Efficacy and safety of s201086/GLPG1972, an ADAMTS-5 inhibitor, in patients with knee osteoarthritis: roccella, a 52-week, randomized, double-blind, dose-ranging phase 2 study

Schnitzer, Thomas J.; Pueyo, Maria; Deckx, H.; Aar, Ellen van der; Bernard, Katy; Hatch, Sandra S.; Stoep, M. van der; Grankov, S.; Phung, De; Imbert, O.; Chimits, D.; Muller, Karine; Hochberg, Marc C.; Bliddal, Henning; Eckstein, F.; Conaghan, Philip G.

doi:10.1016/j.joca.2021.02.348

Cited by 5 publications

(3 citation statements)

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“…Medial JSN was observed to be a strong predictor of subsequent progression in this study, and cartilage damage was no longer associated with subsequent progression when including the presence of medial JSN as an additional predictor. It has also been successfully used before as a criterion in the Roccella DMOAD trial to enroll knees with accelerated cartilage loss (3,35). Still, the results from the current study showed that ~30% of the knees with a medial JSN grade of 1 had no cartilage damage at all in the weight‐bearing medial compartment.…”

Section: Discussionmentioning

confidence: 99%

Selection of Knees With Subsequent Cartilage Thickness Loss Based on Magnetic Resonance Imaging Semiquantitative Grading: Data From the Osteoarthritis Initiative Foundation for the National Institutes of Health Biomarker Cohort

Wirth

Maschek

Wisser

et al. 2023

Arthritis Care & Research

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Objective To investigate which magnetic resonance imaging (MRI)–based articular pathologies are predictive of subsequent medial femorotibial compartment quantitative cartilage thickness loss and therefore suitable for enrichment of clinical trials with participants showing a high likelihood for structural progression. Methods Semiquantitative MRI Osteoarthritis Knee Score (MOAKS) assessments at baseline and quantitative cartilage thickness measurements at baseline and year‐2 follow‐up were performed in 599 participants (age 62 years; body mass index 31 kg/m2; 59% female) from the Osteoarthritis Initiative–based Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium. Knees were classified as medial femorotibial compartment (MFTC) progressors or nonprogressors based on MFTC cartilage thickness change (smallest detectable change threshold −111 μm). Logistic regression was used to investigate the association between baseline presence and severity of MFTC MOAKS pathologies with subsequent MFTC progression. The standardized response mean (SRM) was computed to estimate the sensitivity to change that can be achieved when selecting knees based on MOAKS pathologies. Results Presence of MFTC MOAKS cartilage damage (odds ratio [OR] 2.77 [95% confidence interval (95% CI) 1.76, 4.36]), MFTC bone marrow lesions (OR 2.69 [95% CI 1.89, 3.83]), medial meniscus extrusion or damage (OR 2.21 [95% CI 1.37, 3.55]), as well as MOAKS severity subscales for cartilage and meniscus damage were associated with subsequent progression. The SRM was greater in knees with than in knees without the presence of these pathologies and was associated with the severity of those pathologies. Conclusion MRI‐based grading of articular pathologies makes it possible to specifically select progressor knees suitable for inclusion in clinical trials but also to identify knees in which treatment is not indicated (e.g., knees without cartilage damage despite presence of radiographic osteoarthritis).

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Section: Discussionmentioning

confidence: 99%

Selection of Knees With Subsequent Cartilage Thickness Loss Based on Magnetic Resonance Imaging Semiquantitative Grading: Data From the Osteoarthritis Initiative Foundation for the National Institutes of Health Biomarker Cohort

Wirth

Maschek

Wisser

et al. 2023

Arthritis Care & Research

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“…Radiographic JSN scores [ 93 ] have been reported to be a strong predictor of cartilage loss in the narrowed compartment [ 94 ]. They have recently been successfully used in combination with KL grades to enrich the population of the ROCCELLA trial with knees likely to show medial compartment progression [ 38 , 95 ], but are not only affected by cartilage status but also by meniscus integrity and extrusion [ 10 ].…”

Section: Predictors Of Structural Progressionmentioning

confidence: 99%

“…ROCCELLA was a 52-week, randomized, double-blind phase 2 study that evaluated the efficacy and safety of s201086/GLPG1972 as a potential DMOAD in 932 knee OA patients [ 38 , 95 ]. By enrolling patients with KLG 2 or 3 in combination with the presence of medial JSN 1 or 2, the study successfully enrolled knees with a sufficient loss in cartilage thickness to enable assessment of a structural benefit of s201086/GLPG1972 vs. placebo over 52 weeks.…”

Section: Overview Over Recent Clinical Trialsmentioning

confidence: 99%

Quantitative measurement of cartilage morphology in osteoarthritis: current knowledge and future directions

Wirth

Ladel²,

Maschek

et al. 2022

Skeletal Radiol

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Quantitative measures of cartilage morphology (“cartilage morphometry”) extracted from high resolution 3D magnetic resonance imaging (MRI) sequences have been shown to be sensitive to osteoarthritis (OA)-related change and also to treatment interventions. Cartilage morphometry is therefore nowadays widely used as outcome measure for observational studies and randomized interventional clinical trials. The objective of this narrative review is to summarize the current status of cartilage morphometry in OA research, to provide insights into aspects relevant for the design of future studies and clinical trials, and to give an outlook on future developments. It covers the aspects related to the acquisition of MRIs suitable for cartilage morphometry, the analysis techniques needed for deriving quantitative measures from the MRIs, the quality assurance required for providing reliable cartilage measures, and the appropriate participant recruitment criteria for the enrichment of study cohorts with knees likely to show structural progression. Finally, it provides an overview over recent clinical trials that relied on cartilage morphometry as a structural outcome measure for evaluating the efficacy of disease-modifying OA drugs (DMOAD).

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Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5

Clément-Lacroix

Little

Smith

et al. 2022

Osteoarthritis and Cartilage

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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.

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Efficacy and safety of s201086/GLPG1972, an ADAMTS-5 inhibitor, in patients with knee osteoarthritis: roccella, a 52-week, randomized, double-blind, dose-ranging phase 2 study

Cited by 5 publications

References 0 publications

Selection of Knees With Subsequent Cartilage Thickness Loss Based on Magnetic Resonance Imaging Semiquantitative Grading: Data From the Osteoarthritis Initiative Foundation for the National Institutes of Health Biomarker Cohort

Selection of Knees With Subsequent Cartilage Thickness Loss Based on Magnetic Resonance Imaging Semiquantitative Grading: Data From the Osteoarthritis Initiative Foundation for the National Institutes of Health Biomarker Cohort

Quantitative measurement of cartilage morphology in osteoarthritis: current knowledge and future directions

Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5

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