THU0522 Experimental tendinopathy treatment with sm04755, a topical small molecule inhibitor of the wnt pathway
Authors: V. Deshmukh, T. Seo, Y. Yazici
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Tendinopathy is an inflammatory and degenerative disorder caused by injuries and overuse. Affected tendons become fibrotic, with micro tears that can lead to pain and rupture. Current therapeutic options treat symptoms and not underlying causes. The Wnt pathway is upregulated in chronic tendinopathy and involved in inflammation, tenocyte differentiation and fibrosis. <h3>Objectives</h3> SM04755, a novel, topical, small molecule Wnt pathway inhibitor, has previously been shown to inhibit inflammation, reduce fibrosis and increase tenocyte differentiation in nonclinical models<sup>1</sup>. Two further experiments are presented: 1. SM04755 treatment in an acute dose response tendinopathy model and 2. SM04755 treatment in a repeat injury/delayed treatment (RIDT) tendinopathy model. These models simulate acute and acute-on-chronic clinical tendinopathy, respectively. <h3>Methods</h3> SM04755 was assessed in rodent Achilles tendinopathy models, induced by intra-tendon collagenase injection (500 µg). In the acute dose response model, a single injection of collagenase or sham per animal on Day −4 was followed on Day 0 by daily topical vehicle, or 0.3 mg/cm<sup>2</sup> or 0.9 mg/cm<sup>2</sup> SM04755. Achilles tendons were harvested on Days 7, 14, and 21. In the RIDT model, collagenase injections were given at Days −28 and −14, followed on Day 0 with daily topical vehicle or 0.3 mg/cm<sup>2</sup> SM04755. Achilles tendons were harvested on Days 7, 14, 21 and 28. Blinded histology analyses scored tendon health based on linearity, tendon cell shape, tendon cell density, inflammation, and haemorrhage (range 5–20). Statistical analyses used one-way ANOVA for multiple group comparisons and t-tests for comparison between two groups. <h3>Results</h3> In the acute dose response model, SM04755 improved tendon health from baseline compared to vehicle as assessed by tendon histology scores. Vehicle scores were 10.77 [±1.46] at Day 7, 10.44 [±0.66] at Day 14, and 10.31 [±1.02] at Day 21. SM04755 0.3 mg/cm<sup>2</sup> dose group scores were 12.30 [±0.62] at Day 7 (NS), 10.45 [±1.29] at Day 14 (NS), and 14.37 [±0.82] at Day 21 (p&lt;0.05). SM04755 0.9 mg/cm<sup>2</sup> dose group scores were 12.22 [±1.02] at Day 7 (NS), 14.57 [±0.41] at Day 14 (p&lt;0.05), and 14.67 [±0.76] at Day 21 (p&lt;0.05) (figure 1). In the RIDT model, vehicle scores were 12.35 [±0.30] at Day 7, 10.09 [±0.76] at Day 14, 11.92 [±0.77] at Day 21 and 13.72 [±0.35] at Day 28. SM04755 0.3 mg/cm<sup>2</sup> dose group scores were 11.86 [±2.13] at Day 7 (NS), 9.44 [±0.48] at Day 14 (NS), 14.61 [±0.77] at Day 21 (p&lt;0.05), and 14.93 [±0.46] at Day 28 (NS) (figure 2). <h3>Conclusions</h3> In the acute dose response model, SM04755 0.3 mg/cm<sup>2</sup> dose showed statistically significant improvements in tendon scores compared to vehicle at Day 21. The 0.9 mg/cm<sup>2</sup> dose achieved significance at Days 14 and 21, indicating faster response at higher SM04755 dose. In the RIDT model of repeat collagenase injections and delayed intervention, SM04755 0.3 mg/cm<sup>2</sup> dose promoted accelerated tendon healing compared to vehicle. Therefore, SM04755 demonstrated accelerated improvement of tendon histology in acute and RIDT models compared to vehicle and has potential as a tendinopathy therapy. Clinical studies are planned. <h3>Reference</h3> [1] Deshmukh V, et al. Arthritis Rheumatol2016;68(suppl 10). <h3>Disclosure of Interest</h3> V. Deshmukh Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, T. Seo Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Y. Yazici Shareholder of: Samumed, LLC, Employee of: Samumed, LLC