Ph 2a Study of S48168 (ARM210) for CPVT 1 IND 152773 (09/11/2020)

S48168 (ARM210) CPVT 1 IND 152773 的 Ph 2a 研究 (09/11/2020)

• 批准号: 10280877
• 负责人: EUGENE E. MARCANTONIO
• 金额: $ 50万
• 依托单位: ARMGO PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10280877
• 关键词: Ph; 2a; Study; S48168; ARM210

ARMGO Pharma Inc., is advancing novel small-molecule Rycal® therapeutics for the treatment of human diseases with leaky Calcium efflux channels, ryanodine receptors (RyR). We focus on genetic orphan diseases with high unmet medical need. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a life- threatening disease in which most patients have causative genetic mutations in RyR2 leading to leaky channels. Patients present with stress-mediated ventricular arrhythmias associated with a high incidence of sudden cardiac death. The typical patient with CPVT is a child or young adult (mean age at diagnosis 6-10 years old) free of structural cardiac disease, with a normal resting electrocardiogram, who presents with exercise or emotionally- induced palpitations or syncope. If not managed, CPVT is a highly lethal disease with an untreated mortality rate of 30-50% by the age of 40. The primary standard-of-care regimen is a combination of beta-blockers and sodium channel blockers to prevent elevations of heart rate, which can lead to the fatal arrythmias. The challenge with the current standard of care is that these drugs lead to fatigue and generalized malaise when dosed to a high enough level to prevent elevations of heart rate. Particularly in children, it is challenging to ensure that doses are not missed and that there is no self-reduction of doses, which can be lethal. There is a high unmet need for a medical therapy which repairs leaky RyR channels so that elevations of heart rate with exercise are well tolerated and not associated with sudden death. Rycals are small molecule, orally deliverable therapeutics which offer such a potential therapy. Rycal compounds bind to leaky RyRs and allow them to retain their normal gating properties. In mice expressing a human mutation causing CPVT, treatment with Rycals prevents stress induced arrhythmias and sudden death, yet allowing for a normal elevation of heart rate with stress. A lead Rycal, S48168 (ARM210) has completed multiple phase 1 studies and was well tolerated. This proposal describes a clinical trial evaluating S48168 (ARM210) for the treatment of Catecholaminergic Polymorphic Ventricular Tachycardia Type 1 (CPVT 1) patients. Patients on a standard-of-care regimen presenting with residual exercise-induced ventricular ectopy, but not polymorphic ventricular tachycardia, will be randomized to either S48168 (ARM210) or placebo (2:1) and dosed for 28 days. The safety and pharmacokinetics of S48168 (ARM210) will be evaluated and compared to that previously seen in Phase 1. Most importantly, we will test the efficacy in reducing and eliminating residual ventricular ectopy by a comparison of rhythms with exercise stress testing before and after treatment, which is used annually to assess the efficacy of their medical regimen. S48168 (ARM210) is expected to be disease modifying in these patients as the only known defect is mutations in RyR, allowing them to live safe, normal lives.

Armgo Pharma Inc.，正在推进新型的小分子Rycal®治疗人类治疗 具有漏水的钙外排通道，ryanodine受体（RYR）的疾病。我们专注于遗传孤儿疾病 有高未满足的医疗需求。儿茶酚胺能多态性心室心动过速（CPVT）是一种生命 威胁性疾病，其中大多数患者在RYR2中患有严重的基因突变，导致漏水通道。 患者患有应力介导的心室心律不齐，与突然心脏的高入射有关 死亡。 CPVT的典型患者是儿童或年轻人（6-10岁诊断时的平均年龄） 结构性心脏病，具有正常的静息心电图，他在运动或情感上呈现 诱发呼吸症或晕厥。如果不管理，CPVT是一种高度致命的疾病，死亡率未治疗 到40岁时的30-50％。主要护理标准方案是β受体阻滞剂和钠的组合 通道阻滞剂可防止心率升高，这可能导致致命的雅利亚山脉。挑战 当前的护理标准是，这些药物在高高时会导致疲劳和普遍不适 足够的水平以防止心率升高。特别是在儿童中，确保剂量是 没有错过，也没有自我减少剂量，这可能是致命的。很高的未满足需要 维修泄漏的RYR通道的药物治疗，以使运动升高良好 并且与猝死无关。 Rycals是小分子，口服可兑换疗法，可提供这种潜在的疗法。 Rycal化合物 与泄漏的Ryr结合，并允许它们保留其正常的门控性能。在表达人类突变的小鼠中 引起CPVT，用Rycals治疗可防止压力引起的心律不齐和猝死，但允许 正常的心率升高压力。铅rycal，S48168（ARM210）已完成多个阶段1 研究且耐受性良好。该提案描述了一项评估S48168（ARM210）的临床试验 治疗儿茶酚胺能多态性室心动过速1型（CPVT 1）患者。患者 呈现残留运动诱导的心室外缘的护理标准方案，但不是多态性的 心室心动过速，将随机分为S48168（ARM210）或安慰剂（2：1），并剂量28天。 将评估S48168（ARM210）的安全性和药代动力学 在第1阶段。最重要的是，我们将测试通过通过 在治疗前后，节奏与运动应力测试的比较，每年用于评估 他们的医疗方案的效率。 S48168（ARM210）有望在这些患者中改变疾病 作为唯一已知的缺陷是RYR中的突变，使他们能够过安全，正常的生活。