Abstract Details

Title ACT-1004-1239, a first-in-class CXCR7 antagonist with both immunomodulatory and pro-myelinating effects, for the treatment of inflammatory demyelinating diseases

Topic Multiple Sclerosis

Presentation(s) S11 - MS Immunology and Basic Science (4:40 PM-4:48 PM)

Poster/Presentation
Number 005

Objective

Objectives: In the current studies, the therapeutic effect of ACT-1004-1239 in murine preclinical models of MS was evaluated.

Background Background: Current strategies for the treatment of demyelinating diseases such as multiple sclerosis (MS) are based on anti-inflammatory or immunomodulatory drugs. Those drugs have the potential to reduce the frequency of new lesions but do not directly promote remyelination in the damaged central nervous system (CNS). Targeting CXCR7 (ACKR3) has been postulated as a promising therapeutic approach in demyelinating diseases, leading to both immunomodulation by reducing leukocyte infiltrates and promyelination by enhancing myelin repair. Efforts to elucidate the complex role of CXCR7 in demyelinating diseases have been limited by the lack of potent small molecule CXCR7 antagonists. ACT-1004-1239 is a potent, selective, first-in-class, orally available, CXCR7 antagonist, currently being investigated in phase I clinical development (NCT03869320 and NCT04286750).

Design/Methods

Methods: The therapeutic effect of ACT-1004-1239 was evaluated in the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone-induced demyelination mouse models. In addition, ACT-1004-1239 was assessed in a rat oligodendrocyte precursor cell (OPC) differentiation assay in vitro.

Results In the MOG-induced EAE model, ACT-1004-1239 treatment showed a significant dose-dependent reduction in disease severity along with reduced CNS inflammation, reduced plasma neurofilament light chain concentration, and increased survival. Efficacy of ACT-1004-1239 directly correlated with an increase in plasma CXCL12 concentration, which was used as a biomarker for CXCR7 antagonism. Furthermore, in the cuprizone-induced demyelination model, ACT-1004-1239 treatment significantly increased the number of mature oligodendrocytes and enhanced myelination in vivo. In vitro, ACT-1004-1239 also promoted the maturation of OPCs into mature myelinating oligodendrocytes.

Conclusions The CXCR7 antagonist ACT-1004-1239 both reduced neuroinflammation and enhanced myelin repair in preclinical models of demyelinating neuropathy. Taken together, these studies substantiate the rationale to explore the therapeutic potential of ACT-1004-1239 in a clinical setting.

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
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