VBP15, an Innovative Steroid-like Intervention on DMD: VISION-DMD

描述（由申请人提供）：迄今为止确定的治疗杜氏肌营养不良症（DMD）的最有效药物是每日高剂量糖皮质激素（泼尼松、地夫可特）。然而，糖皮质激素的抗炎药理学活性的益处对于患有DMD或实际上患有大量不同炎性病症之一的患者可能无法实现，这是由于治疗的不可接受的副作用。由于身材矮小、骨质减少、情绪变化和肌肉体积改变的副作用，疗效和副作用的平衡导致糖皮质激素用于DMD临床管理的显著变化。开发了一种新的解离性类固醇VBP 15，用于治疗青年DMD，具有更佳的风险-效益比。VBP 15的临床前研究表明，主要由于抑制NF-κB活化而产生的抗炎机制通过有益调节白细胞外渗和增加质膜稳定性而进一步增强。此外，VBP 15与靶基因增强子和阻遏子中的糖皮质激素反应元件（GRE）的结合显著较少。临床前研究表明，减少的GRE结合导致更少的不良反应，并表明在用VBP 15治疗的人中将存在更少的糖皮质激素诱导的副作用。广泛的临床前疗效和毒理学研究支持VBP 15首次用于人体临床的开发。在炎性疾病的多个临床前模型中，包括DMD的mdx鼠模型，VBP 15相对于传统糖皮质激素减少副作用，拓宽治疗窗，并保持或增强功效。在这个应用程序中，我们建议规划 支持VBP 15的2a期（安全性、耐受性、剂量探索、PK和PD）临床试验的活动。这项2a期研究的扩展将整合药效学生物标志物组和MRI结果，以查询对年轻人（4-7岁）炎症和膜稳定性的时间依赖性影响。DMD患者。

DESCRIPTION (provided by applicant): The most effective drug identified to date for Duchenne muscular dystrophy (DMD) is daily high dose glucocorticoids (prednisone, deflazacort). However, the benefits of the anti-inflammatory pharmacological activities of glucocorticoids may not be realized for a patient with DMD, or indeed with one of a large number of diverse inflammatory conditions, due to unacceptable side effects of the therapy. The balance of efficacy and side effects leads to significant variation in glucocorticoid use for the clinical management of DMD due to side effects of short stature, osteopenia, mood changes, and altered muscle bulk. A novel dissociative steroid, VBP15, was developed with a more optimal risk-benefit ratio for the treatment of youth with DMD. Preclinical research with VBP15 showed that the anti-inflammatory mechanism, due largely to inhibition of NF-κB activation, is further augmented by beneficial modulation of leukocyte extravasation and increased plasma membrane stabilization. Furthermore, VBP15 has significantly less binding to the glucocorticoid response element (GRE) in target gene enhancers and repressors. Preclinical studies demonstrate that reduced GRE binding results in fewer adverse effects and suggests that there will be fewer glucocorticoid-induced side effects in humans treated with VBP15. Extensive preclinical efficacy and toxicology research support the development of VBP15 for first-in-human clinical use. In multiple pre-clinical models of inflammatory disease, including the mdx murine model of DMD, VBP15 reduces side effects, widens therapeutic windows, and retains or enhances efficacy relative to traditional glucocorticoids. In this application, we propose planning activities to support a Phase 2a (safety, tolerability, dose-finding, PK and PD) clinical trial of VBP15. An extension to this Phase 2a study will integrate pharmacodynamics biomarker panels and MRI outcomes to query time-dependent effects on inflammation and membrane stability in young (4-7 yr. old) DMD patients.