Cathepsin K inhibition by VBX1000 alleviates canine periodontitis.

Abstract

INTRODUCTION: The efficacy and safety of a novel cathepsin K inhibitor, VBX1000, were evaluated in client-owned dogs suffering from periodontal disease. METHODS: This open-label study recruited twenty dogs (&#x202f;=&#x202f;20) with at least 3 teeth at stage 2 or 3 of periodontal disease. Dogs were orally treated once-a-day with VBX1000 (25&#x202f;mg/kg or 50&#x202f;mg/kg,&#x202f;=&#x202f;10 per group) for 60&#x202f;days, and then with 50&#x202f;mg/kg once-a-day for an additional 30&#x202f;days. The first objective was to assess evolution compared to pre-treatment of plasma carboxy-terminal telopeptide of collagen type 1 (CTX1) used as a marker of target engagement and bone resorption. In each evaluated tooth (&#x202f;=&#x202f;60; three teeth per dog), evolution counter to baseline of clinical attachment loss (CAL), periodontal probing depth (PPD), and bleeding on probing index (BPI) were evaluated The effects of cathepsin K inhibitor on alveolar bone defects were assessed with intraoral dental radiography (DR) performed at inclusion and at the end of the treatment period. A confirmatory analysis was performed in a subpopulation (&#x202f;=&#x202f;10 dogs; 30 teeth) using the cone beam computed tomography scan (CBCT) imaging technique. RESULTS: Throughout the treatment period, VBX1000 was well tolerated. At Day60, plasma CTX1 was significantly and similarly reduced compared with baseline (&#x202f;<&#x202f;0.05) in the two groups. At the end of the treatment period (at Day90) in the total population (&#x202f;=&#x202f;20), plasma CTX1 was 0.10&#x202f;&#xb1;&#x202f;0.04&#x202f;ng/mL relative to 0.26&#x202f;&#xb1;&#x202f;0.20&#x202f;ng/mL at baseline (&#x202f;<&#x202f;0.001). DR before and after treatment showed decreases in width (&#x202f;=&#x202f;60 teeth; three teeth/dog;&#x202f;<&#x202f;0.0001), depth (&#x202f;<&#x202f;0.05), and height of bone defects measured between the root and the maxillary bone. These effects on bone defects were confirmed in a subpopulation analyzed by CBCT. At the end of the treatment period, clinical attachment loss (CAL) was reduced relative to pretreatment: 2.87&#x202f;&#xb1;&#x202f;1.73&#x202f;mm compared to 3.86&#x202f;&#xb1;&#x202f;2.06&#x202f;mm (&#x202f;=&#x202f;60;&#x202f;<&#x202f;0.0001). Likewise, the periodontal probing depth (PPD) was reduced 2.71&#x202f;&#xb1;&#x202f;1.03&#x202f;mm compared to 3.69&#x202f;&#xb1;&#x202f;1.23&#x202f;mm (&#x202f;=&#x202f;60,&#x202f;<&#x202f;0.0001). CONCLUSION: The findings support the inhibition of cathepsin K by VBX1000 as a new therapeutic approach for mild-to-moderate periodontal disease in dogs. A randomized, double blinded placebo-controlled trial in dogs should confirm the potential of VBX1000 in this indication.