GREES publish new recommendations on the clinical development of disease modifying osteoarthritis drugs (DMOADs)

GREES publish new recommendations on the clinical development of disease modifying osteoarthritis drugs (DMOADs)

DailyUpdates 1st April: Osteoarthritis is the most common form of arthritis and is estimated to affect over 73 million people in the seven major pharmaceutical markets. Disease modifying osteoarthritis drugs (DMOADs) currently represent the ‘holy grail’ in the treatment of osteoarthritis. The Group for the Respect of Ethics and Excellence in Science (GREES) have now published recommendations on the clinical development of DMOADs.

Osteoarthritis is a degenerative joint disease occurring mainly in the elderly. It is the most common form of arthritis and it is estimated to affect over 73 million people in the seven major pharmaceutical markets.

Disease modifying osteoarthritis drugs (DMOADs) currently represent the ‘holy grail’ in the treatment of osteoarthritis, driven by an aging population and recent success of disease modifiers for rheumatoid arthritis. Doxycycline, Amgen’s Kineret and a MMP Inhibitor from Proctor & Gamble offer the most promising DMOAD prospects in the pipeline (for a full analysis of DMOADs click here).

Regulatory agencies acknowledge that compounds may be granted a DMOAD indication, providing that they can slow down disease progression.  Disease progression can be determined by measuring joint space narrowing on X-rays on the assumption that delayed joint space narrowing translates into a clinical benefit for the patient. The lack of accuracy and reproducibility of radiography has however created difficulties for clinical trials and the use of other imaging technologies or research into biomarkers offers possible solutions to both end-point assessment in DMOAD trials and earlier diagnosis of osteoarthritis.

Recently, new technology has been developed to detect a structural change of the osteoarthritic joint earlier than conventional X-rays and The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to x-rays for assessment of DMOADs. The recommendations of GREES, which includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry, have now been reported in the journal Osteoarthritis & Cartilage and offer a framework for the future development of DMOADs. 

Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in osteoarthritis patients. GREES conclude that although some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, GREES suggests that MRI may be used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials.

Biochemical markers of bone and cartilage remodelling are being tested to predict osteoarthritis and measure disease progression. Recently published data are promising but validation as surrogate end-points for osteoarthritis disease progression requires additional study. GREES suggests that biochemical markers remain limited to 'proof of concept' studies or as secondary end-points in phase II and III clinical trials. However, GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in osteoarthritis.

Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD however non-disease-related biasing factors suggest that benefit end-points should primarily be joint space narrowing, pain and function. 

The recommendations of GREES should hopefully lay down a framework for improved DMOADs although they are obviously subject to change in parallel with the anticipated rapid progression of osteoarthritis research.

(Source DailyUpdates 1st April; for a full abstract of the original papers see  Osteoarthritis Cartilage. 2004 Apr;12(4):263-8; for further information on DMOADs see Disease Modifying Osteoarthritis Drugs - The Search for the 'Holy Grail' Continues)