GLPG1972

GLPG1972 (also known as S201086 or Aldumastat) is a **potent, selective, and orally available small molecule inhibitor** of **ADAMTS-5** (a disintegrin and metalloproteinase with thrombospondin motifs 5), a key aggrecanase enzyme responsible for the degradation of aggrecan, a critical component of articular cartilage. Developed by **Galapagos** in collaboration with **Servier**, GLPG1972 was designed as a potential **first-in-class disease-modifying osteoarthritis drug (DMOAD)**. The compound demonstrates an **IC50 of 19 nM** against human ADAMTS-5 and shows **8-fold selectivity** over ADAMTS-4 (IC50 = 156 nM), with even greater selectivity against other metalloproteinases including MMPs and ADAMs. In preclinical studies, GLPG1972 showed anticatabolic activity in mouse cartilage explants (IC50 < 1.5 μM) and reduced glycosaminoglycan release. Early clinical studies demonstrated that the drug could reduce plasma levels of ARGS neoepitope (a biomarker for cartilage breakdown) by up to 50-60% in both healthy volunteers and osteoarthritis patients. The compound received **FDA Fast Track designation** in November 2018 for the treatment of osteoarthritis. However, the Phase 2 **ROCCELLA trial** (NCT03595618), which enrolled 932 patients with knee osteoarthritis, **failed to meet its primary endpoint** in October 2020, showing no significant reduction in cartilage loss or improvement in clinical symptoms compared to placebo after 52 weeks of treatment, despite the drug being generally well-tolerated.

Brand names

Aldumastat