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 Biotechandapos;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 complete preclinical development of this targeted novel therapeutic, the Company will apply its considerable synthetic chemistry expertise with the guidance of experts in medicinal chemistry and preclinical toxicology to optimize its 2 pre-lead candidates, select a lead and take it through IND-enabling studies. Elex Biotechandapos;s Target Product Profile (TPP) was specifically designed to develop a safe and highly effective oral drug that can be taken 1-2 times a day for the treatment of CPVT. With the use of the Companyandapos;s well-established animal models of CPVT and available standard preclinical toxicology and pharmacology assay systems, Elex Biotech will evaluate multiple analogs of each pre-lead and select a best lead candidate based on our TPP along with input from potential pharmaceutical partners. The Company will apply for Orphan Designation for its lead candidate and design and implement a plan for IND-enabling studies based on a pre-IND FDA meeting. At the end of the project, Elex Biotech will have a data package to support an IND filing. In order to accomplish these goals, the following specific aims are proposed: Specific Aim 1. To design and synthesize pre-lead compounds using results from in vitro and preclinical studies. Specific Aim 2. Lead drug candidate selection. Specific Aim 3. Complete IND-enabling studies.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.