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.