A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study

Yazıcı, Yusuf; McAlindon, Timothy E.; Fleischmann, Roy; Gibofsky, Allan; Lane, Nancy E.; Kivitz, A.; Skrepnik, Nebojša; Armas, Eddie; Swearingen, Christopher J.; DiFrancesco, A.; Tambiah, J.; Hood, John; Hochberg, Marc C.

doi:10.1016/j.joca.2017.07.006

Cited by 111 publications

(84 citation statements)

References 21 publications

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“…These results implicate WNT5A and 5B as potential targets of disease-modifying drugs [16][17][18]. Based on the observation of residual MSC failure in OA joints, Wnt inhibitors have recently completed phase I clinical trials as first-in-class drugs [17]. Although these results suggest the efficacy of Wnt inhibitors as DMOADs, WNT ligands and pathways with different effects have not been separately assessed.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of the Wnt Signaling Pathway and Synovial Stem Cell Dysfunction in Osteoarthritis Development

Huang

Chen

Liang

et al. 2020

Stem Cells and Development

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Stem cell dysfunction and failure have been found in joints afflicted by osteoarthritis (OA). However, the exact factors in the OA microenvironment that impair stem cell functions and the role of stem cell dysfunction in OA development have not been fully clarified. In this study, we evaluated the functional status of synovial mesenchymal stem cells (SMSCs) from OA patients and explored the influence of OA-SMSCs on cartilage degradation in a rat model. We then screened 138 Wnt signaling-related genes in the synovium of OA patients, focusing on the effects of five WNT ligands on SMSC functions. The OA synovium showed mild hyperplasia, and we found a large number of CD90 + /CD105 + stem cells in synovial hyperplasia. The OA-SMSCs revealed a cellular senescence phenotype, with decreased proliferation and chondrogenic capacity, accompanied by enhanced migration, proinflammatory and matrix degradation activities. The intra-articular transplantation of these OA-SMSCs significantly aggravated the degradation and destruction of the articular cartilage. Of 138 Wnt signaling genes, the expression of 86 genes was consistently altered in the OA synovium, among which the increased expression of DVL2, WNT10A, and DKK3 was the most marked. In general, we found that canonical Wnt/b-catenin pathways were inhibited in the OA synovium, whereas noncanonical PCP and Wnt/Ca2 + pathways were activated. In vitro, WNT10A had an obvious antisenescence effect on SMSCs. WNT5B significantly inhibited the chondrogenic differentiation of SMSCs, and WNT10A and WNT5A increased the expression of inflammatory cytokines in SMSCs. In a rat model, WNT5A significantly aggravated joint degeneration, whereas WNT10A had a mild protective effect on cartilage integrity. In conclusion, stem cells in the OA synovium were functionally abnormal and promoted the development of OA, whereas dysregulation of the Wnt signaling pathway revealed a comprehensive influence on SMSC functions and cartilage degradation.

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Section: Discussionmentioning

confidence: 99%

“…Wnt signaling disorder plays a critical role in stem cell failures, for example, hematopoietic stem cell senescence [14] and intestinal stem cell failure [15]. Based on this, regulators of Wnt signaling have been suggested as promising diseasemodifying osteoarthritis drugs (DMOADs) [12,16,17].…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of the Wnt Signaling Pathway and Synovial Stem Cell Dysfunction in Osteoarthritis Development

Huang

Chen

Liang

et al. 2020

Stem Cells and Development

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“…These preclinical data have been used to support the use of lorecivivint for the treatment of knee osteoarthritis in human clinical trials. Based on a phase 1 study with an excellent safety profile [45], phase II trials have recently been finished suggesting effectiveness on both signs and symptoms as well as structural damage in patients with knee osteoarthritis, in particular those without widespread pain [46,47]. As a caveat, data are currently only available in meeting abstract format.…”

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?

Lories

Monteagudo

2020

Rheumatol Ther

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Osteoarthritis is the most common chronic joint disease affecting millions of people worldwide and a leading cause of pain and disability. Increasing incidence of obesity and aging of the population are two factors that suggest that the impact of osteoarthritis will further increase at the society level. Currently, there are no drugs available that can manage both structural damage to the joint or the associated pain. Increasing evidence supports the view that the Wnt signaling pathway plays an important role in this disease. The current concept, based on genetic and functional studies, indicates that tight regulation of Wnt signaling in cartilage is essential to keep the joint healthy. In this review, we discuss how this concept has evolved, provide insights into the regulation of Wnt signaling, in particular by Wnt modulators such as frizzled-related protein and DOT1-like histone lysine methyltransferase, and summarize preclinical evidence and molecular mechanisms of lorecivivint, the first Wnt antagonist in clinical development for osteoarthritis.

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“…Completion of phase I clinical trials have demonstrated tolerability in humans with SM04960 undetected in plasma following intra-articular injection. Phase II trial assessment is required to support suggestions of improvement in OA pain and joint function 46 .…”

Section: Signalling Mechanisms Involved In Cartilage Homeostasismentioning

confidence: 99%

Osteoarthritis year in review 2018: biology

Sherwood

2019

Osteoarthritis and Cartilage

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This Year in Review highlights a selection of articles published between the 2017 and 2018 Osteoarthritis Research Society International (OARSI) World Congress meetings within the field of osteoarthritis biology, presented at OARSI 2018. Selected articles were obtained from a PubMed search covering cartilage, subchondral bone, inflammation, ageing, pain and animal models. Studies focused on biomechanics, biomarkers, genetics and epigenetics, imaging and clinical studies were excluded due to their coverage in other articles within the OARSI Year in Review series. Significant themes including the role of progenitor cells in cartilage homeostasis and repair, novel signalling mechanisms controlling chondrocyte phenotypic stability and the influence of disrupted or senescent chondrocytes were identified and are discussed in this review. Overarching conclusions derived from these study areas indicate that promising avenues of intervention are on the horizon, however further understanding is required in order to target therapeutic treatments to suitable patient subgroups and disease stages.

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A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study

Abstract: NCT02095548.

Cited by 111 publications

References 21 publications

Dysregulation of the Wnt Signaling Pathway and Synovial Stem Cell Dysfunction in Osteoarthritis Development

Dysregulation of the Wnt Signaling Pathway and Synovial Stem Cell Dysfunction in Osteoarthritis Development

Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?

Osteoarthritis year in review 2018: biology

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