Pivotal trial of vamorolone in Duchenne muscular dystrophy

摘要 ReveraGen BioPharma是一家临床阶段药物开发公司，正在开发vamorolone（VBP 15）， 一种一流的游离类固醇药物最初的迹象正在测试是杜氏肌营养不良症 (DMD)，其中vamorolone有望保留或增加糖皮质激素的疗效，同时减少 不良反应（骨脆性、生长迟缓、体重增加、胰岛素抵抗）。ReveraGen收到了一份 NINDS SBIR II期资助，支持2016年4至<7岁DMD男孩的2a期研究（方案 VBP15-002; VBP15-003）（R44NS095423）。最初的试验计划为4个剂量组，有2-6个男孩 每个剂量组（最多24例患者）。在获得拨款后，试验规模增加到48 DMD 男孩（12/剂量组; n=48）。尽管罕见疾病的年龄范围很窄，但该试验完全招募 在SBIR的时间范围内，2a期研究于2017年11月完成 第二阶段赠款（2016年2月15日至2018年1月31日）。所有剂量均耐受良好（0.25 mg/kg/day- 6.0 mg/kg/day mg/kg/天;或DMD男孩中典型泼尼松剂量的10倍）。药代动力学显示- 表现药物，PK与皮质类固醇相似（半衰期短，2-3小时， 剂量）。体重指数无显著变化（主要临床安全性结局相对于 强的松）。药效学生物标志物结果显示，与皮质类固醇相比， 在任何剂量下都没有胰岛素抵抗的证据，并且骨转换的安全界限提高了>10倍， 肾上腺抑制在此，我们请求对120例DMD患者的关键性双盲2b期研究提供部分支持 男孩，4至<7岁。2b期研究（VBP 15 -004）包括4组，治疗6个月 （安慰剂，泼尼松，低剂量vamorolone，高剂量vamorolone），然后再治疗6个月 用两种剂量水平的vamorolone治疗。2b期研究的共同资助来自欧洲 委员会（2016年授予的700万美元Horizons 2020赠款），非营利组织的风险慈善事业支持 基金会，以及未来销售和营销的选择权协议。目标1是测试6个月的治疗 两种剂量水平的vamorolone，与安慰剂相比的疗效（站立时间）和安全性（体重变化 指数）与泼尼松。目的2是将药效学生物标志物与安全性和安全性的临床结果联系起来。 功效在拟议的奖励期间，预计新的匹配资金包括第二个里程碑 期权协议的付款（2018年8月1500万美元）。完成拟议的IIB期SBIR 研究将导致与FDA讨论可能的加速批准，III期试验将在 上市后时期。将新型安全性和有效性生物标志物与临床结局联系起来， 使这些生物标志物的利用能够将标记扩展到更年轻的DMD儿童（0-4岁），并且有效地 用于治疗新适应症（例如，幼年型贝克肌营养不良症 皮肌炎），从而提供了显著增加治疗选择和生活质量的潜力 用于遗传性和自身免疫性神经肌肉疾病患者。

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.