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

ARMGO Pharma Inc.正在开发用于治疗人类疾病的新型小分子Rycal®疗法 具有泄漏的钙外流通道的疾病，兰尼定受体(RyR)。我们关注的是遗传性孤儿疾病 有高度未得到满足的医疗需求。儿茶酚胺能多形性室性心动过速(CPVT)是一种生命- 一种威胁性疾病，大多数患者在RyR2上有致病基因突变，导致渠道泄漏。 伴有应激性室性心律失常的患者心脏骤停发生率较高 死亡。典型的CPVT患者是儿童或年轻人(确诊时平均年龄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。如果不加以处理，CPVT是一种高度致命的疾病，未经治疗死亡率高。 到40岁时达到30%-50%。主要的标准护理方案是β-受体阻滞剂和钠的组合。 通道阻滞剂，以防止心率加快，这可能导致致命的心律失常。面临的挑战 目前的护理标准是，这些药物在剂量过高时会导致疲劳和全身不适。 达到足以防止心率升高的水平。特别是在儿童中，确保剂量达到 没有错过，而且没有自我减少剂量，这可能是致命的。有一种高度未得到满足的需求 修复漏水的RyR通道，以便很好地耐受运动引起的心率加快的药物疗法 与猝死无关。 Rycals是一种小分子口服疗法，提供了这样一种潜在的治疗方法。Rycal化合物 绑定到漏水的RYR，并允许它们保持其正常的门控属性。在表达人类突变的小鼠中 导致CPVT的Rycals治疗可以预防应激引起的心律失常和猝死，但允许 应激时心率正常升高。Lead Rycal S48168(ARM210)已完成多个阶段1 学习，并被很好地容忍。本提案描述了一项评估S48168(ARM210)的临床试验 儿茶酚胺能多形性室性心动过速1型患者的治疗接受治疗的病人 标准护理方案表现为运动诱发的残留室性异位，但不是多形性的 室性心动过速的患者将被随机分为S48168(ARM210)或安慰剂(2：1)，并服用28天。 将对S48168(ARM210)的安全性和药代动力学进行评估，并与以前看到的进行比较 在第一阶段。最重要的是，我们将通过以下方式测试减少和消除残留室性异位的有效性 运动负荷试验在治疗前后节律的比较，每年用于评估 他们的医疗方案的疗效。S48168(ARM210)有望成为这些患者的疾病改良剂 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.