Development of Novel Compounds for Treatment of Heart Arrhythmias in CPVT

DESCRIPTION provided by applicant Abstract Current therapies to treat the orphan disease catecholaminergic polymorphic ventricular tachycardia CPVT have potential side effects so severe that hospitalization is required upon treatment initiation and severely exacerbate depression and fatigue in children that already have psychological issues due to this devastating life long life threatening illness The long term goal of Elex Biotech is to create improved pharmaceuticals with minimal side effects thereby providing superior treatment options for CPVT and related ventricular arrhythmias In the current Phase proposal the main objective is to obtain extensive pre clinical data on optimized lead compounds The central hypothesis is that drugs with enhanced electron donor properties that target RyR will be highly effective in decreasing the SR Ca leak associated with ventricular arrhythmias This unique hypothesis guided the development of lead compounds that met or exceeded phase benchmarks including one that was effective in treating CPVT in rodent models at nearly orders of magnitude lower dosage levels compared to the current treatment standard flecainide as well as all other well known RyR inhibitors such as K The specific aims addressing the Phase objective are i to optimize lead compounds via an SAR evaluation based on in vitro and preclinical studies and ii preclinical evaluation of the lead drug candidates One or more lead compounds identified in Aim will be moved into in vivo preclinical evaluation Additional leads will be tested and structural modification made to optimize performance based on screening such as liver microsomal stability plasma stability protein binding secondary pharmacology screening off target effects and in silico genotoxicity A pharmacokinetic PK study in mice is planned to evaluate parameters underlying efficacy to guide dosages for toxicology studies a PK study in rat Acceptable results for bioavailability and half life from th rat PK study will confirm a lead drug candidate to be moved into dose range finding studies DRF in Phase The company has assembled a team with extensive expertise in cardiac ion channels pediatric cardiology and CPVT calcium channel biophysics organic synthesis medicinal chemistry preclinical safety studies and orphan drug regulatory review PUBLIC HEALTH RELEVANCE This project is relevant to NIHandapos s mission because it addresses the need for improved treatment options for catecholaminergic polymorphic ventricular tachycardia CPVT a devastating orphan disease of the lower ventricles of the heart CPVT is estimated to cause a significant number of unexplained sudden cardiac deaths in children The currently prescribed medication for CPVT flecainide can cause death or side effects so severe that a minimum of three days of hospitalization are required for patients beginning treatment Because CPVT typically manifests during childhood often flecainide is sent to compounding pharmacies to create slurries to facilitate dosing in young children that have trouble swallowing pills However it is apparently relatively easy to err in compounding flecainide as a number of tragedies have been reported in cases of children taking these formulations Available prior flecainide beta blockers have been widely used in CPVT treatment However apart from being ineffective in of CPVT patients they cause depression and fatigue They thereby worsen a significant aspect of quality of life for children that are already dealing with having a devastatig long term illness The goal of this proposal is to develop safer and more effective drugs to treat CPVT Proof of concept studies in Phase met or exceeded expectations For example a new molecule was discovered that effectively treated heart arrhythmias in a rodent model of CPVT at nearly a fold smaller dosage compared to flecainide The significantly diminished dose and greater potency achieved as a result of a unique scientific hypothesis will enable the planned Phase development of improved drugs for CPVT