Compositions and methods for treating arrhythmogenic cardiomyopathy - Patents.com

Abstract

The present invention provides methods for treating or alleviating symptoms of arrhythmogenic cardiomyopathy (ACM) by administering a thiadiazolidinedione or a derivative thereof, such as tideglusib or NPE1000928. Symptoms of ACM that are improved by treatment include arrhythmias, pulmonary congestion, heart murmurs, rapid heart rate, chest pain, lightheadedness, myocardial fibrofatty infiltration, heart failure, and the like.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Patent Application No. 63 / 148,346, filed February 11, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates generally to the treatment and / or prevention of arrhythmogenic cardiomyopathies (ACM), such as arrhythmogenic right ventricular cardiomyopathy (ARVC), by administration of a thiadiazolidinedione. [Background technology]

[0003] Arrhythmogenic cardiomyopathy (ACM) is an inherited form of structural heart disease characterized by myocardial fibrofatty infiltration. The majority of cases, termed arrhythmogenic right ventricular cardiomyopathy (ARVC), preferentially involve the right ventricle (RV). Clinical variants characterized by earlier and greater LV involvement have been reported, which may be similar (i.e., biventricular ACM) or exceed (i.e., prominent LV ACM) in severity of RV involvement.

[0004] Affected patients are vulnerable to malignant ventricular arrhythmias, sudden cardiac death (SCD), and heart failure. The development of the ACM phenotype can be influenced by both genetic and environmental factors, such as exercise. An increasingly diverse set of genes has been linked to ACM, but its most prominent genetic causes are components of desmosomes, specialized cellular structures within the intercalated disc that mediate cell-cell adhesion.

[0005] Despite progress in understanding the genetic basis of ACM, insight into its pathophysiology remains limited. This lack of understanding of key biological pathways has hindered the development of tailored treatments and has resulted in medical therapy approaches being adopted primarily from those utilized for more common forms of cardiomyopathies. Such treatments include implantable cardioverter defibrillators (ICDs), antiarrhythmic drugs, beta-blockers, and heart failure medications. However, these treatment approaches are palliative, not curative, and are often inadequate.

[0006] Thus, there is a need for the development of treatments that target the underlying pathophysiology in ACM patients. The present invention fulfills this unmet need. Summary of the Invention

[0007] In various aspects, the present disclosure provides a method for treating or alleviating symptoms of arrhythmogenic cardiomyopathy (ACM) in a subject by administering a thiadiazolidinedione or a derivative thereof. The thiadiazolidinedione or a derivative thereof comprises an inhibitor of glycogen synthase kinase 3β (GSK3β). The GSK3β inhibitor is preferably a selective inhibitor. The GSK3β inhibitor is preferably a reversible inhibitor. Alternatively, the GSK3β inhibitor is an irreversible inhibitor.

[0008] Exemplary thiadiazolidinediones for use in the methods of the invention include tideglusib or NPE100928.

[0009] The subject is suffering from or at risk of suffering from ACM.The symptoms of ACM include ventricular tachycardia, implantable cardioverter defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, rapid heart rate, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibrofatty infiltration, embolism, heart failure, or sudden cardiac death (SCD).In some embodiments, ACM is arrhythmogenic right ventricular cardiomyopathy (ARVC).

[0010] In another aspect, the disclosure provides a method of reducing the number of premature ventricular contractions (PVCs) in a subject by administering a thiadiazolidinedione or a derivative thereof.

[0011] In yet another aspect, the disclosure provides a method of improving ventricular function by administering a thiadiazolidinedione or a derivative thereof.

[0012] The subject has an arrhythmogenic cardiomyopathy (ACM), such as, for example, arrhythmogenic right ventricular cardiomyopathy (ARVC).The subject has an implantable cardioverter defibrillator (ICD).

[0013] Administration of a thiadiazolidinedione or a derivative thereof reduces the number of electrical shocks delivered to a subject by an ICD.

[0014] In various embodiments, administration of a thiadiazolidinedione or derivative thereof improves a measure of ventricular function in a subject, such as, for example, ventricular strain, systolic function, or diastolic function.

[0015] Ventricular function is measured by echocardiography (echo), ambulatory rhythm (Holter) monitoring, cardiac CT scan, or cardiac magnetic resonance imaging.

[0016] The subject has one of the additional mutations in the gene associated with ACM. The gene associated with ACM is, for example, a gene encoding a component of desmosome. The gene encoding a component of desmosome includes, for example, plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), or plakoglobin (JUP). Other genes associated with ACM include, but are not limited to, transmembrane protein 43 (TMEM43), catenin alpha 3 (CTNNA3), desmin (DES), lamin A / C (LMNA), phospholamban (PLN), ryanodine receptor 2 (RYR2), transforming growth factor beta-3 (TGFB3), titin (TTN), filamin C (FLNC), RNA-binding motif protein 20 (RBM20), sodium voltage-gated channel alpha subunit 5 (SCN5A), or BAG co-chaperone 3 (BAG3).

[0017] In a further embodiment, the method for treating or alleviating the symptoms of atrial fibrillation in a subject comprises administering thiadiazolidinedione or its derivative to the subject who has or is at risk of having atrial fibrillation.The subject has ACM.The symptoms of atrial fibrillation include, for example, rapid heartbeat, arrhythmia, chest pain, lightheadedness, fainting, difficulty in breathing, heart failure, stroke or death.

[0018] The present disclosure further provides a method of reducing the number of atrial premature beats or improving atrial function by administering a thiadiazolidinedione or a derivative thereof. A subject has ACM or atrial fibrillation (AF).

[0019] In various methods of the present disclosure, the subject is a human, a canine, a feline, or an equine. Preferably, the subject is a human.

[0020] The thiadiazolidinedione or its derivative is administered orally. For example, the thiadiazolidinedione or its derivative is administered in a daily dose of about 100 mg to about 1500 mg. An exemplary daily dose is about 1000 mg or about 600 mg. The daily dose is administered in a single dose, two doses, three doses, or four doses.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. Similar or equivalent methods and materials to those described herein can be used in the practice of the present invention, and suitable methods and materials are described below. All publications, patent applications, patents, and other references described herein are expressly incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

[0022] Other features and advantages of the invention will be apparent from and are encompassed by the following detailed description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention is based in part on the discovery that the thiadiazolidinedione, tideglusib, prevents the electrical, molecular, and structural changes associated with arrhythmogenic cardiomyopathy (ACM). The ability of tideglusib to halt and even reverse ACM disease progression highlights the potential of targeted therapy to treat this life-threatening condition.

[0024] Thus, the disclosure provides methods of treating, preventing, or alleviating the symptoms of ACM by administering to a patient a thiadiazolidinedione.

[0025] ACM is a gene-related cardiac disorder characterized primarily by right and, more recently, left ventricular dysfunction and fibrofatty replacement of the myocardium, resulting in fatal / severe ventricular arrhythmias leading to sudden cardiac death in young people and athletes. ACM is considered a rare disease, occurring in 1 in 2500-5000 individuals, although the prevalence may be higher as diagnostic challenges have led to some patients going undiagnosed or misdiagnosed.

[0026] Currently, there are no treatments for ACM that address its underlying pathophysiology. As a result, treatment strategies for patients with ACM are primarily directed at preventing sudden cardiac death secondary to malignant ventricular arrhythmias, which most often involves the insertion of an implantable cardioverter defibrillator (ICD) after an arrhythmic event or when accepted risk factors develop. Treatment of malignant ventricular arrhythmias with ICD shocks is painful, which requires treatment with antiarrhythmic drugs and / or catheter ablation. Antiarrhythmic drugs (e.g., flecainide, sotalol, amiodarone, and beta-blockers) often have limited efficacy and are also fraught with the potential for undesirable side effects. When antiarrhythmic drugs become ineffective and patients begin to experience breakthrough arrhythmic events requiring ICD shocks, more invasive treatment with cardiac catheter ablation is often required. This invasive procedure often requires both endocardial and epicardial approaches, carries significant risks, and may have modest efficacy. Despite these treatment options, affected patients remain at risk for heart failure and death, and a significant proportion ultimately require heart transplantation for refractory ventricular arrhythmias.

[0027] Thiazolidinediones, also known as glitazones after the archetypal drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. Thiazolidinediones, or TZDs, are specific for PPARγ (PPAR-gamma, PPARG), a family of nuclear receptors. PPAR (peroxisome proliferator-activated receptors). Thus, they are the PPARG agonist subset of PPAR agonists.

[0028] The present invention involves administering to a subject a composition that includes a thiadiazolidinedione.

[0029] In some embodiments, the methods described herein provide for administering to a subject in need thereof an effective amount of a compound of formula (I):

[0030] [ka]

[0031] or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, R 1 and R 2 are independently H, C 1-7 Alkyl, C 3-7 Cycloalkyl, C 3-10 heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by halo, alkyl, alkoxy, cycloalkyl, aryl, or heteroaryl; X is selected from oxygen, nitrogen, or sulfur.

[0032] As used herein, the term "halo" means halogen and includes fluoro, chloro, bromo, and iodo.

[0033] As used herein, the term "alkoxy" refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. Examples include methoxy, ethoxy, propoxy, and butoxy.

[0034] As used herein, the term "alkyl" refers to a saturated or unsaturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 7 carbon atoms, i.e., C 1-7 Alkyl.

[0035] As used herein, the term "cycloalkyl" refers to a cyclic saturated or unsaturated hydrocarbon ring system. It may be monocyclic, bicyclic, or tricyclic (e.g., fused or bridged bicyclic or tricyclic rings). Unless otherwise specified, cycloalkyl groups typically have 3 to 7 carbon atoms, i.e., C 3-7 Cycloalkyl.

[0036] As used herein, the term "heterocyclyl" means a saturated or unsaturated non-aromatic 3- to 10-membered ring radical containing 1 to 4 ring heteroatoms, which may be the same or different, selected from N, O, or S. It may be monocyclic, bicyclic, or tricyclic (e.g., fused or bridged bicyclic or tricyclic rings). The heterocycle optionally contains one or more double or triple bonds and / or is optionally fused to one or more aromatic rings.

[0037] As used herein, the term "aryl" refers to an aromatic ring group having five to ten ring carbon atoms, which may be monocyclic, bicyclic, or tricyclic (e.g., fused or bridged bicyclic or tricyclic rings).

[0038] As used herein, the term "heteroaryl" refers to an aromatic ring group having five to ten ring atoms selected from carbon and at least one (typically one to four, more typically one or two) heteroatoms (e.g., oxygen, nitrogen, or sulfur). "Heteroaryl" includes monocyclic and polycyclic rings, where a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. "Heteroaryl" includes monocyclic and bicyclic ring systems.

[0039] When a group is described as "substituted," a non-hydrogen substituent replaces a hydrogen on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl is an alkyl where at least one non-hydrogen substituent is in place of a hydrogen substituent on the alkyl substituent. To illustrate, a monofluoroalkyl is an alkyl substituted with a fluoro substituent, and a difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that when a substituent has multiple substitutions, each non-hydrogen substituent may be the same or different (unless otherwise stated). As used herein, many moieties (e.g., alkyl, cycloalkyl, or heterocycle) are referred to as "optionally substituted." When a moiety is modified by this term, it indicates that any portion of the moiety known to one of skill in the art as available for substitution may be substituted and contains one or more substituents, unless otherwise stated. When multiple substituents are present, each substituent is independently selected. Such means for substitution are well known in the art and / or are taught by this disclosure. An optional substituent may be any substituent suitable for attachment to a moiety. One of ordinary skill in the art will recognize that the compounds and definitions provided do not include impermissible substitution patterns (e.g., methyl substituted with five different groups, etc.) that would be clearly recognized by one of ordinary skill in the art.

[0040] It should be understood that the compounds of the present disclosure may further form salts, and that all of these forms are also contemplated within the scope of the claimed disclosure.

[0041] As used herein, the term "pharmaceutical acceptable salt" refers to derivatives of the compounds of the present disclosure, where the parent compound is modified by making its acid or base salt. Examples of pharmaceutical acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.

[0042] It should be understood that the compounds of the present disclosure, for example, salts of the compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules.Non-limiting examples of hydrates include monohydrates, dihydrates, etc.Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0043] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more molecules of water with one molecule of a substance in which the water retains its molecular state as H2O.

[0044] Thiadiazolidinediones useful in the method of the present invention include, for example, inhibitors of glycogen synthase kinase 3β (GSK3β). Preferably, the GSK3β inhibitor is a selective inhibitor. Preferably, the GSK3β inhibitor is a reversible inhibitor. Alternatively, the GSK3β inhibitor is an irreversible inhibitor.

[0045] Exemplary thiadiazolidinediones include compounds of Formula II, Formula III, or derivatives thereof. As used herein, the term "derivative" refers to compounds that share a common core structure and are substituted with various groups as described herein.

[0046] [ka]

[0047] The structure represented by formula II is tideglusib. Tideglusib (CAS No. 865854-05-3) or 4-benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione is also known as NP-031112, NP-12 compound, Nypta®, or Zentylor®.

[0048] Tideglusib is a member of the thiadiazolidine class, a 1,2,4-thiadiazolidine-3,5-dione substituted at position 2 by a naphthalen-1-yl group and at position 4 by a benzyl group. Tideglusib is a selective and irreversible non-ATP-competitive inhibitor of glycogen synthase kinase 3β (GSK3β) with roles as an EC 2.7.11.26 (tau protein kinase) inhibitor, neuroprotectant, anti-inflammatory, and apoptosis inducer. Tideglusib is undergoing clinical trials for the treatment of Alzheimer's disease and progressive supranuclear palsy. Tideglusib is currently being investigated for myotonic dystrophy.

[0049] [ka]

[0050] The structure represented by formula III is NPE100928, a member of the thiadiazolidine class that is a 1,2,4-thiadiazolidine-3,5-dione substituted at the 2-position by a benzyl group and at the 4-position by an ethyl group. NPE100928 is an irreversible, non-ATP-competitive inhibitor of glycogen synthase kinase 3β (GSK3β).

[0051] NPE 100928 (CAS No. 865854-05-3) or 2-benzyl-4-ethyl-1,2,4 thiadiazolidine-3,5-dione, is also known as AMO-05.

[0052] The present invention includes administering a composition comprising a thiadiazolidinedione to a subject. The thiadiazolidinedione, such as tideglusib or its NPE100928, may be provided to a subject in need thereof, alone or as an active ingredient, in a pharmaceutical formulation. The subject in need thereof has cardiomyopathy, is predisposed to cardiomyopathy, or is at risk of developing cardiomyopathy. A subject with cardiomyopathy can be identified by a physician using current methods of diagnosing cardiomyopathy. Tests that aid in the diagnosis of cardiomyopathy include, but are not limited to, echocardiogram (echo), electrocardiogram (ECG), ambulatory rhythm (Holter) monitoring, cardiac CT scan, and cardiac magnetic resonance imaging. A family history of cardiomyopathy, or exposure to risk factors for cardiomyopathy, may also aid in determining whether a subject may have cardiomyopathy or in making a diagnosis of cardiomyopathy.

[0053] Mutations in genes encoding components of desmosomes can also help determine whether a subject may have cardiomyopathy or to diagnose cardiomyopathy.Genes encoding components of desmosomes include, for example, plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), and plakoglobin (JUP).Other genes involved in ACM include, for example, but are not limited to, transmembrane protein 43 (TMEM43), catenin alpha 3 (CTNNA3), desmin (DES), lamin A / C (LMNA), phospholamban (PLN), ryanodine receptor 2 (RYR2), transforming growth factor beta-3 (TGFB3), titin (TTN), filamin C (FLNC), RNA-binding motif protein 20 (RBM20), sodium voltage-gated channel alpha subunit 5 (SCN5A), or BAG co-chaperone 3 (BAG3).

[0054] In some embodiments, the subject has had an implantable cardioverter defibrillator (ICD) inserted due to perceived risk of life-threatening arrhythmia, or has previously experienced cardiac arrest, sustained ventricular tachycardia, or worrying syncope or presyncope episodes.In other embodiments, the patient has begun to manifest clinical features of disease, including frequent premature ventricular contractions (PVCs) or non-sustained ventricular tachycardia on ambulatory monitoring, electrocardiogram (ECG) abnormalities such as epsilon waves or precordial T wave inversions, or evidence of cardiac dysfunction on imaging modalities such as echocardiography and cardiac magnetic resonance imaging.In other embodiments, the patient has a deleterious genetic variant that puts them at risk of developing ACM and suffering from life-threatening arrhythmia.

[0055] Nonsustained ventricular tachycardia is defined as more than 3 beats of ventricular origin at a rate greater than 100 beats per minute for a duration less than 30 seconds. A rhythm is considered sustained ventricular tachycardia if it lasts longer than 30 seconds or if hemodynamic instability occurs in less than 30 seconds.

[0056] The subject in need thereof has a PVC load of 200 or more per 24 hours. For example, the subject has a PVC load of about 200 or more PVC, 250 or more PVC, 300 or more PVC, 350 or more PVC, 400 or more PVC, 450 or more PVC, 500 or more PVC, 600 or more PVC, 700 or more PVC, 800 or more PVC, 900 or more PVC, or 1000 or more PVC in 24 hours.

[0057] As used herein, "cardiomyopathy" refers to diseases of the heart muscle associated with ventricular dysfunction as defined by the World Health Organization.

[0058] The methods described herein are used to treat, prevent, or alleviate the symptoms of arrhythmogenic cardiomyopathy, a subtype of cardiomyopathy associated with a significant risk of arrhythmia.

[0059] As used herein, "relieving symptoms of cardiomyopathy" refers to ameliorating any condition or symptom associated with cardiomyopathy, such reduction being at least 1%, 2%, 3%, 4%, 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99% or more as measured by any standard technique, as compared to an equivalent untreated control.

[0060] Symptoms and / or complications of cardiomyopathies that characterize these conditions and aid in diagnosis are well known in the art and include, but are not limited to, pulmonary congestion, fluid retention, fatigue, heart murmurs, rapid heart rate, arrhythmias, chest pain, lightheadedness, syncope, dyspnea, peripheral edema, abdominal distension, embolism, myocardial fibrofatty infiltration, heart failure, or sudden cardiac death (SCD).

[0061] In various embodiments, the methods of the invention reduce the number of premature ventricular contractions (PVCs) and / or improve ventricular function.

[0062] PVCs are measured by electrocardiogram equipment, such as a Holter monitor. Reduction in PVCs means a reduction of 1% or more, 2% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, or more, compared to the number of PVCs before treatment (i.e., the subject's baseline PVC rate). The number of PVCs and their reduction can be measured over a 24 hour, 48 hour, 72 hour, 96 hour, 120 hour, or more period. Alternatively, the number of PVCs and their reduction can be measured over a 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more period. The number of PVCs and their reduction can be measured over a 1 week, 2 weeks, 3 weeks, 4 weeks, or more period. The number of PVCs and their reduction can be measured over a 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more period.

[0063] As used herein, improved ventricular function refers to an improvement in ejection fraction of 1 or more, 2 or more, 4 or more, 5 or more, 10 or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, or more. In some embodiments, a reduction in ventricular (e.g., right or left ventricular) end diastolic diameter.

[0064] Tideglusib or NPE100928 treatment also results in a reduction in the following: implantable cardioverter defibrillator (ICD) therapy, sustained ventricular tachycardia (VT); the need for additional antiarrhythmic medications (other than beta-blockers); the need for VT ablation procedures; the need for heart transplants; emergency room visits and hospitalizations; incident atrial fibrillation; non-sustained ventricular tachycardia (NSVT); atrial ectopics, sudden cardiac death, cardiac-related mortality, and all-cause mortality.

[0065] Various means for administering the compositions described herein to a subject are known to those skilled in the art.These methods can include, but are not limited to, oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, dermal, injection, or topical administration.

[0066] As used herein, "arrhythmia" refers to any of a group of conditions in which there is abnormal electrical activity in the heart. This can cause the heart to beat too fast (tachycardia). Arrhythmias can affect the atria and / or ventricles and can occur at any age.

[0067] As used herein, "arrhythmogenic right ventricular cardiomyopathy (ARVC)" refers to a cardiac disease characterized by myocardial fibrofatty infiltration. ARVC is a non-ischemic cardiomyopathy that primarily involves the right ventricle and arrhythmias.

[0068] In some embodiments, the methods described herein relate to treating a subject with or diagnosed with cardiomyopathy with a compound of formula (I).Preferably, a compound of formula (II) or formula (III) or derivatives thereof having GSK3β inhibitory activity.The GSK3β inhibitor is a selective inhibitor.The GSK3β inhibitor is a reversible inhibitor or an irreversible inhibitor.

[0069] Administration can be local or systemic.Accordingly, pharmaceutical preparations containing an amount (such as an effective amount, a minimum effective amount, and / or a therapeutically effective amount) of tideglusib, NPE100928 or its derivatives are also described herein.In some embodiments, the pharmaceutical preparation contains a therapeutically effective amount of tideglusib, NPE 100928, or its derivatives.The pharmaceutical preparations described herein can be administered to a subject in need thereof.

[0070] The effective amount of the therapeutic compound is preferably about 0.1 mg / kg to about 150 mg / kg, more preferably 0.5 mg / kg to 10 mg / kg, and even more preferably 1 mg / kg to 5 mg / kg. Effective doses will vary, as will be recognized by those skilled in the art, depending on the route of administration, excipient use, and co-administration with other therapeutic treatments, including the use of other therapeutic agents for the treatment and prevention of ACM.

[0071] For example, tideglusib, NPE 100928 or a derivative thereof is administered in a daily dose of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, or more.

[0072] Doses may be administered once a day, or more than once a day. In some embodiments, it is preferred that the therapeutic compound is administered once a day, twice a day, three times a day, or four times a day. In some cases, chronic administration may be desirable. The term "chronic administration" or "chronically administered" refers to administration of a drug over a long period of time, for a period of more than three months.

[0073] Pharmaceutical compounds are administered to such individuals using methods known in the art.Preferably, compounds are administered orally, rectally, nasally, topically or parenterally, for example subcutaneously, intraperitoneally, intramuscularly and intravenously, preferably intravenously.The inhibitor is optionally formulated as a component of a cocktail of therapeutic drugs.Examples of formulations suitable for parenteral administration include aqueous solutions of active agents in isotonic saline, 5% glucose solution, or another standard pharmaceutically acceptable excipient.Standard solubilizers such as PVP or cyclodextrin are also utilized as pharmaceutical excipients for delivery of therapeutic compounds.

[0074] The therapeutic compounds described herein are formulated into compositions for other routes of administration using conventional methods. For example, the therapeutic compounds are formulated into capsules, tablets, or suspensions that are added to water and stirred for oral administration. Capsules may contain any standard pharma- ceutically acceptable material, such as gelatin or cellulose. Tablets can be formulated according to conventional procedures by compressing a mixture of the therapeutic compounds with solid carriers and lubricants. Examples of solid carriers include starch and sugar bentonite. The compounds are administered in the form of hard-shell tablets or capsules that contain binders, conventional fillers, and tablet-forming agents, such as lactose or mannitol. Other formulations include ointments, suppositories, pastes, sprays, patches, creams, gels, resorbable sponges, or foams. Such formulations are manufactured using methods well known in the art.

[0075] Therapeutic compounds are effective upon direct contact of the compound with the affected tissue, thus the compound is administered locally. Alternatively, the therapeutic compound is administered systemically. EXAMPLES

[0076] Example 1: Evaluation of Tideglusib as a Targeted Therapy for Arrhythmogenic Right Ventricular Cardiomyopathy

[0077] The primary objectives of these trials are to demonstrate that tideglusib reduces PVCs on Holter monitoring, improves ventricular function, reduces life-threatening ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation, reduces ICD therapy including shocks, reduces atrial fibrillation, reduces the need for heart transplant, reduces cardiovascular death, and reduces all-cause mortality compared to placebo in patients with ACM at risk for arrhythmias and sudden cardiac death.

[0078] Other embodiments Although the present invention has been described in conjunction with its detailed description, the foregoing description is intended to be illustrative, and not limiting, of the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A pharmaceutical composition for treating or alleviating symptoms of arrhythmogenic cardiomyopathy (ACM) in a subject, comprising a thiadiazolidinedione or a derivative thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the thiadiazolidinedione is a GSK3 inhibitor.

3. 2. The pharmaceutical composition of claim 1, wherein the thiadiazolidinedione is tideglusib or NPE 100928.

4. 2. The pharmaceutical composition of claim 1, wherein the symptoms of ACM are ventricular tachycardia, implantable cardioverter defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, rapid heart rate, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibrofatty infiltration, embolism, heart failure, or sudden cardiac death (SCD).

5. 2. The pharmaceutical composition of claim 1, wherein the ACM is arrhythmogenic right ventricular cardiomyopathy (ARVC).

6. A pharmaceutical composition comprising a thiadiazolidinedione or a derivative thereof for reducing the number of premature ventricular contractions (PVCs) in a subject in need thereof.

7. A pharmaceutical composition comprising a thiadiazolidinedione or a derivative thereof for improving ventricular function in a subject in need thereof.

8. The pharmaceutical composition according to any one of claims 6 to 7, wherein the subject has arrhythmogenic cardiomyopathy (ACM).

9. 9. The pharmaceutical composition of claim 8, wherein the ACM is arrhythmogenic right ventricular cardiomyopathy (ARVC).

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the subject has an implantable cardioverter defibrillator (ICD).

11. 11. The pharmaceutical composition of claim 10, wherein administration of the thiadiazolidinedione or derivative thereof results in a reduction in the number of electrical shocks delivered to the subject by the ICD.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein administration of the thiadiazolidinedione or derivative thereof results in an improvement in a measure of ventricular performance in the subject.

13. The pharmaceutical composition of claim 12, wherein the measure of ventricular function is ventricular strain, systolic function, or diastolic function.

14. 14. The pharmaceutical composition of claim 12 or 13, wherein the ventricular function is measured by echocardiography (echo), ambulatory rhythm (Holter) monitoring, cardiac CT scan, or cardiac magnetic resonance imaging.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the subject has one or more mutations in genes associated with ACM.

16. The pharmaceutical composition of claim 15 , wherein the gene associated with ACM is a gene encoding a component of the desmosome.

17. 17. The pharmaceutical composition of claim 16, wherein the gene encodes plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), or plakoglobin (JUP).

18. 17. The pharmaceutical composition of claim 16, wherein the gene associated with ACM is transmembrane protein 43 (TMEM43), catenin alpha 3 (CTNNA3), desmin (DES), lamin A / C (LMNA), phospholamban (PLN), ryanodine receptor 2 (RYR2), transforming growth factor beta-3 (TGFB3), titin (TTN), filamin C (FLNC), RNA-binding motif protein 20 (RBM20), sodium voltage-gated channel alpha subunit 5 (SCN5A), or BAG co-chaperone 3 (BAG3).

19. A pharmaceutical composition comprising a thiadiazolidinedione or a derivative thereof for treating or alleviating symptoms of atrial fibrillation in a subject suffering from or at risk of developing atrial fibrillation.

20. 20. The pharmaceutical composition of claim 19, wherein the subject has ACM.

21. 21. The pharmaceutical composition of claim 20, wherein the symptoms of atrial fibrillation are rapid heartbeat, arrhythmia, chest pain, lightheadedness, fainting, difficulty breathing, heart failure, stroke or death.

22. A pharmaceutical composition comprising a thiadiazolidinedione or a derivative thereof for reducing the number of premature atrial contractions in a subject in need thereof.

23. A pharmaceutical composition comprising a thiadiazolidinedione or a derivative thereof for improving atrial function in a subject in need thereof.

24. The pharmaceutical composition of any one of claims 22 to 23, wherein the subject has ACM.

25. The pharmaceutical composition of any one of claims 22 to 23, wherein the subject has atrial fibrillation (AF).

26. The pharmaceutical composition of any one of claims 1 to 25, wherein the subject is a human, a canine, a feline, or an equine.

27. 27. The pharmaceutical composition of claim 26, wherein the subject is a human.

28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the thiadiazolidinedione or derivative thereof is administered orally.

29. A pharmaceutical composition according to any one of claims 1 to 28, wherein the thiadiazolidinedione or derivative thereof is administered in a daily dose of from 100mg to 1500mg.

30. 30. The pharmaceutical composition of claim 29, wherein the daily dose is about 1000 mg.

31. 30. The pharmaceutical composition of claim 29, wherein the daily dose is about 600 mg.

32. The pharmaceutical composition according to any one of claims 29 to 31, wherein said daily dose is administered in a single administration.

33. The pharmaceutical composition according to any one of claims 29 to 31, wherein the daily dose is administered in two doses.

34. The pharmaceutical composition according to any one of claims 29 to 31, wherein the daily dose is administered in three doses.

35. The pharmaceutical composition according to any one of claims 29 to 31, wherein the daily dose is administered in four doses.