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

ARMGO Pharma Inc.，正在推进新型小分子Rycal®疗法，用于治疗人类 钙外排通道渗漏性疾病，ryanodine受体（RyR）。我们专注于遗传性孤儿疾病 高度未满足的医疗需求。儿茶酚胺能多形性室性心动过速（CPVT）是一种生命- 威胁性疾病，其中大多数患者在RyR 2中具有导致渗漏通道的致病基因突变。 应激介导的室性心律失常患者与高发生率的突发性心脏病 死亡典型的CPVT患者是儿童或年轻成人（诊断时平均年龄6-10岁）， 结构性心脏病，静息心电图正常，表现为运动或情绪- 诱发心悸或晕厥。如果不加以管理，CPVT是一种高度致命的疾病，未经治疗的死亡率很高 在40岁时会减少30-50%。主要的标准治疗方案是β受体阻滞剂和钠的组合 通道阻滞剂，以防止心率升高，这可能导致致命的心律失常。的挑战 目前的护理标准是这些药物在高剂量时导致疲劳和全身不适 足以防止心率升高。特别是在儿童中，确保剂量 没有错过，也没有自我减少剂量，这可能是致命的。有一个高度未满足的需要， 修复RyR通道渗漏的药物治疗，使运动引起的心率升高耐受良好 与猝死无关 Rycals是一种小分子的口服治疗药物，提供了这样一种潜在的治疗方法。Rycal化合物 结合到泄漏RyR并允许它们保持其正常的门控特性。在表达人类突变的小鼠中 引起CPVT，Rycals治疗可预防应激诱发的心律失常和猝死， 紧张时心率正常升高。领先的Rycal，S48168（ARM 210）已经完成了多个阶段1 研究并耐受良好。该提案描述了一项临床试验，评估S48168（ARM 210）用于 治疗1型儿茶酚胺能多态性室性心动过速（CPVT 1）患者。中的患者 标准治疗方案表现为残余运动诱发心室异位，但非多态性 室性心动过速，将随机分配至S48168（ARM 210）或安慰剂组（2：1），给药28天。 将评价S48168（ARM 210）的安全性和药代动力学，并与之前观察到的结果进行比较 第一阶段。最重要的是，我们将通过以下方式测试减少和消除残余心室异位的疗效： 治疗前后的节律与运动负荷测试的比较，每年用于评估 他们的医疗方案的有效性预计S48168（ARM 210）可改善这些患者的疾病 因为唯一已知的缺陷是RyR的突变，使他们能够过上安全，正常的生活。

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.