Cathepsin K Inhibitors for Arthritic Diseases

There is a significant unmet therapeutic need for low cost arthritis treatments which prevent or limit joint damage and provide cartilage protection. Degenerative joint damage is a common theme between both rheumatoid and osteoarthritis and Amura’s arthritis programme is directed towards a small molecule therapy aimed at joint protection and the prevention of further joint destruction.  

Establishment of an inflammatory and/or autoimmune state in the affected joints of rheumatoid and osteoarthritic sufferers is accompanied by the appearance of destructive proteolytic enzymes, which begin to degrade the main articular and synovial joint tissue.   This process eventually leads to joint damage and bone erosion. At the molecular level, osteoclasts and synovial fibroblasts produce an extracellular cysteine peptidase, cathepsin K, which is responsible for the degradation of the collagen type I bone matrix and has been implicated in turnover of type II collagen found in cartilage.  Previously, we have shown that AM-3701 in an in vivo surgical menisectomy model of osteoarthritis, gave significant beneficial effects on tibial cartilage degeneration and total joint score compared to the control group. Additionally, AM-3701 demonstrated a significant decrease in serum CTxI biomarker of collagen degradation.

In a second study, an in vivo collagen-induced arthritis model of rheumatoid arthritis, our leading cathepsin K inhibitor, AM-3701 has also demonstrated a significant decrease in joint swelling score and a significant improvement in joint histopathology.

Thus, AM-3701 has shown excellent oral efficacy in PoC models of rheumatoid and osteoarthritis, clearly demonstrating significant beneficial effects on arthritic joint degeneration in an in vivo setting. This provides Amura with significant competitive and therapeutic advantages over existing drugs, with a single molecule aimed at both of the major arthritic diseases

In addition to this in vivo PoC data, the quality of the molecules is confirmed by a comprehensive pre-clinical package which includes pharmacokinetic data, selectivity and safety assessment.  The lead molecule and a first rate back-up molecule are now available for partnering.

These drugs are the product of Amura’s AMcore™ platform which  has reproducibly provided ‘fast-on, slow-off rate’ enzyme inhibitors with good pharmacokinetic half-lives and a very strong IP position. 

Full Compound Information Summaries are available under Confidentiality Agreement.