Emerging concepts and challenges in the development of disease-modifying osteoarthritis drugs - a more refined...

Area of Science:

• Rheumatology
• Pharmacology
• Translational Medicine

Background:

• Osteoarthritis (OA) is a prevalent degenerative joint disease with no approved disease-modifying drugs (DMOADs).
• Numerous therapeutic strategies have failed in clinical trials, necessitating an analysis of underlying reasons.

Purpose of the Study:

• To review and compare preclinical and clinical studies of emerging OA therapeutics.
• To identify factors contributing to the high failure rate of DMOADs in clinical development.

Main Methods:

• Comparative analysis of preclinical and clinical data for various therapeutic classes (antioxidants, senolytics, anti-inflammatories, Wnt inhibitors, growth factors, protease inhibitors).
• Evaluation of limitations in common OA animal models.
• Discussion of challenges in patient stratification and clinical outcome assessment.

Main Results:

• Specific examples like NAC, UBX0101, Anakinra®, Lorecevivint®, and Sprifermin™ illustrate therapeutic approaches and their clinical outcomes.
• Commonly used animal models exhibit limitations in predicting human OA progression and treatment response.
• Challenges in defining OA endotypes/phenotypes and selecting appropriate clinical endpoints hinder trial success.

Conclusions:

• The high failure rate of DMOADs stems from issues in preclinical models, patient selection, and outcome measurement.
• Future DMOAD development requires improved animal models, robust patient stratification strategies, and validated clinical outcome parameters.