Development of Novel Compounds for Treatment of Heart Arrhythmias in CPVT

PROJECT SUMMARY The goal of this project is to complete the preclinical development of Elex Biotech’s novel compounds that target and treat the underlying molecular cause of catecholaminergic polymorphic ventricular tachycardia (CPVT) CPVT. There are no FDA-approved treatments for CPVT, a rare genetic disorder affecting 1/10,000 individuals, with typical onset in children 7-9 years of age and no reported differences by gender. CPVT results in potentially deadly arrhythmias and is responsible for 15% of sudden cardiac deaths in apparently healthy young people. Only 5-10% of pediatric patients survive out-of-hospital cardiac arrests, often with severe neurological sequelae. The overall mortality rate is 30-50% by age 20-30. Approximately 60% of CPVT cases are known to be caused by mutations in type 2 ryanodine receptor (RyR2), the calcium release channel that regulates the strength and frequency of heart muscle contraction. However, current medications (mainly -blockers) do not target RyR2, and are used off-label in spite of limited efficacy and significant side-effects. Approximately 30% - 50% of patients treated with -blockers eventually require an Implantable cardioverter-defibrillator (ICD) to prevent cardiac arrest. ICDs are expensive to implant and maintain, do not prevent arrhythmias and can produce inappropriate shocks which actually induce arrhythmias. In Europe, flecainide is used along with -blockers, but it may cause or exacerbate existing heart rhythm problems and has a Block Box Warning in the US. Delivering a safe, effective and targeted CPVT treatment is the goal of this program. To advance its targeted novel therapeutic IND-enabling (GLP) studies, the Company will evaluate the lead compound it has selected in a non-rodent species for the purpose of establishing in vivo dosing parameters. Elex Biotech will also work with a contract manufacturing organization (CMO) to scale up the synthesis of the lead compound under practice GMP conditions to have a large quantity of material (GMP Demo batch) suitable for GLP studies. The Company will apply for Orphan Designation for its lead candidate and develop clinical and regulatory strategies for later discussion in a pre-IND meeting with FDA. At the end of this project, Elex Biotech will have both a Demo Batch of lead compound and data for determining initial in vivo dosing for initiating GLP IND-enabling studies for the on-going Phase IIB project. In order to accomplish these goals, the following specific aims are proposed: Specific Aim 1. Lead compound pharmacology/toxicology studies in dogs. Specific Aim 2. Synthesized practice GMP method development (GMP Demo) batch of lead compound with draft master batch records.PROJECT NARRATIVE This project is relevant to NIHandapos;s mission because it addresses the need for improved treatment options for catecholaminergic polymorphic ventricular tachycardia (CPVT), an orphan disease with a typical onset in children 7-9 years of age resulting in potentially deadly arrhythmias and is responsible for 15% of unexplained sudden cardiac deaths in apparently healthy children. There are no FDA approved treatments for CPVT; current off-label medications offer limited efficacy and significant side effects the negatively impact quality of life. The goal of this project is to prepare a candidate drug for clinical development as a safe and highly effective oral drug for the treatment of CPVT.