Abstract Details

Title CXCR7 antagonism with ACT-1004-1239 reduces Neuroinflammation and accelerates Remyelination in murine demyelinating models

Topic Multiple Sclerosis

Presentation(s) MS and CNS Inflammatory Disease Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 125

Objective In the current studies, the dual mode of action of ACT-1004-1239 was assessed in a therapeutic setting in two mouse models of MS. Furthermore, the pharmacokinetics (PK) and pharmacodynamics (PD) of ACT-1004-1239 were investigated in the blood and brain.

Background Targeting not only active inflammation but also demyelination and associated neurodegeneration remains a challenge for the treatment of inflammatory demyelinating diseases such as multiple sclerosis (MS). ACT-1004-1239 is a first-in-class, potent, and selective CXCR7 antagonist, currently investigated in phase I clinical trials (NCT03869320 and NCT04286750). In previous studies, prophylactic treatment with ACT-1004-1239 reduced both neuroinflammation and enhanced myelin repair in preclinical MS models.

Design/Methods ACT-1004-1239 was evaluated in the proteolipid protein (PLP)-induced EAE model, starting the treatment at the onset of disease. The PK and PD of ACT-1004-1239 given orally by gavage or food admix was measured in the blood and brain of EAE-diseased and naïve mice. In addition, the therapeutic effect of ACT-1004-1239 on remyelination was assessed in the cuprizone model, starting the treatment after completion of 5 weeks of cuprizone exposure.

Results In the PLP-induced EAE model, therapeutic treatment with ACT-1004-1239 significantly reduced EAE disease in a dose-dependent manner accompanied by reduced CNS T cell infiltrates and increased myelination. Efficacy of ACT-1004-1239 was associated with an increase in plasma CXCL11 and CXCL12 concentrations, valuable biomarkers of CXCR7 antagonism. Furthermore, ACT-1004-1239 was detected in the brain leading also to an increase in brain CXCL12 concentration. In the cuprizone-induced demyelination model, therapeutic treatment with ACT-1004-1239 significantly accelerated remyelination in vivo, already starting one week after cuprizone withdrawal.

Conclusions These results confirm the dual mode of action of ACT-1004-1239 in a therapeutic setting in murine models of MS, providing both an immunomodulatory effect by reducing neuroinflammation and promyelination by accelerating myelin repair.

Authors/Disclosures
Laetitia Pouzol (Idorsia Pharmaceuticals) PRESENTER	Laetitia Pouzol has received personal compensation for serving as an employee of Idorsia. Laetitia Pouzol has stock in Idorsia.
	No disclosure on file
Laetitia Pouzol (Idorsia Pharmaceuticals)	Laetitia Pouzol has received personal compensation for serving as an employee of Idorsia. Laetitia Pouzol has stock in Idorsia.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

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