Background MIV-711 is a novel selective cathepsin K inhibitor with beneficial effects on bone and cartilage in preclinical osteoarthritis models. Objective To evaluate the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographic knee osteoarthritis. Design 26-week randomized, double-blind, placebo-controlled phase 2a study with a 26-week open-label safety extension substudy. (EudraCT: 2015-003230-26 and 2016-001096-73). Setting Six European sites. Participants 244 participants with primary knee osteoarthritis, Kellgren-Lawrence grade 2 or 3, and pain score of 4 to 10 on a numerical rating scale (NRS). Intervention MIV-711, 100 (n = 82) or 200 (n = 81) mg daily, or matched placebo (n = 77). Participants (46 who initially received 200 mg/d and 4 who received placebo) received 200 mg of MIV-711 daily during the extension substudy. Measurements The primary outcome was change in NRS pain score. The key secondary outcome was change in bone area on magnetic resonance imaging (MRI). Other secondary end points included cartilage thickness on quantitative MRI and type I and II collagen C-telopeptide biomarkers. Outcomes were assessed over 26 weeks. Results Changes in NRS pain scores with MIV-711 were not statistically significant (placebo, -1.4; MIV-711, 100 mg/d, -1.7; MIV-711, 200 mg/d, -1.5). MIV-711 significantly reduced medial femoral bone area progression (P = 0.002 for 100 mg/d and 0.004 for 200 mg/d) and medial femoral cartilage thinning (P = 0.023 for 100 mg/d and 0.125 for 200 mg/d) versus placebo and substantially reduced bone and cartilage biomarker levels. Nine serious adverse events occurred in 6 participants (1 in the placebo group, 3 in the 100 mg group, and 2 in the 200 mg group); none were considered to be treatment-related. Limitation The trial was relatively short. Conclusion MIV-711 was not more effective than placebo for pain, but it significantly reduced bone and cartilage progression with a reassuring safety profile. This treatment may merit further evaluation as a disease-modifying osteoarthritis drug. Primary Funding Source Medivir.

中文翻译：

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新型组织蛋白酶K抑制剂在骨关节炎中的疾病改良作用：随机对照试验。

背景MIV-711是一种新型的选择性组织蛋白酶K抑制剂，在临床前骨关节炎模型中对骨骼和软骨具有有益作用。目的评估MIV-711在有症状，放射照相的膝关节骨性关节炎患者中的疗效，安全性和耐受性。设计26周的随机，双盲，安慰剂对照2a期研究，并进行26周的开放标签安全性扩展亚研究。（EudraCT：2015-003230-26和2016-001096-73）。设置六个欧洲站点。参与者244名患有原发性膝部骨关节炎，Kellgren-Lawrence 2级或3级，疼痛评分为4到10（基于数字评分量表（NRS））的参与者。干预MIV-711，每日100（n = 82）或200（n = 81）mg，或匹配的安慰剂（n = 77）。在扩展研究期间，参与者（最初接受200 mg / d的46位患者和接受安慰剂的4位）每天接受200 mg MIV-711。测量主要结果是NRS疼痛评分的变化。关键的次要结果是磁共振成像（MRI）上的骨面积变化。其他次要终点包括定量MRI上的软骨厚度以及I型和II型胶原C-端肽生物标志物。在26周内评估结果。结果MIV-711的NRS疼痛评分变化无统计学意义（安慰剂，-1.4； MIV-711，100 mg / d，-1.7； MIV-711，200 mg / d，-1.5）。MIV-711显着降低了股骨内侧骨区域进展（100 mg / d的P = 0.002和200 mg / d的0.004）和股骨内侧软骨变薄（100 mg / d和0的P = 0.023。与安慰剂相比，剂量为200 mg / d为125），并且骨骼和软骨生物标志物水平大大降低。6名参与者发生了9例严重不良事件（安慰剂组1例，100 mg组3例，200 mg组2例）；没有人被认为与治疗有关。局限性审判时间相对较短。结论MIV-711在疼痛方面并不比安慰剂有效，但可以显着降低骨骼和软骨的发展，并具有安全性。这种治疗可能值得进一步评估，作为治疗疾病的骨关节炎药物。主要资金来源Medivir。结论MIV-711在疼痛方面并不比安慰剂有效，但可以显着降低骨骼和软骨的发展，并具有安全性。这种治疗可能值得进一步评估，作为治疗疾病的骨关节炎药物。主要资金来源Medivir。结论MIV-711在疼痛方面并不比安慰剂有效，但可以显着降低骨骼和软骨的发展，并具有安全性。这种治疗可能值得进一步评估，作为治疗疾病的骨关节炎药物。主要资金来源Medivir。