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

描述(申请人提供)：迄今为止发现的治疗Duchenne肌营养不良症(DMD)最有效的药物是每日大剂量糖皮质激素(泼尼松、呋喃西林)。然而，由于不可接受的副作用，糖皮质激素的抗炎药理活性对于DMD患者，或者实际上是患有大量不同炎症条件的患者，可能无法实现。由于身材矮小、骨量减少、情绪改变和肌肉体积改变等副作用，疗效和副作用的平衡导致糖皮质激素在DMD临床治疗中的使用有显著差异。一种新的解离类固醇VBP15被开发出来，它具有更理想的风险-收益比，用于治疗青少年DMD。对VBP15的临床前研究表明，抗炎机制在很大程度上是由于抑制了NF-κB的激活，并通过有益地调节白细胞外渗和增加质膜稳定性而进一步增强。此外，VBP15与靶基因增强子和抑制子中的糖皮质激素反应元件(GRE)的结合显著减少。临床前研究表明，减少GRE结合导致较少的不良反应，并表明在接受VBP15治疗的人类中，糖皮质激素引起的副作用将较少。广泛的临床前疗效和毒理学研究支持VBP15的开发，使其在人类临床上首次使用。在多种炎症性疾病的临床前模型中，包括DMD的MDX小鼠模型，VBP15与传统的糖皮质激素相比，减少了副作用，拓宽了治疗窗口，并保持或提高了疗效。在本申请中，我们建议规划 支持VBP15 2a期(安全性、耐受性、剂量发现、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、生物标记物小组和MRI结果，以质疑对年轻患者(4-7岁)炎症和膜稳定性的时间依赖效应。老年)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.