammatory compounds lack sufficient central nervous system penetration, limiting their therapeutic impact. MT1980 is a re-formulated brain penetrant PPAR-α agonist with additional anti-inflammatory actions, that also offers meaningful metabolic benefits—particularly relevant for schizophrenia patients, who experience high rates of metabolic syndrome and cardiovascular risk. Aims & Objectives To evaluate the CNS exposure and anti-inflammatory efficacy of MT1980 versus standard formulations to support its development as a novel treatment for inflammation-associated schizophrenia. Specifically, we aimed to characterise the pharmacokinetic and pharmacodynamic profile of MT1980 with a focus on CNS delivery and central target engagement; compare its anti-inflammatory effects with standard formulations at both peripheral and central levels, and assess safety, tolerability, and CNS exposure in humans. Method Preclinical pharmacokinetic and pharmacodynamic studies were conducted to characterise systemic and brain exposure of MT1980 relative to standard formulations. Anti-inflammatory activity was evaluated through assessment of cytokine modulation and microglial activation in an endotoxin-induced (LPS) neuroinflammation model. A Phase I clinical trial assessed safety, tolerability, pharmacokinetics, and measurement of MT1980 levels in cerebrospinal fluid. Planned next steps include a multiple-ascending-dose (MAD) study in healthy volunteers, and a proof-of-principle clinical study in schizophrenia patients with elevated inflammation and negative symptoms. Results MT1980 demonstrated improved systemic exposure and substantially enhanced brain penetration compared with standard formulations in preclinical studies. While both MT1980 and standard drug reduced peripheral inflammatory markers, only MT1980 significantly reduced inflammatory cytokine levels within brain tissue, consistent with effective central target engagement. Phase I studies showed excellent safety and tolerability, with evidence supporting CNS exposure. As a marketed lipid-modifying agent, MT1980 also offers established metabolic benefits, potentially providing a dual therapeutic opportunity in schizophrenia. Discussion & Conclusions MT1980 addresses a key limitation of prior anti-inflammatory approaches in psychiatry by combining effective blood–brain barrier penetration with central anti-inflammatory activity and metabolic benefit. Through PPAR-α–mediated modulation of neuroinflammation and downstream effects on kynurenine pathway activity, MT1980 has the potential to influence signalling relevant to negative symptoms, and possibly positive and cognitive symptom domains. These data support further development of MT1980 for inflammation-associated schizophrenia. We discuss the design for a proof-of-principle clinical study to evaluate efficacy signals in patients with schizophrenia, incorporating inflammatory and pharmacodynamic biomarkers to assess target and predict treatment response.