GLPG1972: a potent, selective, orally available adamts-5 inhibitor for the treatment of OA

Abstract

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.

Recent progress on the role of miR-140 in cartilage matrix remodelling and its implications for osteoarthritis treatment

“…A fine-tuned balance exists between proteases and their inhibitors to maintain articular cartilage integrity. To date, a few inhibitors that target MMP-2 [22], MMP-13 [23,24], ADAMTS-4 [25] and ADAMTS-5 [26] have been found to be effective in explants or rodent models. Several selective inhibitors targeting ADAMTS-4, and ADAMTS-5 have reached clinical trials in OA [27].…”

The Anti-ADAMTS-5 Nanobody® M6495 Protects Cartilage Degradation Ex Vivo

“…Lastly, the GSK2394002 was terminated in the preclinical phase after increased arterial pressure and elevated ST was observed in cynomolgus monkey [ 31 ]. These ADAMTS-5 inhibitors have all shown to inhibit aggrecan degradation in cartilage explant cultures and/or mouse models [ 12 , 32 , 33 ]. GSK2384002 and GLPG1972 have shown to decrease ARGS in human OA cartilage explants or OA patients [ 12 , 34 ].…”

“…GSK2384002 and GLPG1972 have shown to decrease ARGS in human OA cartilage explants or OA patients [ 12 , 34 ]. Similar to M6495, GLPG1972 decreased exAGNxI in a dose-dependent manner in human cartilage explants [ 32 ]. GSK2384002 decreased the ARGS epitope in human cartilage in the same manner as M6495 in the current study [ 12 ].…”

From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside

“…GLPG1972/S201086 confirmed the important protective effect on cartilage and subchondral bone in posttraumatic OA by remarkably diminishing cartilage proteoglycan loss, cartilage impairment, and subchondral bone sclerosis. Furthermore, the safety parameters evaluated indicated that the drug was well tolerated [ 30 ]. A Phase II trial assessing the efficacy and safety of 3 doses of per os GLPG1972/ S201086 once daily in patients with knee OA was completed in July 2020, yet the final results have yet to be reported [ 31 ].…”

“…TPX-100, a peptide derived from matrix extracellular phosphoglycoprotein (MEPE), has expressed positive function when inducing articular cartilage regeneration in animal models. It is considered that this molecule facilitates cartilage formation only in areas with defects, without ectopic bone tissue formation [ 30 ].…”