Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis

Abstract

Objective Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal. Methods The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007–2009 at the behest of the Osteoarthritis Research Society International (OARSI FDA initiative). Results This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers. Conclusions Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within one to two years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical effect. As in vitro biomarkers are increasingly investigated in the context of specific drug treatments, advances in the field can be expected that will lead to rapid expansion of the list of available biomarkers with increasing understanding of the molecular processes that they represent.

Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis

“…This is partly because more effective biomarker analyses and imaging strategies need to be applied to stratify patients according to criteria that are likely to show structure modification and differentiate the pain response [Kraus et al 2011;Patra and Sandell, 2011;Sellam and Berenbaum, 2010]. For example, efficacy of an aggrecanase-specific inhibitor against cartilage damage has been demonstrated in a rat model of meniscal tear-induced joint instability [Chockalingam et al 2011], although clinical trials have not gone forward.…”

Animal Models of Osteoarthritis: Challenges of Model Selection and Analysis

“…In 2011, the OARSI/Federal Drug Administration (FDA) Initiative working group published its consensus document for the application of in vitro biomarkers for the development of drugs for OA (35). This important document was created to summarize and guide the application of in vitro biomarkers for the characterization of OA and the development of drug therapies to treat this disease.…”

“…The Burden of disease, Investigative, Prognostic, Efficacy of intervention, Diagnostic, and Safety classification has been proposed to categorize human markers of OA (35,36). Alternative classification systems use breakdown products of collagen or proteoglycan or levels of inflammatory mediators as biomarkers of disease initiation and progression.…”

“…Since OA represents a process of matrix damage, turnover, and attempted repair, the use of multiple biomarkers, both anabolic and catabolic, will likely be most accurate in characterizing OA disease. The 2011 OARSI/FDA consensus report on biomarkers includes a table with a recommended panel of informative commercially available biomarkers qualified for the study of OA outcomes, as well as a summary of published OA clinical trial biomarker data (35).…”

What Is the Utility of Biomarkers for Assessing the Pathophysiology of Hip Osteoarthritis? A Systematic Review

“…Bony morphology associated with developmental dysplasia of the hip and femoroacetabular impingement (FAI) has been shown to be present in the majority of patients younger than age 50 years who present with hip OA [10]. The pathophysiology of hip OA is increasingly viewed as a continuum, progressing from an asymptomatic molecular phase, to a preradiographic, then radiographic phase, and finally, to end-stage OA [28]. Whereas hip OA may represent the end-stage clinical condition, the pathophysiology of hip OA appears to result from several distinct processes.…”