Commercialization Readiness Pilot (CRP) to maximize vamorolone international labeling and sales

商业化准备试点 (CRP)，以最大限度地提高瓦莫洛龙的国际标签和销售

• 批准号: 10200153
• 负责人: ERIC P. HOFFMAN
• 金额: $ 167.24万
• 依托单位: REVERAGEN BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200153
• 关键词: 2 year old; Adolescent; Adrenal Cortex Hormones; Age; Agonist; Anti-Inflammatory Agents; Area; Award; Binding; Biological Markers; Blinded; Businesses; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Country; Cushingoid habitus; Data; Development; Disease; Dose; Double-Blind Method; Drug Approval; Duchenne muscular dystrophy; Elements; Enrollment; Ensure; Ethics; Europe; European; Family; Goals; Growth; Infant; Intellectual Property; International; Label; Lead; Legal; Legal patent; Marketing; Measures; Medicine; Mineralocorticoids; Motor Skills; Mus; National Institute of Neurological Disorders and Stroke; Newborn Infant; Outcome; Patients; Pharmaceutical Preparations; Phase; Placebos; Prednisone; Preparation; Press Releases; Procedures; Process; Program Development; Property; Protocols documentation; Publishing; Quality Control; Quality of life; Readiness; Research; Safety; Sales; Site; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Steroids; System; Time; Toxic effect; Toxicology; Visit; Voice; Weight Gain; Writing; arm; boys; clinical research site; commercialization; deflazacort; design; drug efficacy; genetic corepressor; innovation; medication safety; off-label use; open label; pre-clinical; preclinical study; programs; quality assurance; receptor; recruit; research and development; response; side effect; standard of care

Abstract Vamorolone is a first-in-class dissociative steroidal drug that is being developed for Duchenne muscular dystrophy as a replacement for corticosteroid standard of care (prednisone, deflazacort) by small business ReveraGen BioPharma. ReveraGen completed first-in-patient studies with the aid of a NINDS SBIR Direct-to- Phase II award (48 DMD boys; sequential clinical trials VBP15-002, VBP15-003, VBP15-LTE, Expanded Access Protocol), and these have been published (Conklin et al. 2018; Hoffman et al. 2019). These studies showed dose-responsive improvements in all measures of motor skills, and loss of side effects (no stunting of growth, less Cushingoid and weight gain). Biomarkers have been integrated throughout the vamorolone program, providing objective readouts of drug efficacy and safety that also showed clear dose-response in these initial open label studies. A double-blind pivotal trial of 120 DMD boys (VBP15-004) is currently 40% enrolled and recruiting at 31 sites in 11 countries. This pivotal study is supported in part by a NINDS SBIR Phase IIB award and European Commission Horizons 2020 award, and includes placebo and prednisone arms. It is anticipated that the trial will be fully enrolled in late 2019 or early 2020, and last-patient last visit anticipated in Q3 2020 leading to initiation regulatory drug approval procedures in both US (FDA NDA) and Europe (EMA MAA). ReveraGen has remained a privately held small business, and this has enabled innovations in clinical trial design, use of biomarkers, and regulatory protocols. For example, ReveraGen requested the FDA consider Expanded Access Protocols for patients leaving vamorolone clinical trials, as this would reduce burden on patient families and clinical sites, while maintaining centralized safety information, and this was approved, leading to a FDA press release encouraging others to consider a similar approach. For this Commercialization Readiness Pilot (CRP) application, ReveraGen seeks support to fill key gaps identified through a formal FDA NDA gap analysis carried out in Q3 2019, and to enable worldwide drug approval thus maximizing thus enabling worldwide drug approval and maximizing market access. Technical assistance request is to both develop a global regulatory strategy, and development of a global intellectual property strategy. Support for late stage research and development activities include filling identified gaps is Design and Quality Systems Controls, and conducting a GLP juvenile toxicity study supporting labeling and prescription to the newborn period. Completing the goals of the proposed CRP would lead to worldwide commercialization of vamorolone, and set the stage for expanding vamorolone use in many other clinical disorders were corticosteroids are effective but the severe burden of side effects limits use.

抽象的 Vamorolone 是一种一流的解离类固醇药物，正在开发用于治疗杜兴肌病 小企业将营养不良作为皮质类固醇标准护理（泼尼松、地夫可特）的替代品 ReveraGen 生物制药公司。 ReveraGen 在 NINDS SBIR Direct-to- 的帮助下完成了首次患者研究 II 期奖（48 名 DMD 男孩；序贯临床试验 VBP15-002、VBP15-003、VBP15-LTE、扩展 访问协议），并且这些已经发布（Conklin et al. 2018；Hoffman et al. 2019）。这些研究 在所有运动技能测量中都显示出剂量反应性改善，并且副作用消失（没有发育迟缓） 增长，减少库欣伊德和体重增加）。生物标志物已整合到整个瓦莫洛龙中 计划，提供药物功效和安全性的客观读数，也显示出明确的剂量反应 这些最初的开放标签研究。对 120 名 DMD 男孩 (VBP15-004) 进行的双盲关键试验目前为 40% 在 11 个国家的 31 个地点进行注册和招募。这项关键研究得到了 NINDS SBIR 的部分支持 IIB 期奖项和欧盟委员会 Horizo​​ns 2020 奖项，包括安慰剂和泼尼松 武器。预计该试验将于 2019 年底或 2020 年初全面入组，最后一位患者最后一次就诊 预计将于 2020 年第三季度在美国（FDA NDA）和美国启动监管药物审批程序 欧洲 (EMA MAA)。 ReveraGen 仍然是一家私营小企业，这使得 临床试验设计、生物标志物的使用和监管方案方面的创新。例如，ReveraGen 要求 FDA 考虑对退出瓦莫洛龙临床试验的患者实施扩展准入协议，因为这 将减轻患者家属和临床场所的负担，同时维护集中的安全信息，以及 该方案获得批准，FDA 发布新闻稿鼓励其他人考虑采取类似方法。为了这 商业化准备试点 (CRP) 申请，ReveraGen 寻求支持以填补已确定的关键空白 通过 2019 年第三季度进行的正式 FDA NDA 差距分析，从而实现全球药物批准 从而实现全球药物批准并最大限度地提高市场准入。技术援助 要求既制定全球监管战略，又发展全球知识产权 战略。对后期研究和开发活动的支持包括填补已确定的空白、设计和 质量体系控制，并进行 GLP 青少年毒性研究，支持标签和处方 新生儿期。完成拟议的 CRP 目标将导致该技术在全球范围内商业化 瓦莫龙，并为扩大瓦莫龙在许多其他临床疾病中的使用奠定了基础 皮质类固醇是有效的，但严重的副作用限制了其使用。

项目成果

Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug.

杜氏肌营养不良症的 IIa 期试验表明，伐莫龙是一流的解离性类固醇抗炎药。

• 发表时间: 2018-10
• 影响因子: 9.3
• 作者: Conklin, Laurie S;Damsker, Jesse M;Hoffman, Eric P;Jusko, William J;Mavroudis, Panteleimon D;Schwartz, Benjamin D;Mengle;Smith, Edward C;Mah, Jean K;Guglieri, Michela;Nevo, Yoram;Kuntz, Nancy;McDonald, Craig M;Tulinius, Mar;Rya
• 通讯作者: Rya

Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy.

杜氏肌营养不良症男孩的瓦莫龙 (VBP15) 暴露反应分析。

• 发表时间: 2020
• 影响因子: 2.9
• 作者: Li, Xiaonan;Conklin, Laurie S;van den Anker, John;Hoffman, Eric P;Clemens, Paula R;Jusko, William J
• 通讯作者: Jusko, William J

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes.

瓦莫洛龙（一种一流的类固醇）的一期试验显示，通过与临床结果相联系的生物标志物可以改善副作用。

• 发表时间: 2018-06
• 影响因子: 2.7
• 作者: Hoffman, Eric P;Riddle, Valerie;Siegler, Maxime A;Dickerson, Daniel;Backonja, Miroslav;Kramer, William G;Nagaraju, Kanneboyina;Gordish;Damsker, Jesse M;McCall, John M
• 通讯作者: McCall, John M