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

摘要 瓦莫龙是一流的游离甾体药物，正在开发用于杜氏肌痛 营养不良作为替代皮质类固醇标准治疗（泼尼松，deflazacort）的小企业 ReveraGen BioPharma。ReveraGen在NINDS SBIR直接到 II期奖励（48名DMD男孩;连续临床试验VBP 15 -002、VBP 15 -003、VBP 15-LTE、扩展 入路方案），这些研究已发表（Conklin et al. 2018;霍夫曼et al. 2019）。这些研究 在运动技能的所有测量中显示出剂量反应性改善，并且副作用消失（没有发育迟缓）。 生长，更少的Cushingoid和体重增加）。生物标志物已整合到整个vamorolone 程序，提供药物疗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。一项120名DMD男孩的双盲关键试验（VBP 15 -004）目前有40% 在11个国家的31个研究中心入组和招募。这项关键性研究得到了NINDS SBIR的部分支持 IIB期奖和欧盟委员会Horizons 2020奖，包括安慰剂和泼尼松 怀里预计该试验将于2019年底或2020年初全部入组，最后一例患者末次访视 预计2020年第三季度将启动美国（FDA NDA）和 欧洲（EMA MAA）。ReveraGen一直是一家私人控股的小企业，这使得 临床试验设计、生物标志物的使用和监管协议方面的创新。例如，ReveraGen 要求FDA考虑离开vamorolone临床试验的患者的扩大使用方案，因为这 将减轻患者家属和临床研究中心的负担，同时保持集中的安全性信息， 这被批准了，导致FDA发布新闻稿，鼓励其他人考虑类似的方法。为此 商业化就绪试点（CRP）应用，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，并使全球药物批准， 最大化从而使全世界的药物批准和最大化的市场准入。技术援助 要求既要制定全球监管战略，又要制定全球知识产权 战略对后期研发活动的支持，包括填补已确定的差距， 质量体系控制，并进行GLP幼龄动物毒性研究，支持标签和处方， 新生儿时期。完成拟议的CRP的目标将导致全球商业化， 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使用。

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.