Osteoarthritis (OA) is the most common form of arthritis affecting nearly 27 million people in the United States. OA is caused by the loss of articular cartilage due to increased production of proteolytic enzymes such as matrix metalloproteinases (MMPs) and aggrecanases. Depletion of aggrecan is one of the earliest changes observed in osteoarthritis. Aggrecan is a chondroitin sulfate and keratan sulfate-bearing proteoglycan. Two cartilage aggrecanases, Aggrecanase 1 (ADAMTS4) and Aggrecanase 2 (ADAMTS5) cleave aggrecan within the interglobular domain between residues Glu373 and Ala 374.
There are no disease-modifying therapies for the treatment of OA. The current study describes the chondroprotective effect of an oral aggrecanase-selective inhibitor (AGG-523) in a rat model of osteoarthritis and demonstrates that the significant protection, and lack of phenotypic alteration, observed with gene-deleted ADAMTS-5 and ADAMTS-4/5 mice, can also be observed with the use of a selective ADAMTS-4/5 inhibitor in the rat meniscal tear model of OA. This paradigm of selective ADAMTS-4/5 inhibition avoids the side-effects observed clinically and pre-clinically with broad-spectrum MMP inhibition.
Disclosure of Interest K. Georgiadis Shareholder of: Pfizer, Employee of: Pfizer