There are currently no approved disease-modifying osteoarthritis (OA) drugs (DMOADs). The aggrecanase ADAMTS-5 is key in the degradation of human aggrecan (AGC), a component of cartilage. Therefore, ADAMTS-5 is a promising target for the identification of DMOADs. We describe the discovery of GLPG1972/S201086, a potent and selective ADAMTS-5 inhibitor obtained by optimization of a promising hydantoin series following an HTS. Biochemical activity against rat and human ADAMTS-5 was assessed via a fluorescence-based assay. ADAMTS-5 inhibitory activity was confirmed with human aggrecan using an AGC ELISA. The most promising compounds were selected based on reduction of glycosaminoglycan release after interleukin-1 stimulation in mouse cartilage explants and led to the discovery of GLPG1972/S201086. The anticatabolic activity was confirmed in mouse cartilage explants (IC50 < 1.5 μM). The cocrystal structure of GLPG1972/S201086 with human recombinant ADAMTS-5 is discussed. GLPG1972/S201086 has been investigated in a phase 2 clinical study in patients with knee OA (NCT03595618).

Objective: A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. Methods: Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently-labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1a-stimulated glycosaminoglycan release in mouse femoral head cartilage explants, and on interleukin-1bstimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. Results: GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC 50 ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60e>5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 mM and 10 mM, respectively). In DMM mice, GLPG1972/S201086 (30e120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23 e37%), cartilage structural damage (23e39%) and subchondral bone sclerosis (21e36%). In MNX rats, GLPG1972/S201086 (10e50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6 e23%), and decreased proteoglycan loss (~27%) and subchondral bone sclerosis (77e110%). Conclusions: GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.

using an adapted version of the Downs and Black instrument. Data were extracted independently by two reviewers using a standardized form and a qualitative synthesis of the data was performed. Results: Of the 2,777 studies retrieved, 88 full-texts were assessed for eligibility and 34 studies met the inclusion criteria. Most studies investigated phenotypes based on a single patient or disease characteristic and only five studies included characteristics from more than one domain (e.g. clinical and imaging) to identify patients subgroups. Clinical phenotypes were investigated with the most frequency, followed by imaging, biochemical biomarkers, genetics and aetiologic phenotypes. Eight studies identified homogenous subgroups based on outcome trajectories (pain, function and joint space narrowing trajectories) and used a backwards approach to correlate these with baseline variables. Most studies assessed the statistical difference in outcomes across phenotypes, but few attempted to determine the clinical significance of the subgroups. Overall, phenotypes based on differences in sensory and psychological profile, comorbid conditions and radiographic severity were associated with distinct pain and/or function outcomes, while biochemical biomarkers phenotypes (of inflammation, bone and cartilage metabolism) were predominantly associated with different structural outcomes. Body mass index, gender and metabolic profile were, in general, associated with both clinical and structural outcomes. The prospective validity of the phenotypes using longitudinal outcomes was investigated only in a limited number of studies, and the majority of them did not assess stability or external validity of the phenotypes. Conclusions: There is marked heterogeneity in the data selected by the studies that defined possible knee OA phenotypes. Various classifications have been proposed using different approaches and only a few studies attempted to define a comprehensive phenotype classification. Nevertheless, there is evidence supporting the existence of etiologically distinct phenotypes that may also have prognostic and therapeutic implications. A framework for the investigation of phenotypes could be useful for future studies.

BackgroundDegradation of articular cartilage and alterations of the underlying subchondral bone are hallmarks of osteoarthritis (OA)1. A disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is a key aggrecan-cleaving enzyme involved in this pathogenic process from the earliest stages of cartilage degradation2 and as such, is an attractive drug target for the development of a disease-modifying OA drug (DMOAD)3.ObjectivesIn this report we describe the in vitro and in vivo characterization of the small molecule GLPG1972, an inhibitor of ADAMTS-5. GLPG1972 anti-catabolic activity was evaluated in murine and human cartilage explants and DMOAD activity was investigated in the destabilization of the medial meniscus (DMM) mouse model4.MethodsThe ADAMTS-5 biochemical assay is based on the cleavage of a fluorescent substrate by recombinant ADAMTS-5. Mouse femoral head cartilage explants were stimulated by interleukin-1a (IL-1a) for 3 days and GAG release quantified2b. Human articular cartilage explants were stimulated with IL-1β for 12 or 19 days and the NITEGE epitope quantified using the AGNx1 assay. Unilateral OA was induced in C57BL6 mice by DMM4. Mice were treated with vehicle or GLPG1972 at 30, 60 or 120 mg/kg, b.i.d. for 8 weeks. Medial femorotibial joint sections were scored by an evaluator blinded to treatment.ResultsGLPG1972 showed potent inhibition of human ADAMTS-5 (IC50=20 nM). Inhibition of ADAMTS-4 was moderate (IC50=57 nM), and selectivity over 100-fold was observed against a large panel of zinc metalloproteinases. GLPG1972 displayed potent anti-catabolic activity in cartilage explants, with IC50 values being 2 μM and <1 μM in mouse and human, respectively. In the DMM mouse model, GLPG1972 demonstrated DMOAD activity, as shown by significant reduction of femorotibial cartilage proteoglycan loss and cartilage damage score, as well as significant impact on subchondral bone sclerosis.ConclusionsGLPG1972 is an orally bioavailable, potent and selective ADAMTS-5 inhibitor showing significant anti-catabolic activity in cartilage explants. In the DMM model, treatment with GLPG1972 resulted in significant protective effects on both cartilage and subchondral bone pathology. Taken together these results provide support to progress GLPG1972 into the clinic as an oral treatment for OA.References Hunter, D.J., et al. Curr. Opin. Rheumatol. 2009, 21,110–117.a) Glasson, S.S., et al Nature. 2005, Vol 434: 644–8; b) Stanton, H., et al. Nature. 2005, Vol 434: 648–5; c) Little, C.B., et al. Journal of Clinical Investigation. 2007, Vol 117(6):1627–36.Larkin, J. et al. Osteoarthritis Cartilage. 2015, 23 (8): 1254–1266.Little, C.B. and Hunter, D.J. Nat. Rev. Rheumatol. 2013, 9(8):485–497. Disclosure of InterestNone declared

BackgroundAggrecan cleavage is an early process in cartilage degradation observed in OA. As a result, aggrecanase inhibition is an attractive therapeutic strategy for the treatment of OA.1 2 A disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is an aggrecanase playing a key role in the catabolic events leading to OA.3 We previously described the pharmacological characterisation of GLPG1972, a potent, selective and orally bioavailable ADAMTS-5 inhibitor showing anti-catabolic activity in cartilage explants and displaying disease-modifying OA drug (DMOAD) potential in the destabilisation of the medial meniscus (DMM) model in mice.4 5 ObjectivesIn this communication we report the activity of GLPG1972 in a second model of surgery-induced OA, the rat meniscectomy (MNX) model.6 MethodsOA pathology was induced by meniscectomy in the right hind leg of each rat. On day 1 post surgery, rats were randomly assigned to a treatment group (n=20 per group) according to their body weight. GLPG1972 was administered orally over 3 weeks at dose levels of 10, 25 and 50 mg/kg b.i.d. At sacrifice, the right tibias were collected and processed for histological analysis. OA development in the tibial plateau was evaluated using the OARSI score. The following structural parameters were measured by imaging histomorphometry analysis: subchondral bone plate thickness, proteoglycan content and fibrillation index. Blood samples were collected at steady state at predose, 1, 3 and 6 hour postdose for the determination of GLPG1972 plasma concentrations.ResultsThree weeks post-surgery, a significant reduction in OARSI score compared to vehicle-treated rats was observed with GLPG1972 at 25 and 50 mg/kg b.i.d. (−24% and −23%, respectively). Treatment with GLPG1972 also resulted in a significant reduction in cartilage fibrillation as of 25 mg/kg b.i.d. and prevented proteoglycan loss and subchondral bone plate thickening at all doses. At 25 mg/kg b.i.d. GLPG1972 average plasma concentration over 24 hour was found to be in line with the value observed in other rat MNX experiments (385 ng/mL). GLPG1972 bio-distribution in the target tissue was also determined: the average condyle to plasma ratio was found to be 0.14.ConclusionsOral dosing with GLPG1972 in rat MNX model resulted in significant chondroprotection confirming the DMOAD potential of GLPG1972. A Phase 1 first-in-human study was successfully completed with GLPG1972 (NCT02612246), and a dose-escalation Phase 1b study in OA patients is ongoing (NCT03311009). GLPG1972 is a promising OA drug candidate and a Phase 2 program is currently under preparation.References[1] Little CB, et al. J Clin Invest2007;117:1627–1636.[2] Larsson S, et al. Arthritis Res Ther2009;11:R92.[3] Fosang AJ. Osteoarthritis Cartilage2015;23(8):1231–1232.[4] Clement-Lacroix P, et al. OARSI congress2017.[5] Clement-Lacroix P, et al. EULAR congress2017.[6] Little CB, Smith MM. Curr RheumatoloRev2008;4:175–182.Disclosure of InterestNone declared

Purpose: Sprifermin, a novel recombinant human fibroblast growth factor-18, is currently being investigated as a potential disease-modifying osteoarthritis (OA) drug. Two-year results of the 5-year Phase II FORWARD study showed a statistically significant dose-dependent increase in total femorotibial joint (TFJ) cartilage thickness, as well as in the medial, lateral and central medial sub-region TFJ compartments by quantitative magnetic resonance imaging (qMRI). Here we report the results of the pre-specified 3-year analyses. Methods: Patients (pts) aged 40e85 years with symptomatic radiographic knee OA, Kellgren-Lawrence grade (KLG) 2 or 3, and medial Abstracts / Osteoarthritis and Cartilage 26 (2018) S10eS59 S26