SBIR-STTR Award

Sudden cardiac death (SCD) is a major cause of death, responsible for greater than 300,000 adult deaths per year in the United States alone. Cardiac arrest and SCD are caused by ventricular arrhythmias, in particular ventricular fibrillation, which leads to the inability of the heart to circulate blood throughout the body. Approximately 50% of patients suffering from heart failure die as a result of ventricular arrhythmias. Treatment options for the termination or suppression of episodes of ventricular tachycardia include implantable cardioverter-defibrillators (ICD), catheter ablation, and anti-arrhythmic drugs. The efficacy of anti-arrhythmic drugs for the treatment of ventricular tachycardia remains suboptimal, and in some cases their use results in an increased the risk of mortality. There is a clear need for a new innovative approach for developing more effective, specific and safer anti- arrhythmic drugs for the treatment and prevention of ventricular tachycardia. Given the prominent role of RyR2 in the control of Ca2+ homeostasis, pharmacological strategies to modulate RyR2 stability and gating have shown great promise as a therapy for cardiac arrhythmias. Unfortunately, many of the drugs presently used to treat arrhythmias are non-specific in their action. The approach taken in this proposal involves generating a small library of new RyR2 inhibitors with enhanced electron donor properties. This approach is based on our observation that the electron donor properties of drugs targeting RyR2 are prime determinants of the effectiveness of these new molecules. Progress to date demonstrates that new drugs with enhanced electron donor properties act as highly effective inhibitors of RyR2 and as effective inhibitors of arrhythmias in an arrhythmogenic mouse model. The specific aims of this project are as follows: 1) to design and synthesize new RyR2 inhibitors with enhanced electron donor properties. 2) To evaluate the potency of these compounds as electron donors, and as inhibitors of RyR2 at the molecular, cellular and whole animal level. To determine their potency in normalizing Ca2+ homeostasis and decreasing arrhythmias at the cellular, and whole animal level, and to determine the specificity of these new compounds. 3) To evaluate the toxicity of these new drugs in ventricular myocytes. To carry out in vivo and in vitro toxicity studies, and to determine the metabolic stability of these new drugs. Success in phase 1 will be evaluated on the basis of the potency of the new drugs developed in this study. The goal of ELEX Biotech in phase 1 is to develop a group of new drugs which are 100 to 1000 times more effective than our starting compounds in normalizing Ca2+ homeostasis in ventricular myocytes, and decreasing arrhythmias.

Public Health Relevance:
Cardiac Arrest and sudden cardiac death caused by arrhythmias is a major cause of death in the United States and in the world. Existing medications tend to be only mildly effective and are relatively non-specific. In order to meet the urgent need for effective therapeutics, ELEX Biotech will create new more potent medications to treat ventricular arrhythmias via a novel approach toward drug design.

Public Health Relevance Statement:
Cardiac Arrest and sudden cardiac death caused by arrhythmias is a major cause of death in the United States and in the world. Existing medications tend to be only mildly effective and are relatively non-specific. In order to meet the urgent need for effective therapeutics, ELEX Biotech will create new more potent medications to treat ventricular arrhythmias via a novel approach toward drug design.

NIH Spending Category:
Cardiovascular; Heart Disease

Project Terms:
Adult; Animals; Anti-Arrhythmia Agents; Arrhythmia; base; Blood; Cardiac ablation; Cardiac Myocytes; Cause of Death; Cessation of life; Congenital Disorders; Death, Sudden, Cardiac; design; Development; Drug Delivery Systems; Drug Design; Drug toxicity; Effectiveness; electron donor; Goals; Heart; Heart Arrest; Heart failure; Homeostasis; Implantable Defibrillators; In Vitro; in vivo; inhibitor/antagonist; innovation; Laboratories; Libraries; Measures; Mediating; meetings; Metabolic; Molecular; Mortality Vital Statistics; mouse model; Muscle Cells; Myocardial Ischemia; non-drug; novel strategies; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase; Prevention; Property; Risk; Role; RyR2; Sarcoplasmic Reticulum; Specificity; success; Testing; Therapeutic; Time; Toxic effect; United States; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia

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 2 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 RyR2 will be highly effective in decreasing the SR Ca2+ leak associated with ventricular arrhythmias. This unique hypothesis guided the development of lead compounds that met or exceeded phase 1 benchmarks, including one that was effective in treating CPVT in rodent models at nearly 4 orders of magnitude lower dosage levels compared to the current treatment standard flecainide as well as all other well- known RyR2 inhibitors such as K201. The specific aims addressing the Phase 2 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 1 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 3. 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 Statement:


Public Health Relevance:
This project is relevant to NIH'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 30 % 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 1 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 10,000-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 2 development of improved drugs for CPVT.

Project Terms:
abstracting; Address; Adrenergic beta-Antagonists; Adverse effects; Affect; animal efficacy; Animals; Arrhythmia; base; Benchmarking; Biological Assay; Biological Availability; Biophysics; Calcium Channel; Cardiac; Cardiology; Cause of Death; Cells; Child; Childhood; Chronic; Clinical; Clinical Data; Computer Simulation; Congenital Heart Defects; Coupling; cytotoxicity test; Data; Death, Sudden, Cardiac; Defect; Deglutition; Development; Disease; DNA Sequence Alteration; dosage; Dose; drug candidate; Drug Formulations; Drug Kinetics; electron donor; Evaluation; Exhibits; expectation; Fatigue; Flecainide; Frequencies (time pattern); genotoxicity; Goals; Half-Life; Heart Arrest; heart rhythm; Heart Ventricle; Hospitalization; Implantable Defibrillators; improved; In Vitro; in vivo; in vivo Model; Inborn Genetic Diseases; Individual; inhibitor/antagonist; Inhibitory Concentration 50; Ion Channel; Lead; Life; Liver; meetings; Mental Depression; Mission; Modification; Molecular; mouse model; Mus; Muscle Cells; mutant; Mutation; Nature; novel; Oral; Organic Synthesis; Orphan Drugs; Patients; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacy facility; Phase; pill (pharmacologic); Plasma; pre-clinical; preclinical evaluation; preclinical safety; preclinical study; prevent; programs; Property; Protein Binding; psychologic; public health relevance; Publishing; Quality of life; Rare Diseases; Rattus; Reporting; Research; Risk; Rodent Model; Ryanodine Receptor Calcium Release Channel; RyR2; safety study; Sarcoplasmic Reticulum; Scientist; screening; Series; Shock; Small Business Technology Transfer Research; standard care; Sudden Death; Testing; Therapeutic; Toxic effect; Toxicology; Ventricular Arrhythmia; Ventricular Tachycardia; Work