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

VBP15，一种针对 DMD 的创新类固醇干预措施：VISION-DMD

• 批准号: 8960452
• 负责人: Paula R Clemens
• 金额: $ 30万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8960452
• 关键词: Address; Adverse effects; Age; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological Markers; Cell membrane; Clinical; Clinical Management; Clinical Trials; Clinical Trials Design; Development; Disease; Documentation; Dose; Drug Kinetics; Duchenne muscular dystrophy; Enhancers; Equilibrium; Extravasation; Gene Targeting; Glucocorticoids; Health; Human; Industry; Inflammation; Inflammatory; International; Intervention; Lead; Leukocytes; Magnetic Resonance Imaging; Medical; Membrane; Modeling; Monitor; Moods; Mus; Muscle; Muscular Dystrophies; Osteopenia; Outcome; Outcome Measure; Ownership; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physician Executives; Pre-Clinical Model; Prednisone; Readiness; Relative (related person); Research Infrastructure; Research Support; Response Elements; Safety; Site; Steroids; Testing; Therapeutic; Time; Toxicology; United States; Variant; Weight Gain; Youth; deflazacort; drug development; innovation; muscle form; novel; pre-clinical research; preclinical efficacy; preclinical study; programs; risk benefit ratio; safety testing

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.

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）最有效的药物是每日高剂量糖皮质激素（泼尼松、地夫可特）。然而，由于治疗的不可接受的副作用，糖皮质激素的抗炎药理活性的益处对于患有 DMD 的患者或实际上患有多种炎症性疾病之一的患者来说可能无法实现。由于身材矮小、骨质减少、情绪变化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用于 DMD 临床治疗的显着变化。一种新型解离类固醇 VBP15 被开发出来，具有更佳的风险效益比，用于治疗患有 DMD 的青少年。 VBP15 的临床前研究表明，抗炎机制主要是由于抑制 NF-κB 激活，通过白细胞外渗的有益调节和增强质膜稳定性进一步增强。此外，VBP15 与靶基因增强子和阻遏子中糖皮质激素反应元件 (GRE) 的结合显着减少。临床前研究表明，GRE 结合减少会导致不良反应减少，并表明接受 VBP15 治疗的人类中糖皮质激素引起的副作用会减少。广泛的临床前疗效和毒理学研究支持 VBP15 的首次人体临床应用的开发。在多种炎症性疾病临床前模型中，包括 DMD 的 mdx 小鼠模型，与传统糖皮质激素相比，VBP15 减少了副作用，拓宽了治疗窗口，并保留或增强了疗效。在此应用中，我们建议规划 支持 VBP15 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，以询问年轻（4-7 岁）DMD 患者炎症和膜稳定性的时间依赖性影响。

项目成果

Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy: A 30-Month Nonrandomized Controlled Open-Label Extension Trial.

• DOI: 10.1001/jamanetworkopen.2021.44178
• 发表时间: 2022-01-04
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Mah JK;Clemens PR;Guglieri M;Smith EC;Finkel RS;Tulinius M;Nevo Y;Ryan MM;Webster R;Castro D;Kuntz NL;McDonald CM;Damsker JM;Schwartz BD;Mengle-Gaw LJ;Jackowski S;Stimpson G;Ridout DA;Ayyar-Gupta V;Baranello G;Manzur AY;Muntoni F;Gordish-Dressman H;Leinonen M;Ward LM;Hoffman EP;Dang UJ;NorthStar UK Network and CINRG DNHS Investigators
• 通讯作者: NorthStar UK Network and CINRG DNHS Investigators

Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.

• DOI: 10.1371/journal.pmed.1003222
• 发表时间: 2020-09
• 期刊: PLoS medicine
• 影响因子: 15.8
• 作者: Smith EC;Conklin LS;Hoffman EP;Clemens PR;Mah JK;Finkel RS;Guglieri M;Tulinius M;Nevo Y;Ryan MM;Webster R;Castro D;Kuntz NL;Kerchner L;Morgenroth LP;Arrieta A;Shimony M;Jaros M;Shale P;Gordish-Dressman H;Hagerty L;Dang UJ;Damsker JM;Schwartz BD;Mengle-Gaw LJ;McDonald CM;CINRG VBP15 and DNHS Investigators
• 通讯作者: CINRG VBP15 and DNHS Investigators