THU0138 Glpg0634m1, A Major Metabolite of the Jak1-Selective Inhibitor Glpg0634, is Also Jak1-Selective and Efficient in the Rat CIA Model
Authors: C. Belleville-Da-Costa, D. Merciris, B. Vayssière, N. Houvenaghel, A. Monjardet, L. Lepescheux, S. Dupont, T. Christophe, M. Borgonovi, P. Clément-Lacroix, C. Menet, L. Van Rompaey, R. Brys, R. Galien
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> GLPG0634 is a JAK inhibitor displaying a high selectivity for JAK1 over JAK2 in human whole blood assays. It is currently being developed as an oral treatment for rheumatoid arthritis (RA) and showed good efficacy and tolerability in two 4-week Phase 2a RA studies. GLPG0634 has a major metabolite, GLPG0634m1, with a half-life which might contribute to its clinical efficacy in RA patients. <h3>Objectives</h3> Characterize the pharmacological properties of the GLPG0634m1, its activity on JAK-driven pathways and its efficacy in the rat CIA (collagen-induced arthritis) model. <h3>Methods</h3> Selectivity of the metabolite GLPG0634m1 was measured <i>in vitro</i> in radiometric recombinant kinase assays and <i>ex vivo</i> in whole blood assays (human, dog and monkey) by monitoring STAT phosphorylation by flow cytometry. Rats with established arthritis were treated with the GLPG0634m1 molecule (60 mg/kg po, QD) or etanercept (10 mg/kg ip, 3 times a week). The clinical score as well as histological parameters were used to monitor/quantify disease progression. Plasma concentration of the molecule was quantified by LC-MS/MS. <h3>Results</h3> Biochemical analysis of potency of GLPG0634m1 on recombinant JAK kinases showed that this compound is 10-fold less active against JAK1 and JAK2 than GLPG0634 with IC<sub>50</sub>s of 546 nM and 624 nM, respectively. Potency on JAK3 and TYK2 over 3 μM indicates that this molecule is more selective for JAK1 and JAK2 compared to JAK3 and TYK2. In human whole blood assays (WBA), GLPG0634m1 inhibited a JAK1-dependent event (IL-6-induced STAT1 phosphorylation) with an IC<sub>50</sub> of 11.9 μM and a JAK2-dependent event (GMCSF-induced STAT5 phosphorylation) with an IC<sub>50</sub> exceeding 100 μM, revealing the &gt;10-fold selectivity of this molecule for JAK1 over JAK2. The JAK1 potency was confirmed with assays using IL2-induced STAT5 and IFNα-induced STAT1 phosphorylation, respectively triggering the JAK1/JAK3 and JAK1/TYK2 pathways. When given orally to rats with established arthritis, GLPG0634m1 displayed a pronounced efficacy comparable to etanercept, strongly reducing the impact of disease on e.g. paw swelling and Larsen score. These effects were confirmed at histological level with decreased pannus severity, bone and cartilage lesion as well as cell infiltration indexes. Plasma levels of GLPG0634m1 exceeded its WBA-derived JAK1 IC<sub>50</sub> but were far below its WBA-derived JAK2 IC<sub>50</sub>, implying that the metabolite efficacy in the CIA model is driven by JAK1 inhibition, as observed previously with the parent molecule. <h3>Conclusions</h3> While displaying a lower potency compared to its parent molecule, GLPG0634m1 has a similar JAK1 selectivity. Oral administration of this metabolite, albeit at a 10-times higher dose than GLPG0634, reduces inflammation in the rat CIA model to the same extent as parenteral etanercept, an effect that is supported by JAK1 inhibition but appears independent of JAK2 inhibition. These findings, together with the high exposure and long half-life of this metabolite observed in phase 1 and phase 2 clinical studies in humans, strongly suggest that it may contribute to the clinical efficacy of the parent compound GLPG0634 in RA. <h3>Disclosure of Interest</h3> : C. Belleville-Da-Costa Grant/research support: Abbvie, Employee of: Galapagos SASU, D. Merciris Grant/research support: Abbvie, Employee of: Galapagos SASU, B. Vayssière Grant/research support: Abbvie, Employee of: Galapagos SASU, N. Houvenaghel Grant/research support: Abbvie, Employee of: Galapagos NV, A. Monjardet Grant/research support: Abbvie, Employee of: Galapagos SASU, L. Lepescheux Grant/research support: Abbvie, Employee of: Galapagos SASU, S. Dupont Grant/research support: Abbvie, Employee of: Galapagos SASU, T. Christophe Grant/research support: Abbvie, Employee of: Galapagos NV, M. Borgonovi Grant/research support: Abbvie, Employee of: Galapagos SASU, P. Clément-Lacroix Grant/research support: Abbvie, Employee of: Galapagos SASU, C. Menet Grant/research support: Abbvie, Employee of: Galapagos NV, L. Van Rompaey Grant/research support: Abbvie, Employee of: Galapagos NV, R. Brys Grant/research support: Abbvie, Employee of: Galapagos NV, R. Galien Grant/research support: Abbvie, Employee of: Galapagos SASU <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4291