Pivotal trial of vamorolone in Duchenne muscular dystrophy

瓦莫龙治疗杜氏肌营养不良症的关键试验

• 批准号: 9767888
• 负责人: Paula R Clemens
• 金额: $ 149.91万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767888
• 关键词: 7 year old; Adrenal Cortex Hormones; Adrenal Glands; Adverse drug effect; Adverse effects; Affinity; Age; Agonist; Agreement; Anti-inflammatory; Autoimmune Process; Award; Becker Muscular Dystrophy; Binding; Biological Markers; Blinded; Body mass index; Capital; Chemistry; Child; Clinical; Clinical Research; Clinical Trials; Controlled Study; Dermatomyositis; Development; Dose; Double-Blind Method; Drug Kinetics; Duchenne muscular dystrophy; Enrollment; Essential Drugs; European; Exercise; Formulation; Foundations; Funding; Future; Genetic; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Government; Grant; Growth; Half-Life; Hydrocortisone; Insulin Resistance; International; Label; Leadership; Legal patent; Marketing; Measures; Mediating; Mineralocorticoid Receptor; Monitor; NR3C1 gene; NR3C2 gene; National Institute of Neurological Disorders and Stroke; Neuromuscular Diseases; Osteopenia; Outcome; Outcome Measure; Pamphlets; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebos; Prednisone; Program Development; Protocols documentation; Quality of life; Randomized; Rare Diseases; Research; Research Contracts; Research Personnel; Risk Management; Safety; Sales; Small Business Innovation Research Grant; Steroids; Structure; Testing; Therapeutics for Rare and Neglected Diseases; Time; Toxicology; Transactivation; United States National Institutes of Health; Weight Gain; actigraphy; biomarker panel; bone fragility; bone turnover; boys; clinical development; clinical efficacy; commercialization; community setting; deflazacort; drug development; improved; innovation; mHealth; neuromuscular; novel; off-patent; open label; payment; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; phase III trial; preclinical development; preservation; programs; research clinical testing; standard of care; tool; trial design

Abstract ReveraGen BioPharma is a clinical stage drug development company that is developing vamorolone (VBP15), a first-in-class dissociative steroidal drug. The initial indication being tested is Duchenne muscular dystrophy (DMD), where vamorolone holds promise for retaining or increasing efficacy of glucocorticoids, while reducing adverse effects (bone fragility, stunting of growth, weight gain, insulin resistance). ReveraGen received a NINDS SBIR Phase II grant in support of the Phase 2a studies in 4 to <7 year old DMD boys in 2016 (protocols VBP15-002; VBP15-003) (R44NS095423). The original trial was planned for four dose groups, with 2-6 boys per dose group (up to 24 patients). After award of the grant, the size of the trial was increased to 48 DMD boys (12 per dose group; n=48). Despite the narrow age range in a rare disease, the trial was fully enrolled within 15 months, and the Phase 2a study completed in November 2017, within the time frame of the SBIR Phase II grant (15 February 2016-31 January 2018). All doses were well-tolerated (0.25 mg/k/gday – 6.0 mg/kg/day; or to 10-times the typical prednisone dose in DMD boys). Pharmacokinetics showed a well- behaved drug, with PK similar to corticosteroids (short half-life of 2-3 hrs, and no drug accumulation between doses). There was no significant change in body mass index (primary clinical safety outcome relative to prednisone). Pharmacodynamic biomarker results showed improved safety compared to corticosteroids, with no evidence of insulin resistance at any dose, and a >10 fold improved safety margin for bone turnover and adrenal suppression. Here, we request partial support for the pivotal double blind Phase 2b study of 120 DMD boys, ages 4 to <7 years. The Phase 2b study (VBP15-004) includes four groups with six months treatment (placebo, prednisone, low dose vamorolone, high dose vamorolone), followed by an additional 6 months treatment with two dose levels of vamorolone. Co-funding for the Phase 2b study is from the European Commission ($7M Horizons 2020 grant awarded in 2016), venture philanthropy support by non-profit foundations, and an option agreement for future sales and marketing. Aim 1 is to test 6 months of treatment of two dose levels of vamorolone, with efficacy (time to stand) vs. placebo, and safety (change in body mass index) vs. prednisone. Aim 2 is to bridge pharmacodynamic biomarkers to clinical outcomes of both safety and efficacy. Anticipated new matching funding during the proposed award period includes a 2nd milestone payment on the option agreement ($15M August 2018). The completion of the proposed Phase IIB SBIR research will lead to discussions with the FDA regarding possible accelerated approval, with Phase III trials in the post-marketing period. The bridging of novel safety and efficacy biomarkers to clinical outcomes will enable the utilization of these biomarkers to expand labeling to younger DMD children (0-4 years), and efficient testing of vamorolone for treatment of new indications (eg. Becker muscular dystrophy, juvenile dermatomyositis), thus providing the potential to significantly augment the treatment options and quality of life for patients with genetic and autoimmune neuromuscular disorders.

抽象的 Reveragen Biopharma是一家正在开发Vamorone（VBP15）的临床阶段药物开发公司， 一种一流的分离型类固醇药物。测试的最初指示是Duchenne肌肉营养不良 （DMD），瓦莫洛烯具有保留或提高糖皮质激素效率的承诺，同时还原 不良反应（骨骼脆弱性，生长发育迟缓，体重增加，胰岛素抵抗）。 Reveragen收到了 Ninds SBIR II期授予支持2016年4至7岁的DMD男孩的2A期研究（协议） VBP15-002; VBP15-003）（R44NS095423）。原始试验计划针对四个剂量组，有2-6个男孩 每剂组（最多24例）。授予赠款后，审判的规模增加到48 DMD 男孩（每个剂量组12个； n = 48）。尽管罕见疾病的年龄范围狭窄，但该试验已完全注册 在15个月内，第2A期研究于2017年11月完成，在SBIR的时间范围内 第二阶段赠款（2016年2月15日，2018年1月15日）。所有剂量均耐受性良好（0.25 mg/k/gday - 6.0 mg/kg/day;或10次DMD男孩中典型的泼尼松剂量）。药代动力学显示出良好的 表现的药物，具有类似于皮质类固醇的PK（半衰期短的2-3小时，并且之间没有药物积累 剂量）。体重指数没有显着变化（主要的临床安全结果相对于 强的松）。与皮质类固醇相比 没有任何剂量的胰岛素抵抗的证据，> 10倍的骨骼更新和 肾上腺抑制。在这里，我们要求对120 DMD的关键双盲阶段2B研究部分支持 男孩，4至7岁。 2B期研究（VBP15-004）包括四组和六个月的治疗 （安慰剂，泼尼松，低剂量vamorollone，高剂量vamorollone），然后再增加6个月 用两种剂量的vamorollone处理。 2B期研究的共同资助来自欧洲 委员会（2016年700万美元的Horizo​​ns 2020赠款），非营利组织的风险投资慈善支持 基金会以及未来销售和营销的期权协议。目标1是测试6个月的治疗 两种剂量水平的Vamorone，具有效率（站立时间）与安慰剂和安全性（体重变化） 索引）与泼尼松。目标2是将药效生物标志物桥接到安全性和安全性的临床结果 功效。拟议颁奖期间预期的新匹配资金包括第二个里程碑 期权协议付款（2018年8月1500万美元）。拟议的IIB SBIR阶段的完成 研究将导致与FDA有关可能加速批准的讨论，并进行III期试验 销售后期。将新型安全性和有效生物标志物与临床结局桥接将 使这些生物标志物的利用能够将标签扩展到年轻的DMD儿童（0-4岁），并有效 对新适应症治疗的Vamorone测试（例如，贝克尔肌肉营养不良，少年 皮肤病），因此提供了显着增强治疗选择和生活质量的潜力 适用于遗传和自身免疫性神经肌肉疾病的患者。