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

Abstract

Osteoarthritis (OA) is the most common joint disease worldwide. Despite significant efforts byresearchers, no disease-modifying osteoarthritis drugs (DMOADs) have been approved yet. This review compares preclinical and clinical studies of promising therapeutic approaches to gain insights into the potential reasons for their failure in clinical trials. For this purpose, prime examples of different therapeutic groups, including the antioxidant NAC, senotherapeutic UBX0101, anti-inflammatory drug Anakinra®, Wnt inhibitor Lorecevivint®, chondroanabolic growth factor Sprifermin™, and various protease inhibitors, are discussed in detail. The limitations of commonly used OA animal models are elaborated to understand this failure better. Moreover, this review addresses the challenges of patient stratification into different endotypes and phenotypes, the consideration of subgrouping in clinical trials, and the lack of suitable clinical outcome parameters. In summary, this review highlights potential reasons for the high failure rate of DMOADs in clinical trials and outlines key points for future improvement.

Keywords: Animal models; Clinical trials; Disease-modifying osteoarthritis drugs; Drug development; Endotypes; Osteoarthritis.

Fig. 1

Theoretical procedure of drug development. Theoretically, a candidate potential drug is initially tested in vitro, followed by a preclinical validation in vivo. Subsequently, the compound undergoes testing in a clinical trial in patients, selected by pre-defined criteria to ensure a preferably homogenous study cohort

Fig. 2

Tackling oxidative stress by the antioxidant N-acetyl cysteine (NAC). As a crucial driver of OA, oxidative stress has detrimental effects on tissue homeostasis. The antioxidant NAC efficiently eliminates ROS in various joint cell types, thus attenuating pathophysiologic processes, including cell death, subchondral sclerosis, inflammation, and catabolic enzyme expression. Overall, reducing oxidative stress facilitates normal cell function and therefore pro-regenerative processes. Please see the main text for further details

Fig. 3

Tackling cellular senescence by the senolytic UBX0101. Oxidative stress and chronic low-grade inflammation result in the accumulation of senescent cells in joint-related tissues. Due to the excessive release of catabolic and pro-inflammatory mediators, senescence substantially contributes to OA progression. Senescent cells can be selectively eliminated using senolytics, such as UBX0101, thus attenuating the secretion of SASP factors and consequent tissue degeneration and inflammation. While the efficient clearance of dysfunctional chondrocytes and synovial cells has been intensively studied, the therapeutic effects of senolytics on subchondral bone remodeling during OA development must be determined (McCulloch et al. 2017)

Fig. 4

Tackling inflammation by the anti-inflammatory drug Anakinra^. Pro-inflammatory cytokines, including IL-1β, mainly derive from the synovium in the synovial joint. Besides cytokine-directed antibodies, inhibition of cytokine receptors represents a promising therapeutic option to reduce the detrimental effects on cartilage integrity. One well-studied example of this approach is the treatment with recombinant IL-1RA, Anakinra®. Please see the main text for further details

Fig. 5

Tackling Wnt signaling by the Wnt inhibitor SM04690. The Wnt signaling pathway plays an essential role in cartilage homeostasis by modulating the chondrocyte phenotype in various ways, depending on the Wnt protein and accordingly on the subsequent canonical or non-canonical signaling pathways. Inhibition of the Wnt signaling, e.g., by SM04690, represents a potential therapeutic option in OA. Please see the main text for further details

Fig. 6

Tackling catabolism by protease inhibitors. Different MMPs and ADAMTS mainly drive matrix degradation. In the context of OA, MMP-13 and ADAMTS5 represent the predominant proteases causing proteolytic cleavage of type II collagen and aggrecan, the main components of hyaline cartilage. Accordingly, application of protease inhibitors, such as GLPG1972/S201086 and M6495 (ADAMTS-5 specific) as well as PG-116800 (broader MMP inhibitor also inhibiting MMP-13), exerts chondroprotective effects and is thus considered a potentially suitable treatment in OA. Please see the main text for further details

Fig. 7

Tackling impaired anabolism by chondroanabolic growth factor 18. Recombinant human FGF18 (Sprifermin™) is OA’s first drug promoting chondroanabolic effects. The growth factor not only induces matrix production but also chondrogenesis and proliferation, which are crucial processes in terms of cartilage repair. Please see the main text for further details

Fig. 8

Real-life conditions of drug development. Although the theoretical procedure of drug testing – from in vitro studies, over animal models, and finally to application in clinical trials – will still prove reasonable in the future, it is essential to recognize the specific strengths and weaknesses of each step, as they may lead to potential discrepancies in the outcome