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Abstract Number: 1015

Preclinical Investigation of the First-in-Class SIK2/SIK3 Inhibitor GLPG3970 in Models of Arthritis

Catherine Jagerschmidt1, Stephanie Lavazais1, Maikel Colli2, Michael Drennan2, Erik Verschueren2, David Amantini1, Nicolas Desroy1 and Steve De Vos2, 1Galapagos SASU, Romainville, France, 2Galapagos NV, Mechelen, Belgium

Meeting: ACR Convergence 2021

Keywords: Mouse Models, RA, Psoriatic arthritis, rheumatoid arthritis

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Session Information

Date: Monday, November 8, 2021

Session Title: RA – Animal Models Poster (1014–1021)

Session Type: Poster Session C

Session Time: 8:30AM-10:30AM

Background/Purpose: Improved management of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) remains an unmet need. Salt-inducible kinases (SIKs) modulate immune cells by a dual mechanism of action (MoA) in inflammatory conditions.1–3 SIK2/SIK3 inhibition governs a molecular transcriptional switch resulting in reduced expression of pro-inflammatory mediators coupled with enhanced immunoregulatory activity. GLPG3970 is a first-in-class SIK2/SIK3 inhibitor in development for inflammatory indications. We evaluated the therapeutic activity of GLPG3970 in murine arthritis models.

Methods: GLPG3970’s selectivity and potency were profiled in biochemical and target-based cell assays. The dual MoA of SIK2/SIK3 inhibition with GLPG3970 was evaluated in LPS-stimulated human whole blood measuring TNFα and IL-10 release and by performing RNA sequencing. Functional enrichment analysis of KEGG pathways among the differentially expressed genes (DEGs) was performed using a standard hypergeometric test.

Three doses of GLPG3970 treatment were evaluated in two murine models of arthritis: the IL23-induced PsA model and the collagen-induced-arthritis (CIA) model. First, B10.RIII mice received hydrodynamic i.v. injection of 0.1 µg mIL-23 enhanced Episomal Expression Vector to induce PsA disease. Efficacy of 5 weeks of treatment with GLPG3970 was evaluated by clinical score analysis and X-ray imaging (analysis of osteophyte formation). Inflammatory mediators were quantified in paws. Second, in the CIA model, DBA1J mice were classically immunized with a type II bovine collagen emulsion on day 1 and day 21. Efficacy of GLPG3970 treatment from day 32–47 was compared with an anti-TNF agent (Enbrel®) and evaluated by clinical score analysis and bone erosion (Larsen score after X-ray imaging). Anti-collagen type-II antibodies were quantified in serum.

Results: GLPG3970 was shown to inhibit SIK2/SIK3 with high selectivity against a panel of 372 kinases. Activity in LPS-stimulated whole blood led to dose-dependent reduction of TNFα levels coupled with increased IL-10 release (Fig 1). GLPG3970 DEGs in LPS-stimulated whole blood were functionally enriched with RA as part of the top 3 most statistically significant pathways from the KEGG database. GLPG3970 treatment in the PsA model decreased clinical score (Fig 2), osteophyte formation and pro-inflammatory mediators. GLPG3970 reduced clinical score in the CIA model (Fig 3). The highest dose effect was comparable with anti-TNF treatment and correlated with reduced Larsen score and anti-collagen type-II antibody levels.

Conclusion: This study associates the underlying mechanism of SIK2/SIK3 inhibition with RA and highlights the therapeutic activity of GLPG3970 in murine arthritis models, supporting GLPG3970 as a promising novel approach for the treatment of arthritis. GLPG3970 is being tested in a phase 2a study in patients with RA (NCT04577781).

References
1. Clark K et al. PNAS 2012;109:16986–91.
2. Lombardi M et al. J Leukoc Biol 2016;99:711–21.
3. Darling N et al. Biochem J 2017;474:521–37.

Figure 1: GLPG3970 activity in LPS-stimulated human whole blood assay (mean values, n=52, healthy donors)

Figure 2: Clinical score over time in PsA model (IL_23 induced)

Figure 3: Clinical score over time in RA model (therapeutic CIA model)


Disclosures: C. Jagerschmidt, Galapagos NV, 3; S. Lavazais, Galapagos NV, 3; M. Colli, Galapagos NV, 3; M. Drennan, Galapagos NV, 3; E. Verschueren, Galapagos NV, 3; D. Amantini, Galapagos NV, 3; N. Desroy, Galapagos NV, 3; S. De Vos, Galapagos NV, 3.

To cite this abstract in AMA style:

Jagerschmidt C, Lavazais S, Colli M, Drennan M, Verschueren E, Amantini D, Desroy N, De Vos S. Preclinical Investigation of the First-in-Class SIK2/SIK3 Inhibitor GLPG3970 in Models of Arthritis [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/preclinical-investigation-of-the-first-in-class-sik2-sik3-inhibitor-glpg3970-in-models-of-arthritis/. Accessed June 1, 2023.
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