Cyclo-HEXA-2,5-diene-1,4-diones for use in the treatment of cardiomyopathy

Abstract

The present disclosure provides methods, compounds, compositions / formulations / medicaments and related uses for treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy, such as hypertrophic cardiomyopathy, in a mammalian subject, such as a subject diagnosed with, or suspected or having, Friedreich's ataxia. In some embodiments, administration of the disclosed compounds to the subject may result in one or more of the following in the subject: (i) an increase in survival, (ii) reduction in iron deposits in cardiomyocytes, (iii) improvement and / or normalization of mitochondria size in cardiomyocytes; (iv) reduction in cardiac fibrosis, and (v) reverse remodeling of the subject's heart.

Description

CYCLO-HEXA-2,5-DIENE-1 ,4-DIONES FOR USE IN THE TREATMENT OF CARDIOMYOPATHYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 597,433, filed November 9, 2023, the entire contents of which is incorporated herein by reference for any and all purposes.TECHNICAL FIELD

[0002] The present application relates generally to methods, compositions / formulations / medicaments and related uses for treating, preventing, delaying the onset of or delaying the progression of cardiomyopathy, such as hypertrophic cardiomyopathy, in a mammalian subject in need thereof, such as subjects diagnosed with, or suspected of having, Friedreich’s ataxia. The methods, compositions / formulations / medicaments and related uses all relate to the administration to the mammalian subject of one or both of two compounds specifically identified herein as Compound A and Compound B.INTRODUCTION

[0003] The following description is provided to assist the understanding of the reader. None of the information provided or references cited herein is admitted as being prior art to the compounds, compositions, products and / or methods disclosed herein.

[0004] Friedreich's ataxia (FA) is a fatal, monogenic, autosomal recessive disease caused by mutations in the gene encoding the nuclear encoded mitochondrial protein frataxin. Tissues in both the peripheral and central nervous systems are affected in FA, and include the dentate nucleus, Clark’s column, spinocerebellar tract and dorsal root ganglia. Progressive degeneration of these tissues leads to a worsening ataxia which for most patients ends in loss of independent ambulation by the third decade of life.

[0005] Friedreich’s ataxia occurs when the FXN gene contains amplified intronic GAA repeats. The mutant FXN gene contains expanded GAA triplet repeats in the first intron; in a few pedigrees, point mutations have also been detected. Since the defect is located in an intron, which is removed from the mRNA transcript between transcription and translation, the mutatedFXN gene does not result in the production of abnormal proteins. Instead, the mutation causes gene silencing, i.e., the mutation decreases the transcription of the gene and thereby a decrease in frataxin expression. The decrease in frataxin expression causes iron accumulation within mitochondria, leading to dysfunctional respiratory chain activity (i.e., dysfunctional oxidative phosporylation). Iron accumulation in the mitochondria has been observed in transmission electron microscopy (TEM) images of cardiomyocytes of a frataxin knockout mouse model that leads to deletion of frataxin in the heart and skeletal muscle. (See: Chiang et al., Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation, Redox Biology, 46 (2021) 102038; and Martelli et al., Dysregulation of cellular iron metabolism in Friedreich ataxia: from primary ironsulfur cluster to mitochondrial iron accumulation, Frontiers in Pharmacology, 5 (2014) 130). A decrease in the cross-sectional area of mitochondria was also observed in the cardiomyocytes of 10-week old mice (but not of the 4-week old mice) of the FA model examined. (See: Chiang et al., at Section 3.1).

[0006] Symptoms typically begin between the ages of 5 and 15 years, although they sometimes appear in adulthood. The first symptom to appear is usually gait ataxia, or difficulty walking. The ataxia gradually worsens and slowly spreads to the arms and the trunk. There is often loss of sensation in the extremities, which may spread to other parts of the body. Other features include loss of tendon reflexes, especially in the knees and ankles. Most people with Friedreich's ataxia develop scoliosis, which often requires surgical intervention for treatment. Dysarthria (slowness and slurring of speech) develops and can get progressively worse. Many individuals with later stages of Friedreich’s ataxia develop hearing and vision loss.

[0007] Heart disease often accompanies Friedreich's ataxia, such as hypertrophic cardiomyopathy, myocardial fibrosis (formation of fiber-like material in the muscles of the heart), and cardiac (heart) failure. Heart rhythm abnormalities such as tachycardia (fast heart rate) and heart block (impaired conduction of cardiac impulses within the heart) are also common. Other symptoms that may occur include chest pain, shortness of breath, and heart palpitations.

[0008] The rate of progression of the disease varies from person to person. Generally, within 10 to 20 years after the appearance of the first symptoms, the person diagnosed with Friedreich’sataxia is confined to a wheelchair, and in later stages of the disease individuals may become completely incapacitated. Friedreich's ataxia can shorten life expectancy, and heart disease is the most common cause of death.

[0009] There is no known cure for Friedreich’s ataxia. Generally, therapies involve treatment of the symptoms. Because patients with Friedreich’s ataxia are at a risk of developing heart disease, they are often prescribed medications such as beta blockers, ACE inhibitors and / or diuretics. Because it is believed that damage caused by oxidative stress is involved in the progression of Friedreich’s ataxia, antioxidants such as vitamin E, idebenone and coenzyme Q10 are often co-administered to persons diagnosed or suspected of having Friedrich’s ataxia. These compounds have been used in various clinical trials.

[0010] Vatiquinone (also known as EPI743) has been tested in the clinic as a possible treatment for Friedreich’s ataxia but has not been approved by the FDA for that purpose. Vatiquinone is believed to be an inhibitor of 15-lipoxygenase, an enzyme that regulates energetic and oxidative stress pathways.

[0011] Omaveloxolone is a second generation synthetic oleanane triterpenoid that is believed to exhibit antioxidative and anti-inflammatory activity. Omaveloxolone has been studied in the clinic for the treatment of a variety of indications, including Friedreich’s ataxia, mitochondrial myopathies and ophthalmic conditions / diseases. Omaveloxolone has recently been approved by the FDA for the treatment of Friedreich’s ataxia. According to the clinical trial data, treatment with omaveloxolone resulted in statistically significant lower modified Friedreich Ataxia Rating Scale (mFARS) scores relative to placebo at Week 48, accounting for a placebo-corrected difference between the groups of -2.41 points (P = .0138). There does not appear to be any data indicating that treatment with omaveloxolone affects the heart of the subject treated.

[0012] Treatments generally are directed to treating signs and symptoms of Friedreich’s ataxia based on an mFARS score. Better treatments are needed to address this devastating rare disease.SUMMARY

[0013] In one aspect, the present technology provides a method for treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy, in a mammalian subject in need thereof, comprising administering to said subject a therapeutically effective amount ofCompound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:

[0014] In some embodiments of the foregoing method, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the foregoing method, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing method, the subject is human. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis (e.g., myocardial fibrosis) in the subject’sheart tissue. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject results in reverse remodeling of the subject’s heart. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves hearing and / or vision of the subject. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject increases the lifespan of the subject. In some embodiments of the foregoing method, Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0015] In one aspect, the present technology provides a composition, medicament or formulation comprising Compound A, Compound B, or a mixture of Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof for use in treating, preventing, delaying theprogression of or delaying the onset of cardiomyopathy in a mammalian subject in need thereof, wherein Compound A and Compound B have the following structures:

[0016] In some embodiments of the foregoing composition, medicament or formulation, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the foregoing composition, medicament or formulation, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing composition, medicament or formulation, the subject is human. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis in the subject’s heart tissue. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject results in reverse remodeling of the subject’s heart. In some embodiments of the foregoing composition, medicament or formulation, administration of thecomposition, medicament or formulation to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject improves hearing and / or vision of the subject. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject increases the lifespan of the subject. In some embodiments of the foregoing composition, medicament or formulation, the composition, medicament or formulation is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0017] In one aspect, the present technology provides for use of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, in treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy in a mammalian subject in need thereof, wherein Compound A and Compound B have the following structures:Compound A

[0018] In some embodiments of the foregoing use, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the foregoing use, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing use, the subject is human. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis in the subject’s heart tissue. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject results in reverse remodeling of the subject’s heart. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing use, administration ofCompound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves hearing and / or vision of the subject. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject increases the lifespan of the subject. In some embodiments of the foregoing use, Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0019] In one aspect, the present technology provides for a method for reducing iron accumulation in the cardiomyocytes of a mammalian subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:In some embodiments of the method, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the method, the subject is human.

[0020] In one aspect, the present technology provides for a method for improving or normalizing the size of mitochondria in the cardiomyocytes of a mammalian subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:mbodiments of the method, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the method, the subject is human.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Fig. 1 is an illustration of the chemical structures of Compound A, Compound B and (comparator compound) vatiquinone.

[0022] Fig. 2 is a graphic illustration of comparative data obtained in a mouse pharmacokinetic (PK) profde study for plasma where Compound B was studied at 20 mg / kg and 60 mg / kg SC dosing and Compound A was studied at 60 mg / kg SC dosing as described in Example 1.

[0023] Fig. 3 is a graphic illustration of comparative data obtained in a PK profile study for plasma where Compound B was studied at 20 mg / kg SC dosing in mouse and 10 mg / kg SC dosing in rat (effectively 60 mg / m2regardless of species examined) as described in Example 1.

[0024] Fig. 4 is a graphic illustration of comparative data obtained in a PK profile study examining uptake of drug in mouse heart tissue resulting from subcutaneous administration of Compound B at 20 mg / kg and 60 mg / kg dosing and Compound A at 60 mg / kg dosing as described in Example 1.

[0025] Fig. 5 is a graphic illustration of comparative data obtained in a PK profile study examining uptake of drug in mouse brain tissue resulting from subcutaneous administration of Compound B at 20 mg / kg and 60 mg / kg dosing and Compound A at 60 mg / kg dosing as described in Example 1.

[0026] Fig. 6 is a graphic illustration of the survival in the study of the effect of administration of Compound A, and vati quinone on mice as described below in Example 2.

[0027] Fig. 7 is a graphic illustration of the survival in the study of the effect of administration of Compound B, and vatiquinone on mice as described below in Example 2.

[0028] Fig. 8 is a graphic illustration of cardiac ultrasound (i.e., cardiac echo, a.k.a., echocardiogram) data of the left ventricular mass obtained in the study of the effect of administration of Compound A, and vatiquinone on mice as described below in Example 2.

[0029] Fig. 9 is a graphic illustration of cardiac ultrasound (i.e., cardiac echo) data of the left ventricular mass obtained in the study of the effect of administration of Compound B, and vatiquinone on mice as described below in Example 2.

[0030] Fig. 10 is a graphic illustration of cardiac ultrasound (i.e., cardiac echo) data of the left ventricle anterior wall thickness (diastole) obtained in the study of the effect of administration of Compound A, and vatiquinone on mice as described below in Example 2.

[0031] Fig. 11 is a graphic illustration of cardiac ultrasound (z.e., cardiac echo) data of the left ventricle anterior wall thickness (diastole) obtained in the study of the effect of administration of Compound B, and vatiquinone on mice as described below in Example 2.

[0032] Fig. 12 is a graphic illustration of cardiac ultrasound (i.e., cardiac echo) data of the left ventricle anterior wall thickness (systole) obtained in the study of the effect of administration of Compound A, and vatiquinone on mice as described below in Example 2.

[0033] Fig. 13 is a graphic illustration of cardiac ultrasound (z.e., cardiac echo) data of the left ventricle anterior wall thickness (systole) obtained in the study of the effect of administration of Compound B, and vatiquinone on mice as described below in Example 2.

[0034] Fig. 14 is a bar graph of cardiac ultrasound (z.e., cardiac echo) data of the left ventricle anterior wall thickness (diastole) obtained in the study of the effect of administration of Compound A, and vatiquinone on mice as described below in Example 2.

[0035] Fig. 15 is a bar graph of cardiac ultrasound (z.e., cardiac echo) data of the left ventricle anterior wall thickness (systole) obtained in the study of the effect of administration of Compound A, and vatiquinone on mice as described below in Example 2.

[0036] Fig. 16 is a bar graph of cardiac ultrasound (z.e., cardiac echo) data of the left ventricle anterior wall thickness (diastole) obtained in the study of the effect of administration of Compound B, and vatiquinone on mice as described below in Example 2.

[0037] Fig. 17 is a bar graph of cardiac ultrasound (z.e., cardiac echo) data of the left ventricle anterior wall thickness (systole) obtained in the study of the effect of administration of Compound B, and vatiquinone on mice as described below in Example 2.

[0038] Fig. 18A is a bar graph illustrating the absolute relative total cross-sectional area of mitochondria in mouse heart (cardiac) tissue obtained as described and processed in Example 3 for the WT untreated mouse cohort, the MUT untreated mouse cohort, and the MUT mouse cohort treated with Compound A.

[0039] Fig. 18B is a violin plot illustrating the size distribution of the cross-sectional area of the mitochondria in mouse heart (cardiac) tissue obtained as described and processed in Example3 for the WT untreated mouse cohort, the MUT untreated mouse cohort, and the MUT mouse cohort treated with Compound A.

[0040] Figs. 19A-19C are transmission electron micrographs (TEMs) of mouse heart (cardiac) tissue obtained as described and processed in Example 3. Fig. 19A is from the WT untreated mouse cohort, Fig. 19B is from the MUT untreated mouse cohort, and Fig. 19C is from the MUT mouse cohort treated with Compound A.DETAILED DESCRIPTION

[0041] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the present disclosure are described below in various levels of detail in order to provide a substantial understanding of the present technology. The definitions of certain terms as used in this specification are provided below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this present technology belongs.

[0042] In practicing the present technology, many conventional techniques in molecular biology, protein biochemistry, cell biology, immunology, microbiology and recombinant DNA are used. These techniques are well-known and are explained in, e.g., Current Protocols in Molecular Biology, Vols. I-III, Ausubel, Ed. (1997); Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989); DNA Cloning: A Practical Approach, Vols. I and II, Glover, Ed.(1985); Oligonucleotide Synthesis, Gait, Ed. (1984); Nucleic Acid Hybridization, Hames & Higgins, Eds. (1985); Transcription and Translation, Hames & Higgins, Eds. (1984); Animal Cell Culture, Freshney, Ed. (1986); Immobilized Cells and Enzymes (IRE Press, 1986); Perbal, A Practical Guide to Molecular Cloning,' the series, Meth. Enzymol., (Academic Press, Inc., 1984); Gene Transfer Vectors far Mammalian Cells, Miller & Calos, Eds. (Cold Spring Harbor Laboratory, N Y, 1987); and Meth. Enzymol., Vols. 154 and 155, Wu & Grossman, and Wu, Eds., respectively.I. Definitions

[0043] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, GAS version, Handbook of Chemistry and Physics, 7Sh Ed., inside cover.Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0044] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the technology are described below in various levels of detail in order to provide a substantial understanding of the present disclosure. The definitions of certain terms as used in this specification are provided below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs.

[0045] As used in this specification and the appended embodiments, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, reference to “a cell” includes a combination of two or more cells, and the like.

[0046] As used herein, “administering” or the “administration” of an agent (z.c., a therapeutic agent) or compound / drug product (including a composition (i.e., a formulation or medicament)) to a subject includes any route of introducing or delivering to a subject a compound / drug product to perform its intended function. Administration may be carried out by any suitable route, such as oral administration. Administration can be carried out subcutaneously. Administration can be carried out intravenously. Administration can be carried out intraocularly. Administration can be carried out systemically. Alternatively, administration may be carried out topically, intranasally, intraperitoneally, intradermally, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, orintramuscularly. Administration includes self-administration, the administration by another or administration by use of a device (e.g., an infusion pump).

[0047] As used herein, to “ameliorate” or “ameliorating” a disease, disorder or condition refers to results that, in a statistical sample or specific subject, make the occurrence of the disease, disorder or condition (or a sign, symptom or condition thereof) better or more tolerable in a sample or subject administered a therapeutic agent relative to a control sample or subject.

[0048] As used herein the terms “carrier” or “pharmaceutically acceptable carrier” refer to a diluent, adjuvant, excipient, or vehicle with which a compound / drug product / composition (including a formulation or medicament) is administered or formulated for administration. Nonlimiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, oils and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, silica particles (nanoparticles or microparticles) urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington 's Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.

[0049] As used herein, the phrase “delaying the onset of’ refers to, in a statistical sample, postponing or hindering the occurrence of a disease, disorder or condition (or a sign, symptom or condition thereof), in a sample or subject administered a therapeutic agent or agents relative to a control sample or subject.

[0050] As used herein, the phrase “delaying the progression of’ refers to, in a statistical sample, causing a disease, disorder or condition (or a sign, symptom or condition thereof) to occur more slowly than normal, in a sample or subject administered a therapeutic agent or agents relative to a control sample or subject.

[0051] As used herein, the term “effective amount” refers to a quantity of a compound / composition / drug product sufficient to achieve a desired therapeutic and / or prophylactic effect, e.g., an amount that treats, prevents, inhibits, ameliorates, or delays the onset of the disease, disorder or condition, or the physiological signs, symptoms or conditions of the disease or disorder. In the context of therapeutic or prophylactic applications, in someembodiments, the amount of a compound / composition / drug product administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. In some embodiments, it will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compounds / compositions / drug products can also be administered in combination with one or more additional therapeutic compounds / agents (a so called “co-administration” where, for example, the additional or other therapeutic agent(s) could be administered simultaneously, sequentially or by separate administration).

[0052] As used herein, the term "hydrate" refers to a compound which is associated (e.g, complexed) with water. The number of the water molecules contained in a hydrate of a compound may be (or may not be) in a definite ratio to the number of the compound molecules in the hydrate.

[0053] As used herein, “inhibit” or “inhibiting” refers to the reduction in a sign, symptom, or condition (e.g., risk factor) associated with a disease or disorder (e.g., Friedreich’s ataxia). In one embodiment, inhibit or inhibiting refers to the reduction by at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibit or inhibiting refers to a reduction by at least 5 percent compared to control (or control subject). In various individual embodiments, inhibit or inhibiting refers to a reduction by at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, 95, or 99 percent compared to a control (or control subject).

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a therapeutic compound that can be prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salt, or a similar salt. When compounds contain relatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine (NEts), trimethylamine, tripropylamine, tromethamine and the like, such as where the salt includes the protonated form of the organic base (e.g., [HNEt3]+). Salts derived from pharmaceutically acceptable inorganic acids include salts of boric, carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamic and sulfuric acids. Salts derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxyl acids (e.g., citric, gluconic, glycolic, lactic, lactobionic, malic, and tartaric acids), aliphatic monocarboxylic acids (e.g., acetic, butyric, formic, propionic and trifluoroacetic acids), amino acids (e.g., aspartic and glutamic acids), aromatic carboxylic acids (e.g., benzoic, p-chlorobenzoic, diphenylacetic, gentisic, hippuric, and triphenylacetic acids), aromatic hydroxyl acids (e.g., o-hydroxybenzoic, p-hydroxybenzoic, 1- hydroxynaphthalene-2-carboxylic and 3-hydroxynaphthalene-2-carboxylic acids), ascorbic, dicarboxylic acids (e.g., fumaric, maleic, oxalic and succinic acids), glucuronic, mandelic, mucic, nicotinic, orotic, pamoic, pantothenic, sulfonic acids (e.g., benzenesulfonic, camphorsulfonic, edisylic, ethanesulfonic, isethionic, methanesulfonic, naphthalenesulfonic, naphthalene-!, 5-disulfonic, naphthalene-2,6-disulfonic, p-toluenesulfonic acids (PTSA)), xinafoic acid, and the like. In some embodiments, the pharmaceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride, chlorotheophyllinate, citrate, ethanedi sulfonate, fumarate, gluceptate, gluconate, glucoronate, hippurate, iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, mesylate, methyl sulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, andtri fluoroacetate. In some embodiments, the salt is a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt, a maleate salt, a trifluoroacetate salt, a hydrochloride salt, or a tosylate salt. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts or exist in zwitterionic form. These salts may be prepared by methods known to those skilled in the art. Any other pharmaceutically acceptable carriers known to those of skill in the art are suitable for use with the present technology.

[0055] As used herein, “prevention” or “preventing” of a disease, disorder, or condition (or a sign, symptom or condition thereof) refers to results that, in a statistical sample, exhibit a reduction in the occurrence of the disease, disorder, or condition in a sample or subject administered a therapeutic agent or agents relative to a control sample or subject. Such prevention is sometimes referred to as a prophylactic treatment.

[0056] As used herein, the term “reverse remodeling” is used with reference to physical changes to the heart and refers to reversion of the heart to a healthier form after remodeling of the heart to a modified (e.g., less healthy) form has occurred. For example, by conversion of a hypertrophic characteristic of a subject’s heart back to a normal heart. Such reverse remodeling is known with respect to physiological hypertrophy occurring because of exercise (See: Nakamura et al., Mechanisms of Physiological and Pathological Cardiac Hypertrophy, Nature Reviews - Cardiology, (July 2018) 15: 387-407).

[0057] As used herein, the term “separate” therapeutic use refers to an administration of at least two active ingredients (e.g., therapeutic agents) at the same time or at substantially the same time by different routes.

[0058] As used herein, the term “sequential” therapeutic use refers to administration of at least two active ingredients (e.g., therapeutic agents) at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients (e.g., therapeutic agents) before administration of the other or otherscommences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this definition.

[0059] As used herein, the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients (e.g., therapeutic agents) by the same route and at the same time or at substantially the same time.

[0060] As used herein, the term "solvate" refers to forms of the compound that are associated with a solvent, possibly by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane(s), DMSO, THF, diethyl ether, and the like.

[0061] As used herein, a “subject” refers to a living animal. In various embodiments, a subject is a mammal. In various embodiments, a subject is a non-human mammal, including, without limitation, a mouse, rat, hamster, guinea pig, rabbit, sheep, goat, cat, dog, pig, minipig, horse, cow, or non-human primate. In certain embodiments, the subject is a human. As used herein, the term “patient” is interchangeable with the term “subject.”

[0062] It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described herein, in some embodiments, are intended to mean “substantial,” which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.

[0063] As used herein, a “synergistic therapeutic effect” refers to a greater-than-additive therapeutic effect which is produced by a combination of at least two agents, and which exceeds that which would otherwise result from the individual administration of the agents.

[0064] As used herein, the term "tautomer" refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0065] As used herein, the terms “treating” or “treatment” refer to therapeutic treatment, wherein the object is to reduce, alleviate or slow down (lessen) a pre-existing disease, disorder or condition, or its related signs, or symptoms. By way of example, but not by way of limitation, a subject is successfully “treated” for a disease if, after receiving an effective amount of the compound / composition / drug product or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, the subject shows observable and / or measurable reduction in or absence of one or more signs, symptoms or conditions associated with the disease, disorder or condition. It is also to be appreciated that the various modes of treatment of medical conditions as described are intended to mean “substantial,” which includes total alleviation of conditions, signs or symptoms of the disease or disorder, as well as “partial,” where some biologically or medically relevant result is achieved.II. Pharmaceutical Compositions / Formulations / Medicaments, Routes of Administration, and Dosing

[0066] The methods, uses and compositions of the present application utilize a therapeutically effective amount of Compound A, Compound B, or a mixture of Compounds A and B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compounds A and B have the following structures:Compounds A and B, or a mixture of Compounds A and B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof can be formulated into a drug product suitable for administration to a subject in need thereof. Such drugproduct can be referred to as a composition, formulation or medicament depending on its usage. Any mixture prepared by mixing Compounds A and B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof with a solvent and / or other compound(s) is a composition or formulation and may or may not be intended for administration to a subject. A medicament is generally considered a composition or formulation specifically prepared for administration to a subject to address a disease, disorder, or condition (e.g., Friedreich’s ataxia), including signs or symptoms thereof. For purposes of brevity, whenever there is a reference to “Compounds A”, “Compound B” or “mixtures of Compounds A and B” herein, this reference is intended to implicitly include pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of Compounds A and B unless a clearly contrary meaning is intended.

[0067] Compound A, Compound B, or a mixture of Compounds A and B disclosed herein can be used, alone or in combination, with other therapeutic agent(s) to address the needs of subjects suffering from Friedreich’s ataxia. In order to be administered to a subject in need thereof, Compound A, Compound B, or a mixture of Compounds A and B will generally need to be formulated (for individual administration or in a combined formulation) for the intended route of administration. In some embodiments, the same route of administration can be used to deliver Compound A, Compound B, or a mixture of Compounds A and B. The formulated product(s) can be considered a composition or medicament comprising Compound A, Compound B, or a mixture of Compounds A and B and optionally one or more other (i.e., additional) therapeutic agents.

[0068] In some embodiments, the therapeutic agent(s) (e.g., Compound A, Compound B, or a mixture of Compounds A and B and one or more other therapeutic agents) can be formulated with little or no excipient or carrier. In some embodiments, the therapeutic agent(s) can be formulated such that the majority of the formulation is excipient or carrier. In brief, one of skill in the art will tailor the formulation to have a suitable amount of excipient or carrier based on the needs / condition of the subject, the kind and extent of the disease to be treated; the properties of the therapeutic agent or agents to be delivered and the selected mode of administration of the particular therapeutic agent or agents.

[0069] In certain embodiments, a pharmaceutical composition may further comprise at least one therapeutic agent other than Compound A, Compound B, or a mixture of Compounds A and B. The at least one other / additional therapeutic agent can be an agent useful in the treatment of Friedreich’s ataxia or could, for example, be administered to ameliorate the side effect of the administration of Compound A, Compound B, or a mixture of Compounds A and B. Thus, in some embodiments, pharmaceutical compositions can be prepared, for example, by combining Compound A, Compound B, or a mixture of Compounds A and B with a pharmaceutically acceptable carrier and, optionally, one or more additional therapeutical agents or otherwise merely administering the other / additional therapeutic agent(s) in combination with the administration of Compound A, Compound B, or a mixture of Compounds A and B.

[0070] Pharmaceutical compositions may contain an effective amount of one or more of the therapeutic agent or agents as described herein and may optionally be disbursed (e. . dissolved, suspended or otherwise) in a pharmaceutically acceptable carrier. The components of the pharmaceutical composition(s) may also be capable of being commingled with the compounds of the present application, and with each other, in a manner such that there is no interaction that would substantially impair the desired pharmaceutical efficiency.

[0071] As stated above, an “effective amount” refers to any amount of a particular therapeutic agent that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various therapeutic compound(s) and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic (i.e. preventative) or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to address the particular condition, disorder or disease of a particular subject in a therapeutic way. The effective amount of a therapeutic agent for any particular indication can vary depending on such factors as the disease, disorder or condition being treated, the particular compound or compounds being administered, the size of the subject, the age of the subject, the overall health of the subject and / or the severity of the disease, disorder or condition. The effective amount may be determined during pre-clinical trials and / or clinical trials by methods familiar to physicians and clinicians. One of ordinary skill in the art can empirically determine the effective amount of a particular therapeutic agent or agents without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to somemedical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. A dose may be administered by oneself, by another or by way of a device (e.g., a pump).

[0072] For any therapeutic compound described herein the therapeutically effective amount can, for example, be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.

[0073] Therapeutic compounds (alone or as formulated in a pharmaceutical composition / medicament) for use in therapy or prevention can be tested in suitable animal model systems. Suitable animal model systems include, but are not limited to, rats, mice, chicken, cows, monkeys, rabbits, pigs, minipigs and the like, prior to testing in human subjects. In vivo testing of any animal model system known in the art can be used prior to administration to human subjects. In some embodiments, dosing can be tested directly in humans.

[0074] Dosage, toxicity and therapeutic efficacy of any therapeutic agents or compositions (e.g., formulations or medicaments comprising Compound A, Compound B, or a mixture of Compounds A and B, other / additional therapeutic agents, or mixtures thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indices are advantageous. While compounds that exhibit toxic side effects may be used, in such cases it may be prudent to design a delivery system that targets suchcompounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[0075] An exemplary treatment regime can, for example, entail administration once per day, twice per day, thrice per day, once a week, or once a month. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is delayed, reduced or terminated, or until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regimen (i.e., a regimen designed to avoid or curtail progression or subsequent recurrence of the disease, disorder or condition).

[0076] For use in therapy, an effective amount of the therapeutic compound (alone or as formulated) can be administered to a subject by any mode that delivers the compound to the desired surface or tissue. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmical, intrathecal, intracerebroventricular, iontophoretical, transmucosal, intravitreal, or intramuscular administration. Administration includes self-administration, administration by another and administration by a device (e.g., a pump).

[0077] A therapeutic compound / agent disclosed herein (e.g., Compound A, Compound B, or a mixture of Compounds A and B) can be delivered to the subject in a formulation or medicament (i.e., a pharmaceutical composition). Formulations and medicaments can be prepared by, for example, dissolving or suspending a therapeutic compound / agent disclosed herein (e.g., Compound A, Compound B, or a mixture of Compounds A and B) in water, a solvent, a pharmaceutically acceptable carrier, salt, (e.g., NaCl or sodium phosphate), buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutically acceptable ingredients.

[0078] The pharmaceutical compositions (e.g. a formulation or medicament) can include a carrier (e.g., a pharmaceutically acceptable carrier), which can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerasol, and the like. Glutathione and other antioxidants can be included to prevent oxidation. In many cases, it will be advantageous to include isotonic agents, for example, sugars (e.g., trehalose), polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0079] Solutions or suspensions (e.g., a formulation or medicament) used for parenteral, intradermal, subcutaneous or intraocular application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. For convenience of the patient or treating physician, the dosing formulation can be provided alone or in a kit containing all necessary equipment e.g., vials of drug, vials of diluent, syringes and needles) for a treatment course (e.g., 1, 2, 3, 4, 5, 6, 7 days or more of treatment).

[0080] The therapeutic compounds / agents or pharmaceutical compositions, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion (for example by IV injection or via a pump to meter the administration over a defined time). Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. Pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Additionally, suspensions of the therapeutic compounds (e.g., Compound A, Compound B, or a mixture of Compounds A and B) may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injectionsuspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0081] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[0082] For intravenous and other parenteral routes of administration, a compound (e.g., Compound A, Compound B, or a mixture of Compounds A and B) can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or lipid- encapsulated therapeutic compound(s), as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.

[0083] Pharmaceutical compositions (e.g., a formulation or medicament) suitable for injection can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). A composition for administration by injection will generally be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and may be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0084] Sterile injectable solutions (e.g., a formulation or medicament) can be prepared by incorporating the therapeutic compound(s) (e.g., Compound A, Compound B, or a mixture of Compounds A and B and optionally other therapeutic agents) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound(s) into a sterile vehicle, that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation include vacuum dryingand freeze drying, which can yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-fdtered solution thereof.

[0085] For oral administration, the compounds can be formulated readily by combining the therapeutic compound(s) (e.g., Compound A, Compound B, or a mixture of Compounds A and B and optionally other therapeutic agents) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the therapeutic compound(s) to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel®, or corn starch; a lubricant such as magnesium stearate or sterates; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0086] Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.

[0087] Also specifically contemplated are oral dosage forms of the above that may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the therapeutic agent(s), ingredient(s), and / or excipient(s), where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the therapeutic agent(s), ingredient(s), and / or excipient(s) and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol,copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer- Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly-1, 3-dioxolane and poly-1, 3, 6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol (PEG) moieties of various molecular weights are suitable.

[0088] For the formulation of the therapeutic agent(s), ingredient(s), and / or excipient(s), the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of a therapeutic compound / agent or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[0089] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (c. ., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

[0090] The therapeutic compound(s) / agent(s) (which term “therapeutic compound(s) / agent(s)” as used herein is intended to refer to Compound A, Compound B, or a mixture of Compounds A and B and any other active pharmaceutical ingredient (e.g., other therapeutic agent) that can be administered in a combination with Compound A, Compound B, or a mixture of Compounds A and B. The formulation can comprise fine multi-particulates in the form of granules or pellets of particle size about 1-2 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets.The therapeutic compound(s) / agent(s) or pharmaceutical composition(s) could be prepared by compression.

[0091] Colorants and flavoring agents may all be included. For example, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may be formulated and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.

[0092] One may dilute or increase the volume of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) with an inert material. These diluents could include carbohydrates, especially mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo®, Emdex®, STARCH 1500®, Emcompress® and Avicel®.

[0093] Disintegrants may be included in the formulation of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycol ate, Amberlite®, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, karaya gum or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0094] Binders may be used to hold the therapeutic agent(s) together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic agent(s).

[0095] An anti -frictional agent may be included in the formulation of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calciumsalts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol (PEG) of various molecular weights, Carbowax™ 4000 and 6000.

[0096] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.

[0097] To aid dissolution of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) into the aqueous environment, a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation or medicament as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation or medicament disclosed herein or derivative either alone or as a mixture in different ratios.

[0098] Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the therapeutic compound(s) may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0099] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0100] For topical administration, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Solutions, gels, ointments, creams or suspensions may be administeredtopically. The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0101] For administration by inhalation, therapeutic compound(s) / agent(s) or pharmaceutical composition(s) for use according to the present application may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide or other suitable gas. In some embodiments, the formulation, medicament and / or therapeutic compound(s) / agent(s) can be delivered in the form of an aerosol spray from a pressurized container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in U.S. Pat. No. 6,468,798. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. For example, capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the therapeutic compound / agent and a suitable powder base such as lactose or starch. Alternatively, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0102] Nasal delivery of a therapeutic compound(s) / agent(s) or pharmaceutical composition(s) is also contemplated. Nasal delivery allows the passage of therapeutic compound(s) / agent(s) or pharmaceutical composition(s) to the blood stream directly after administering the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

[0103] For nasal administration, one type of useful device is a small, hard bottle to which a metered dose sprayer is attached. In some embodiments, the metered dose is delivered by drawing a pharmaceutical composition (in solution form) into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer thetherapeutic compound(s) / agent(s) or pharmaceutical composition(s). In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0104] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed can be used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s).

[0105] Also contemplated herein is pulmonary delivery of the compounds disclosed herein. The therapeutic compound(s) / agent(s) or pharmaceutical composition(s)is / are delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63: 135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5): 143-146 (1989) (endothelin-1); Hubbard et al., Anna! Int Med 3.2Q6-2 2 (1989) (al -antitrypsin); Smith et al., 1989, J Clin Invest 84: 1145-1146 (a-1- proteinase); Oswein et al., 1990, “Aerosolization of Proteins”, Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995, to Wong et al.

[0106] Contemplated for use in the practice of this technology are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0107] Some specific examples of commercially available devices suitable for the practice of this technology are the Ultravent™ nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II® nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.;the Ventolin® metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler® powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[0108] All such devices require the use of formulations suitable for the dispensing of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s). Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, microcapsules, microspheres, nanoparticles, nanospheres, inclusion complexes, or other types of carriers is contemplated.

[0109] Formulations suitable for use with a nebulizer, either jet or ultrasonic, can, for example, comprise therapeutic compound(s) / agent(s) or pharmaceutical composition(s) dissolved in water at a concentration of about 0.01 to 50 mg of biologically active compound per mb of solution. The formulation may also include a buffer and optionally a simple sugar (e. , for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) disclosed herein caused by atomization of the solution in forming the aerosol.

[0110] Formulations for use with a metered-dose inhaler device may generally comprise a finely divided powder comprising the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) disclosed herein suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.

[0111] Formulations for dispensing from a powder inhaler device may comprise a finely divided dry powder containing the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound(s) / therapeutic agent(s) / pharmaceutical composition(s) can advantageously be prepared in particulate or nanoparticulate form with an average particlesize of less than 10 micrometers (pin), most preferably 0.5 to 5 pm, for most effective delivery to the deep lung.

[0112] For ophthalmic or intraocular indications, any suitable mode of delivering the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) to the eye or regions near the eye can be used. For ophthalmic formulations generally, see Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, N.Y. (1993) and also Havener, W. H., Ocular Pharmacology, C.V. Mosby Co., St. Louis (1983). Nonlimiting examples of pharmaceutical compositions suitable for administration in or near the eye include, but are not limited to, ocular inserts, minitablets, and topical formulations such as eye drops, ointments, and in situ gels. In one embodiment, a contact lens is coated with a pharmaceutical composition (or contains a pharmaceutical composition encapsulated therein) comprising a therapeutic compound / agent. In some embodiments, a single dose can comprise from between 0.1 ng to 5000 pg, 1 ng to 500 pg, or 10 ng to 100 pg of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) administered to the eye.

[0113] Eye drops can comprise a sterile liquid formulation that can be administered directly to the eye. In some embodiments, eye drops comprise at least one therapeutic agent (and possibly several) and may further comprise one or more preservatives. In some embodiments, the optimum pH for eye drops equals that of tear fluid and is about 7.4, the pH may be within any range that is not harmful to the eye of the subject. For eye drops, the therapeutic compound(s) / agent(s) can be present in the drop solution from about 0.1% to about 5% (w / v or v / v depending on the physical nature (i.e. solid or liquid) of the active ingredient). In some embodiments, the therapeutic compound / agent can be present in the drop solution from about 1% to about 3% (w / v or v / v, as appropriate). In some embodiments, the therapeutic compound / agent can be present in the drop solution from about 0.2% to about 1.5% (w / v or v / v, as appropriate). In some embodiments, the therapeutic compound / agent can be present in the drop solution from about 0.1% to about 1.0% (w / v or v / v, as appropriate).

[0114] In situ gels are viscous liquids, showing the ability to undergo sol-to-gel transitions when influenced by external factors, such as appropriate pH, temperature, pressure and / or the presence of electrolytes. This property causes slowing of drug drainage from the eyeball surface and increase of the active ingredient bioavailability. Polymers commonly used in in situ gelformulations include, but are not limited to, gellan gum, poloxamer, silicone containing formulations, silica-based formulations, and cellulose acetate phthalate. In some embodiments, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) is / are formulated into an in-situ gel (as the formulation / medicament).

[0115] For topical ophthalmic administration, therapeutic compound(s) / agent(s) or pharmaceutical composition(s) is / are may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Ointments are semisolid dosage forms for external use such as topical use for the eye or skin. In some embodiments, ointments comprise a solid or semisolid hydrocarbon base of melting or softening point close to human core temperature. In some embodiments, an ointment applied to the eye decomposes into small drops, which stay for a longer time period in conjunctival sac, thus increasing bioavailability.

[0116] Ocular inserts are solid or semisolid dosage forms without disadvantages of traditional ophthalmic drug forms. They are less susceptible to defense mechanisms like outflow through nasolacrimal duct, show the ability to stay in conjunctival sac for a longer period, and can be more stable than conventional dosage forms. They also offer advantages such as accurate dosing of one or more therapeutic compound(s) / agent(s) or pharmaceutical composition(s), slow release of one or more therapeutic compound(s) / agent(s) with constant speed and limiting of one or more therapeutic compounds’ / agents’ systemic absorption. In some embodiments, an ocular insert comprises one or more therapeutic compound(s) / agent(s) and one or more polymeric materials. The polymeric materials can include, but are not limited to, methylcellulose and its derivatives (e. ., hydroxypropyl methylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the aforementioned polymers. An ocular insert can comprise silica. An ocular insert can comprise liposomes, nanoparticles or microparticles of degradable or biodegradable polymer (as described in more detail below).

[0117] Minitablets are biodegradable, solid drug forms, that transit into gels after application to the conjunctival sac, thereby extending the period of contact between active ingredient (i.e., the therapeutic compound(s) / agent(s)) and the eyeball surface, which in turn increases a therapeutic compounds’ / agents’ bioavailability. The advantages of minitablets include easy application to conjunctival sac, resistance to defense mechanisms like tearing or outflow through nasolacrimalduct, longer contact with the cornea caused by presence of mucoadhesive polymers, and gradual release of the active ingredient from the formulation in the place of application due to the swelling of the outer carrier layers. Minitablets can comprise one or more therapeutic compound(s) / agent(s) and one or more polymers. Nonlimiting examples of polymers suitable for use in in a minitablet formulation include cellulose derivatives, like hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose, acrylates (e.g., polyacrylic acid and its cross-linked forms), Carbopol® or carbomer, chitosan, and starch e.g., drum-dried waxy maize starch). In some embodiments, minitablets further comprise one or more excipients. Nonlimiting examples of excipients include mannitol and magnesium stearate.

[0118] The ophthalmic or intraocular formulations and medicaments may contain non-toxic auxiliary substances such as antibacterial components which are generally non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenyl ethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid (EDTA), and the like.

[0119] In some embodiments, the viscosity of the ocular formulation comprising one or more therapeutic compound(s) / agent(s) is increased to improve contact with the cornea and bioavailability in the eye. Viscosity can be increased by the addition of hydrophilic polymers of high molecular weight which do not diffuse through biological membranes and which form three-dimensional networks in the water. Nonlimiting examples of such polymers include polyvinyl alcohol, poloxamers, hyaluronic acid, carbomers, and polysaccharides, cellulose derivatives, gellan gum, and xanthan gum.

[0120] In addition to the formulations described above, therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0121] In some embodiments, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) is / are administered as a depot formulation wherein the active therapeutic agent(s) is / are encapsulated by, or disposed within, silica-based microparticles. Such a formulation may be a controlled-release, delayed-release or extended release formulation (terms are defined below). Such controlled-release, delayed release or extended release formulation may comprise particles, such as microparticles or nanoparticles.

[0122] The pharmaceutical compositions also may comprise suitable solid or gel-phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, silica / silicone and polymers such as polyethylene glycols.

[0123] Suitable liquid or solid pharmaceutical preparation forms (e.g., a formulation or medicament) can, for example, be aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions / formulations may also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of therapeutic compound(s), in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions can be suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527-33 (1990).

[0124] The therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the therapeutic compound(s) / agent(s) as described herein. The particles may contain the therapeutic compound(s) / agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic compound(s) / agent(s) also may be dispersed throughout the particles. The therapeutic compound(s) / agent(s) also may be adsorbed into the particles. The particles maybe of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to any therapeutic compound(s) / agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, non-erodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the therapeutic compound(s) / agent(s) in a solution or in a semi-solid state. The particles may be of virtually any shape.

[0125] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic compound(s) / agent(s). Such polymers may be natural or synthetic polymers. The polymer can be selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, polyethylene glycols (PEGs), polyvinylalcohols (PVAs), poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly-lactic acid (PLA), poly(lactic -co- glycolic) acid (PLGA), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and poly(E-caprolactone) or mixtures of two or more of the foregoing. The biodegradable polymeric materials may be substantially pure single polymer or mixes of two or more polymers wherein the materials comprise mixtures of single monomers, block co-polymers or a mixture thereof.

[0126] Therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) can be formulated in a carrier system. The carrier can be a colloidal system. The carrier or colloidal system can be a liposome, a phospholipid bilayer vehicle. In one embodiment, therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) can be encapsulated in a liposome while maintaining integrity of the therapeutic compound(s) / agent(s). One skilled in the art would appreciate that there are a variety of methods to prepare liposomes. (See Lichtenberg, et al., Methods Biochem. Anal., 33:337-462 (1988); Anselem, etal., Liposome Technology, CRC Press (1993)). Liposomal formulations candelay clearance and increase cellular uptake (See Reddy, Ann. Pharmacother 34(7-8):915-923 (2000)). For example, a therapeutic agent can also be loaded into a particle prepared from pharmaceutically acceptable ingredients including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable or gastroretentive polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles and viral vector systems.

[0127] The carrier can also be a polymer, e.g., a biodegradable, biocompatible polymer matrix. In one embodiment, the therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) can be embedded in the polymer matrix, while maintaining integrity of the composition. The polymer can be a microparticle or nanoparticle that encapsulates therapeutic compound(s) / agent(s). The polymer may be natural, such as polypeptides, proteins or polysaccharides, or synthetic, such as poly a-hydroxy acids. Examples include carriers made of, e.g., collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharide, fibrin, gelatin, and combinations thereof. In some embodiments, the polymer is poly-lactic acid (PLA), poly lactic / glycolic acid (PLGA) or a mixture thereof. The polymeric matrices can be prepared and isolated in a variety of forms and sizes, including microspheres and nanospheres. Polymer formulations can lead to prolonged duration of therapeutic effect. (See Reddy, Ann.Pharmacother ., 34(7-8):915-923 (2000)). A polymer formulation for human growth hormone (hGH) has been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).

[0128] Examples of polymer microsphere sustained release formulations are described in PCT publication WO 99 / 15154 (Tracy, et al.), U.S. Pat. Nos. 5,674,534 and 5,716,644 (both to Zale, et al.), PCT publication WO 96 / 40073 (Zale, et al.), and PCT publication WO 00 / 38651 (Shah, et al.). U.S. Pat. Nos. 5,674,534 and 5,716,644 and PCT publication WO 96 / 40073 describe apolymeric matrix containing particles of erythropoietin that are stabilized against aggregation with a salt.

[0129] In some embodiments, the nanoparticles or microparticles can be silica-based or silane- based (See for example: W02002 / 080977 entitled: “Biodegradable carrier and method for preparation thereof’).

[0130] In some embodiments, the therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) can be prepared with carriers that will protect the therapeutic compound(s) / agent(s) or other therapeutic agent(s) or mixtures thereof against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using known techniques. The materials can also be obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to specific cells with monoclonal antibodies to cell-specific antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0131] The therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) may be contained in controlled release systems. The term “controlled- release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non- immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained-release” (also referred to as “extended-release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed-release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom to thereby make it available to the subject. “Delayedrelease” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”

[0132] Use of a long-term controlled-release or sustained-release implant or depot formulation may be particularly suitable for treatment of chronic conditions. The term “implant” and “depot formulation” is intended to include a single composition (such as a mesh) or composition comprising multiple components (e.g., a fibrous mesh constructed from several individual pieces of mesh material) or a plurality of individual compositions where the plurality remains localized and provides the long-term sustained-release of active pharmaceutical ingredient(s) occurring from the aggregate of the one or plurality of compositions. “Long-term” release, as used herein, means that the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 2 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 7 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 14 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient for at least 90 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least one year. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 15-30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 30-60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 60-90 days. In someembodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 90-120 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 120-180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for up to one year. In some embodiments, the long-term sustained-release implants or depot formulation are well-known to those of ordinary skill in the art and include some of the release systems described above. In some embodiments, such implants or depot formulation can be administered surgically. In some embodiments, such implants or depot formulation can be administered topically or by injection.III. Characteristics of Cardiac Hypertrophy

[0133] Cardiac hypertrophy is a compensatory response to increased preload or afterload cardiac stress. Cardiac hypertrophy falls into two distinct categories. These are physiological hypertrophy and pathological hypertrophy. Physiological hypertrophy is reversible and maintains cardiac function, whereas pathological hypertrophy is typically degenerative, leading to arrhythmias, heart failure, and ultimately death. Nakamura et al., Mechanisms of Physiological and Pathological Cardiac Hypertrophy, Nature Reviews - Cardiology, (2018) 15: 387-407.

[0134] Physiological hypertrophy is characterized by increased cardiac mass and cardiomyocyte growth, usually as a consequence of physical stress (e.g., pregnancy or endurance training). This physical change in heart structure occurs to compensate for the increased stress. Once the stress is relieved, the heart will return to normal size (i.e., the heart of the subject will return to its original mass without any lasting adverse effects). Id.

[0135] Pathological hypertrophy is characterized by increased cardiac mass as well as an increase in left ventricle wall thickness, with individual cardiomyocytes increasing in width (thickness) more than in length. As a result of these changes, the left ventricle size becomes decreased (i.e., reduction in left ventricle chamber dimension) as the walls of the heart thicken. These changes in heart structure are often referred to as maladaptive remodeling or cardiac remodeling. Stimuli that often cause pathological hypertrophy include, but are not limited to,myocardial infarction, valvular disease, diabetes, metabolic syndrome, and genetic causes such as Friedreich’s ataxia. Pathologic hypertrophy typically leads to decreased cardiomyocyte contractility, cardiomyocyte death, and fibrosis (e.g., myocardial fibrosis). Maladaptive remodeling (i.e., cardiac remodeling) is not known to be reversible but there is hope that treatments / drugs may eventually “reverse remodel” the heart as occurs with physiological hypertrophy. Absent treatments, pathological hypertrophy is degenerative, leading to arrhythmias, heart failure, and ultimately death. Id.IV. Cardiac Fibrosis

[0136] Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins (e.g., collagen) in the cardiac interstitium and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. Fibrotic remodeling of the heart can occur either directly by producing matrix proteins (e.g., fibroblasts), or indirectly by secreting fibrogenic mediators (e.g., macrophages, mast cells, lymphocytes, cardiomyocytes and vascular cells). Hypertrophic cardiomyopathy is also often associated with the development of significant cardiac fibrosis. Cardiac fibrosis is not known to be reversible but there is experimental and clinical evidence suggesting that cardiac fibrotic alterations may be reversible. Kong et al., The Pathogenesis of Cardiac Fibrosis, Cell Mol. Life Set, (2014) 71(4): 549-574.V. Cardiac Remodeling and Cardiac Reverse Remodeling

[0137] As discussed above, cardiac remodeling is a term used to refer to naturally occurring adaptive change in the physical structure of the heart in response to stimuli, such as stress induced by pregnancy, exercise or disease. Cardiac hypertrophy is an example of cardiac remodeling. Cardiac fibrosis is an example of cardiac remodeling. Whereas physiological cardiac hypertrophy is naturally reversible, pathological hypertrophy is generally permanent and progressively maladaptive. Cardiac fibrosis is not known to be reversible but recent evidence suggests that it might be with suitable intervention. The term “reverse remodeling” or “cardiac reverse remodeling”, as used herein, is intended to refer to any positive change in physical structure of the heart that reverses an already occurred damaging cardiac remodeling event.With respect to cardiac hypertrophy, such reverse remodeling could be reduction in mass of the heart or reduction in ventricle (often the left ventricle but can be the left or right ventricle) wallthickness in a subject in response to a stimuli, such as treatment with (administration of) Compound A, Compound B or a mixture thereof (including, of course, any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof). With respect to cardiac hypertrophy or cardiac fibrosis, such reverse remodeling could be reduction in the amount of or inhibition of or delay in the progression of cardiac fibrosis observed after treatment with (administration of) Compound A, Compound B or a mixture thereof (including, of course, any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof).

[0138] With reference to Example 2 and Figs. 8-17, the data presented suggest not only is administration of Compound A or Compound B to the mouse model studies capable of reducing the formation of cardiac hypertrophy, but also possibly capable of reversing the cardiac hypertrophy (i.e., cardiac reverse remodeling).VI. Improving / Normalizing Mitochondria Size in the Cardiomyocytes

[0139] In at least one known mouse model of Friedreich’s ataxia, it has been observed that as the mice age, the cross-sectional area of the mitochondria of cardiomyocytes decreases as compared with wild type mice. (See: Chiang et al. at section 3.1) With reference to Example 3 and Figs. 18A & 18B, the data suggests that administration of Compound A to the mouse model of FA studied in that experiment helped to improve or normalize the size of the mitochondrial (making them more like the wild type mice) as compared to the untreated mice of the mouse model.VII. Reducing Iron in Cardiomyocytes

[0140] Iron is known to accumulate in the cardiomyocytes of a mouse model of Friedreich’s ataxia (See: Chiang et al.). The iron accumulation can be visualized in transmission electron micrographs (TEM). Id. at Fig. 2A.

[0141] With reference to Example 3 and Figs. 19A-19C, the data suggests that cardiomyocytes of the mouse model known to exhibit cardiac hypertrophy treated with Compound A exhibited a reduction in iron accumulation in their mitochondria as compared with mitochondria in the cardiomyocytes of untreated mice of the disease model.VIII. Therapeutic Methods of the Disclosed Compounds in Addressing Cardiomyopathy, including Hypertrophic Cardiomyopathy.

[0142] The examples provided below demonstrate that Compound A and Compound B are particularly well suited for treatment of cardiomyopathies in mammalian subjects because they are well tolerated in animal models and are effectively taken up in heart tissues in amounts believed to be therapeutically active. Furthermore, Compound A and Compound B (and by extension a mixture of Compound A and Compound B) appear to be protective of the hearts of animals (i.e., mice) that otherwise experience maladaptive cardiac remodeling, such as development of pathological cardiac hypertrophy and cardiac fibrosis. Compound A and Compound B also appear to be superior in their effects on the heart of subjects as compared with the comparator molecule, vatiquinone - which small molecule has been extensively studied in the laboratory and in human clinical trials. Therefore, Compound A, Compound B, and mixtures thereof (including pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof) appear to be well suited for treating, preventing, delaying the progression of or delay in the onset of cardiomyopathy, including hypertrophic cardiomyopathy and cardiac fibrosis, such as is often seen subjects having Friedreich’s ataxia.

[0143] In addition to the compelling cardiac dysfunction that occurs in subjects with Friedrich’s ataxia, the disease is known for its neurodegenerative effects as well as degenerative effects on hearing and vision of subjects later in life. The data in Example 1, below demonstrates that Compound A and Compound B are taken up in the brain in amounts believed to be therapeutically effective. As such, these compounds may be well suited for treatment of the neurodegenerative effects of Friedreich’s ataxia, in addition to the cardiac dysfunction associated with the disease.

[0144] Thus, in one aspect, the present disclosure provides a method for treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy, in a mammalian subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound A or Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:

[0145] In some embodiments of the foregoing method, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the foregoing method, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing method, the subject is human. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis (e.g., myocardial fibrosis) in the subject’s heart tissue. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject results in reverse remodeling of the subject’s heart. In some embodimentsof the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves hearing and / or vision of the subject. In some embodiments of the foregoing method, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject increases the lifespan of the subject. In some embodiments of the foregoing method, Compound A, Compound B, or a mixture comprising Compound A and Compound B is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.IX. Compositions, Formulations or Medicaments Comprising the Disclosed Compounds For Addressing Cardiomyopathy, Including Hypertrophic Cardiomyopathy.

[0146] In another aspect, the present disclosure provides a composition, medicament or formulation comprising Compound A, Compound B, or a mixture of Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof for use in treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy in a mammalian subject in need thereof, wherein Compound A and Compound B have the following structures:In one aspect, the present technology provides a composition, medicament or formulation comprising Compound A, Compound B, or a mixture of Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof for use in treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy in a mammalian subject in need thereof, wherein Compound A and Compound B have the following structures:

[0147] In some embodiments of the foregoing composition, medicament or formulation, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the foregoing composition, medicament or formulation, the cardiomyopathy ishypertrophic cardiomyopathy. In some embodiments of the foregoing composition, medicament or formulation, the subject is human. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis in the subject’s heart tissue. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject results in reverse remodeling of the subject’s heart. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject improves hearing and / or vision of the subject. In some embodiments of the foregoing composition, medicament or formulation, administration of the composition, medicament or formulation to the subject increases the lifespan of the subject. In some embodiments of the foregoing composition, medicament or formulation, the composition, medicament or formulation is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.X. Uses of the Disclosed Compounds For Addressing Cardiomyopathy, Including Hypertrophic Cardiomyopathy.

[0148] In one aspect, the present technology provides for use of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof in treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy in a mammalian subject in need thereof, wherein Compound A and Compound B have the following structures:Compound B

[0149] In some embodiments of the foregoing use, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the foregoing use, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing use, the subject is human. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing use, administration of Compound A, Compound B, or amixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis in the subject’s heart tissue. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject results in reverse remodeling of the subject’s heart. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves hearing and / or vision of the subject. In some embodiments of the foregoing use, administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B to the subject increases the lifespan of the subject. In some embodiments of the foregoing use, Compound A, Compound B, or a mixture comprising Compound A and Compound B is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.XL Other Methods.

[0150] In one aspect, the present technology provides for a method for reducing iron accumulation in the cardiomyocytes of a mammalian subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound A, Compound B,or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:embodiments of the method, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the method, the subject is human.

[0151] In one aspect, the present technology provides for a method for improving or normalizing the size of mitochondria in the cardiomyocytes of a mammalian subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:In some embodiments of the method, the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia. In some embodiments of the method, the subject is human.EXAMPLES

[0152] The present technology is further illustrated by the following examples, which should not be construed as limiting in any way.Example 1: In Vivo Plasma & Tissue Uptake Assays in Mouse and Rat (Compounds A & B)I. ASSESSMENT OF THE PHARMACOKINETICS OF COMPOUND A ANDCOMPOUND B FOLLOWING FIVE DAILY SUBCUTANEOUS DOSES TO MALEC57BL / 6 MICE

[0153] a) Dosing Protocol:• Animals: Male / C57Bl / 6 mice / -18-25 grams were received from an approved vendor.• Fasting was not required for this study.• Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal's body weight.• This was a multiple dose terminal study dosed once per day over 5 days. Mice were taken down following their 5thand final dose.• Doses were administered in accordance with test facility standard operating procedures. Post-dose flushes were administered as applicable.• All dose syringes were weighed prior to and following dosing to gravimetrically determine the amount of formulation administered.• All animals were observed at dosing and each scheduled collection. Any abnormalities were recorded.• Pre-formulated Compound A, Compound B and comparator vatiquinone were prepared for dosing in accordance with the Study Design set forth in Table 1, below. These compounds (i.e., Compound A and Compound B) were prepared as described in WO2021 / 202986. Vatiquinone was prepared using the procedures described in WO202 1 / 202986 as applicable to produce vatiquinone.Table 1: Study DesignSC = subcutaneous administration

[0154] b) Sample collection - Post Dosing:• Terminal blood samples were collected via cardiac puncture following inhalation of anesthesia in accordance with test facility standard operating procedures.• Blood samples were collected into tubes with appropriate anticoagulant. The tubes were stored on wet ice until processed to plasma by centrifugation (3500 rpm at 5 °C for 10 minutes) within 20 minutes of collection. Sample aliquots of 100 pL were transferred into individual uniquely labeled matrix tubes and stored at nominal -80 °C until transferred to analytical chemistry for analysis by LC / MS / MS.• Immediately following each terminal blood collection for all groups, animals were sacrificed and perfused with cold PBS. The following tissues were collected: heart and brain in accordance with Table 2, below.• Plasma and tissue samples were processed for analysis by LC / MS / MS to determine the amounts / concentrations reported in the Figs. 2-5.Table 2: Sample Collection Design

[0155] c) Results: Results are discussed below and presented graphically in Figs. 2-5 . It is also worth noting that administration of each of Compound A and Compound B was well tolerated under the concentrations and conditions employed.II. AN ASSESSMENT OF THE PHARMACOKINETICS OF COMPOUND B FOLLOWING REPEATED (5 DAYS) SUBCUTANEOUS DOSE ADMINISTRATION TO MALE SPRAGUE DAWLEY RATS

[0156] a) Dosing Protocol:• Animals: Rat / Sprague Dawley / Male / Naive 225-250 grams were received from an approved vendor.• Fasting was not required for this study.• Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal's body weight.• This was a multiple dose terminal study dosed once per day over 5 days. Rats were taken down following their 5thand final dose.• Doses were administered in accordance with test facility standard operating procedures. Post-dose flushes were administered as applicable.• All dose syringes were weighed prior to and following dosing to gravimetrically determine the amount of formulation administered.• All animals were observed at dosing and each scheduled collection. Any abnormalities were recorded.Pre-formulated Compound B was prepared for dosing in accordance with the Study Design set forth in Table 3, below.Table 3: Study DesignSC = subcutaneous administration

[0157] b) Sample collection - Post Dosing:• Terminal blood samples were collected via cardiac puncture following inhalation anesthesia in accordance with test facility standard operating procedures.• Blood samples were collected into tubes with appropriate anticoagulant. Tubes were stored on wet ice until processed to plasma by centrifugation (3,500 rpm at 5 °C for 10 minutes) within 20 minutes of collection. Sample aliquots of 100 pL were transferred into individual uniquely labeled matrix tubes and stored at nominal -80 °C until transferred to analytical chemistry for analysis.• Immediately following each terminal blood collection for all groups, animals were sacrificed and perfused with cold PBS. The following tissues were collected: heart and brain, in accordance with Table 4.• Plasma and tissue samples were processed for analysis by LC / MS / MS to determine the amounts / concentrations in plasma is reported in Fig. 2.Table 4: Sample Collection Design

[0158] c) Results: Are discussed below in Section III and presented graphically in Fig. 3. It is also worth noting that administration of Compound B was well tolerated under the concentrations and conditions employed.III. RELEVANT RESULTS OF THE MOUSE AND RAT PK EXPERIMENTS

[0159] With reference to Fig. 2, the plasma concentrations of Compound B (dosed both at 20 mg / kg and 60 mg / kg dosing) and Compound A (dosed only 60 mg / kg dosing) are plotted from 30 minutes to 24 hours post-administration. Because the route of administration is subcutaneous injection (SC), the drug (i.e., each of Compounds A and B) needs to migrate within the tissue to be taken up into the blood stream to provide for potentially efficacious systemic tissue dosing. The data demonstrates that both Compound A and Compound B migrate into the blood stream of the mouse plasma and that higher dosing elicits a roughly proportional increase in plasma concentrations. Furthermore, the plasma concentrations drop off over time as would be expected as they are cleared from the subject.

[0160] In Fig. 3, the data obtained with Compound B for plasma concentrations for the 20 mg / kg dose in mouse is graphically compared with the data obtained at 10 mg / kg dosing (also Compound B) in rats over the period of 30 minutes to 24 hours post administration. Because the comparison is between species (i.e., mouse and rat), these doses are approximately equal if you base them on mg / m2of body area (i.e., in this case 60 mg / m2) of each species. With reference to Fig. 3, the data suggests that uptake of Compound B to plasma resulting from SC dosing across the two species of mammal is roughly equivalent over the period tested.

[0161] Delivery of a drug to the heart can be difficult because the body contains certain barriers (See: Sahoo et al., Targeted Delivery of Therapeutic Agents to the Heart, Nat. Rev Cardiol., (2021) 18(6): 389-399). With reference to Fig. 4, the concentrations of Compound B (dosed both at 20 mg / kg and 60 mg / kg dosing) and Compound A (dosed only 60 mg / kg dosing) in heart tissue are plotted from 30 minutes to 24 hours post-administration. The data demonstrate that up to microgram quantities of drug per gram of heart tissue were found at up to 2 hours post (after 5 days of) drug administration and that clearance of the drugs from the tissuesproceeded over time as expected. These data suggest that efficacious quantities of Compound B and Compound A can be delivered to heart tissue of mice under these dosing conditions and they can be cleared from the subject’s tissues without any difficulty.

[0162] Delivery of a drug to the brain can be difficult because the blood-brain barrier or BBB protects the brain (and other central nervous system (CNS) tissues) against the penetration of certain types of molecules. With reference to Fig. 5, the concentrations of Compound B (dosed both at 20 mg / kg and 60 mg / kg dosing) and Compound A (dosed only 60 mg / kg dosing) in brain tissue are plotted from 30 minutes to 24 hours post-administration. The data demonstrate that up to microgram quantities of drug per gram of brain tissue were found up to 2 hours post (after 5 days of) drug administration and that clearance of the drugs from the tissues proceeded over time as expected. These data suggest that efficacious quantities of Compound B and Compound A can be delivered to brain tissue of mice under these dosing conditions and they can be cleared from the subject’s tissues without any difficulty. d) Summary / Discussion of Results:• Both Compound A and Compound B were well tolerated at dose levels up to 60 mg / kg in mouse (administered by SC injection).• Compound B dose scales well by allometry in rodents (20 mg / kg in mouse ~ 10 mg / kg in rat).• Compound B plasma exposure is roughly proportional to dose (compare data for 20 mg / kg and 60 mg / kg).• Compound A plasma concentrations often were higher than Compound B plasma concentrations.• Tmax was typically later for Compound A than Compound B, and half-life tended to be longer.• Compound B exposure (Cmax (maximum observed concentration) and AUC (area under the concentration-time curve)) was higher in heart than in brain; there was no significant difference in the two tissue exposures for Compound A.• Based on AUC, heart exposure was similar between the two compounds; brain exposure of Compound A was somewhat higher than Compound B.• Concentrations achieved in the plasma and heart tissues represent amounts expected to be efficacious for purposes of treatment, prevention, delay in the onset of or delay in the progression of cardiomyopathies, and hypertrophic cardiomyopathy in particular.Example 2: Efficacy Study of Small Molecule Compounds (Compound A, Compound B, and a comparator compound Vatiquinone) in a Friedreich’s Ataxia (FA) Mouse Model a) Disease Characteristics and Mouse Model

[0163] Friedreich's ataxia (FA) is a mitochondrial disease characterized by cardiac failure, hypertrophic cardiomyopathy and diabetes (Weidemann et al., 2012). People with FA have many different symptoms with multiple body systems including degeneration of nervous tissue, cardiac damage, gait disturbances, scoliosis, and diabetes. Optical neuropathy and retinitis pigmentosa-like syndrome have also been documented in human FA patients.

[0164] The mouse model, 36 F^,-Fxnem2LutzyFxHem2 1LutzyTg(Ckmm-cre)5Khn / J mice (The Jackson Laboratories (J AX) stock# 029720), harbor a conditional frataxin allele (flanking exon 2), a null frataxin allele (exon 2) and a transgene expressing cre-recombinase driven off the creatine kinase muscle specific promoter, similar, but not identical, to the conditional frataxin allele created by Helene Puccio. This allelic combination results in the specific ablation of frataxin expression in cardiac and skeletal muscle. The resulting phenotype in this model includes progressive weight loss associated with functional cardiac deficits leading to morbidity by 10-12 weeks of age. Hence, this mouse model provides a suitable means to study the progressive heart conditions that mimic those observed in patients with Friedreich’s ataxia.

[0165] This FA mouse model was generated by inter-crossing the following two mouse lines: Line #1 : 36 C -Fxriem2-1LutzyTg(Ckmm-cre)5Khn / J (J AX Stock# 029100) harbor a frataxin global knock-out allele and a cardiac / skeletal muscle-specific Cre recombinase transgene. When heterozygous for Fxnllox'nul1and hemizygous or homozygous for MCK-Cre, these double mutant mice are phenotypically normal. Line #2: C5133l6FFxnem2Lutzyl (JAX Stock# 028520) mice have a CRISPR / Cas9-generated, Cre-conditional FXN allele. The mice generated in this study are referred to in this Example 2 as mutant (MUT; 5F / 5M Fxnl,ox ,1ull::MCK-Cre) and controlnon-transgenic animals are referred to as wildtype (WT; J AX Stock# 000664). The mouse breeding and the resulting study were performed at The Jackson Laboratories. b) Study Purpose

[0166] The present study was designed to evaluate efficacy in a cardiac-specific FA mouse model after chronic exposure to novel small molecule therapeutics (i.e., Compound A and Compound B) administered by subcutaneous injection. Vatiquinone was also studied as a comparator molecule (but administered orally as it is typically administered), because vatiquinone has been extensively studied as a treatment for FA, including in human clinical trials of patients with FA. The study protocol was IACUC approved. c) Test Articles, Vehicles, Formulations

[0167] Stock solutions of vatiquinone (stock at 5 mg / mL), Compound A (stock at 6 mg / mL) and Compound B (stock at 6 mg / mL) were prepared and stored as shown in Table 5, below. Compound A, Compound B and vatiquinone were obtained as described in Example 1, above.Table 5d) Basic Study & Experimental DesignTable 6: Basic Study InformationTable 7: Grouping of Mice for StudySC = subcutaneous administration; PO = administration by oral gavage. Vatiquinone wasincluded in this study as a comparator molecule since it has been studied in this mouse model and has been studied in human patients diagnosed with Friedreich’s ataxia. e) SC Dosing

[0168] Frequency: Daily for ~8 weeks (until mice meet endpoint) - Groups 1, 2, 4, and 5.

[0169] Procedure: Injections using a 27G needle were made in the flanks. Animals were restrained and the syringe held parallel to the mouse. The needle was inserted just under the skin of the flank of the mouse. The needle was lifted and if the skin “tents” over the needle then the needle was in a subcutaneous position. If / when the needle did not lift easily, the needle was withdrawn slightly, as it likely penetrated the muscle mass underneath. The desired dose volume(1 OmL / kg (BWxl 0)) per mouse was injected. Proper injection was indicated by a bleb or “bubble” forming under the skin. The mouse was then returned to its home cage. f) Oral Gavage (PO) Dosing

[0170] Frequency: Daily for ~8 weeks (until mice meet endpoint) - Group 3

[0171] Procedure: Injections using a 22 or 23G needle was used for animals 21-27 days of age and 20 or 22 G needle was used for animals 28 days and older.

[0172] Animals were restrained vertically so that the ball, syringe and the mouse’s mouth are visible to the individual restraining the mouse. Holding syringe firmly, the needle was inserted into the mouse’s mouth and followed the roof of the mouth with the needle. Once the ball of the needle reached the back of the throat, the nose of the mouse was gently raised upwards, by moving the syringe vertically such that it was parallel with the spine, until the mouse swallowed and then the needle slides easily down the esophagus. The needle would then empty of its own accord. Once the needle stopped moving, the syringe plunger was slowly depressed (without moving the syringe or needle) until the desired amount of liquid was administered to the mouse. The needle was then gently removed from the animal’s mouth. Between pens, reusable gavage needles were wiped with a paper towel (or similar) moistened with 70%ethanol. Desired dose volume was lOmL / kg (BWxlO) per mouse. After proper test article / vehicle administration, the mouse was returned to its home cage. g) Cardiac Imaging by Ultrasound

[0173] Cardiac function was measured by ultrasound echocardiography (echo) at The Jackson Laboratory Center for Biometrics Core Service. Cardiac assessment was carried out using the Vevo 770 / 2100 high frequency ultrasound with 30 and 40MHz probes (VisualSonics Inc. Toronto, Canada). Mice were anesthetized with up to 5% isoflurane at a flow rate of 0.8-2.0 L / min in oxygen. Fur was removed using a depilatory cream just prior to imaging. B-mode and M-mode images were recorded in parasternal short-axis (PSA) view for measurement of left ventricular wall thickness and inner diameter. From these direct measurements, diastolic and systolic blood volumes, ejection fraction, fractional shortening, cardiac output, and stroke volume were calculated / determined. For details on echocardiography measurements and calculations please refer to the Table 8, below:Table 8: Echocardiography Measurements and Calculationsh) Tissue Collection

[0174] Heart was collected and then snap frozen for further analysis if desired. i) Survival Analysis

[0175] Animal survival was constantly assessed by cage side observation. Survival was monitored for all groups and included in study records. Survival data is summarized in Fig. 6 and Fig. 7. j) Results

[0176] With reference to Fig. 6, survival data is presented graphically for the mice treated with vati quinone (Group 3) and Compound A (Group 4) as compared with the WT vehicle (Group 1) and MUT vehicle (Group 2) control groups. None of the wild type mice expired within the time studied (top line). Mutant mice (z.e., the FA mouse model) treated with vehicle (Group 2) and those treated with vatiquinone (Group 3) began to expire starting at about 50 days. By comparison, the MUT mice treated with Compound A (Group 4) only began to expire starting at about 70 days. All mutant mice (regardless of treatment type) expired by 80 days. In brief, this data appears to demonstrate that administration of Compound A to the FA mouse model delayed the onset of mortality of this group of mice by about 20 days compared with the Group 2 (MUT, vehicle control) and Group 3 (vatiquinone treated comparator molecule) mice. These datatherefore support the conclusion that administration of Compound A (Group 4) can increase the lifespan / survival of the FA mouse model as compared with control Groups 2 and 3.

[0177] With reference to Fig. 7, survival data is presented graphically for the mice treated with vati quinone (Group 3) and Compound B (Group 5) as compared with the WT vehicle (Group 1) and MUT vehicle (Group 2) control groups. None of the wild type mice expired within the time studied (top line). Mutant mice (i.e., the FA mouse model) treated with vehicle (Group 2) and those treated with vatiquinone (Group 3) began to expire starting at about 50 days. By comparison, the MUT mice treated with Compound B (Group 5) only began to expire starting at about 70 days. All mutant mice (regardless of treatment type) expired by 80 days. In brief, this data appears to demonstrate that administration of Compound B to the FA mouse model delayed the onset of mortality of this group of mice by about 20 days. These data therefore support the conclusion that administration of Compound B (Group 5) can increase the lifespan / survival of the FA mouse model as compared with control Groups 2 and 3.

[0178] With reference to Fig. 8, echocardiogram data for left ventricle mass normalized to body weight is presented for each group of mice using time points at 4 weeks post commencement of first administration of drug and 7 weeks post commencement of first administration of drug. In this figure, mice treated with vatiquinone (Group 3) and Compound A (Group 4) are compared with the WT vehicle (Group 1) and MUT vehicle (Group 2) control groups. With reference to the figure, Group 2 (MUT, vehicle) and Group 3 (MUT, vatiquinone) mice both exhibited a large increase in left ventricular mass between weeks 4 and 7, with vatiquinone appearing to exhibit at least some benefit over the Group 2 control. In contrast, there was a much smaller increase in left ventricle mass observed in Group 1 (WT, vehicle) and Group 4 (MUT, Compound A) mice between weeks 4 and 7 and indeed, the increase in left ventricle mass in Group 4 mice was substantially similar to that seen in the WT control. These data suggest that administration of Compound A was effective in preventing, or at least delaying the progression of or onset of left ventricle mass increase in the FA mouse model and was superior in its effect as compared with vatiquinone. As left ventricle mass increase is a hallmark of cardiac hypertrophy, these data suggest that Compound A is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in this FA mouse model.

[0179] With reference to Fig. 9, echocardiogram data for left ventricle mass normalized to body weight is presented for each group of mice using time points at 4 weeks post commencement of first administration of drug and 7 weeks post commencement of first administration of drug. In this figure, mice treated with vatiquinone (Group 3) and Compound B (Group 5) are compared with the WT vehicle (Group 1) and MUT vehicle (Group 2) control groups. With reference to the figure, Group 2 (MUT, vehicle) and Group 3 (MUT, vatiquinone) mice both exhibited a large increase in left ventricular mass between weeks 4 and 7, with vatiquinone appearing to exhibit at least some benefit. In contrast, there was a smaller increase in left ventricle mass observed in Group 1 (WT, vehicle) and a somewhat larger increase in left ventricle mass in the Group 5 (MUT, Compound B) mice between weeks 4 and 7. While the increase in left ventricle mass in Group 5 (MUT, Compound B) mice appears to be larger than seen with Group 4 (MUT, Compound A) the increase was lower than what was observed with comparator compound, vatiquinone. These data suggest that administration of Compound B was effective in preventing, or at least delaying the progression of or onset of left ventricle mass increase in the FA mouse model, and was superior in its effect as compared with vatiquinone. As left ventricle mass increase is a hallmark of cardiac hypertrophy, these data suggest that Compound B is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model.

[0180] With reference to Fig. 10, echocardiogram data for left ventricle anterior wall thickness (diastole) is presented for each group of mice using time points at 4 weeks post commencement of first administration of drug and 7 weeks post commencement of first administration of drug. In this figure, mice treated with vatiquinone (Group 3) and Compound A (Group 4) are compared with the WT vehicle (Group 1) and MUT vehicle (Group 2) control groups over the three week treatment period. With reference to the figure, Group 2 (MUT, vehicle) mice exhibit a small increase in wall thickness over the three week treatment period. Similarly, Group 3 (MUT, vatiquinone) mice exhibit a small increase in wall thickness over the three week treatment period, albeit apparently less significant than that observed with the Group 2 (MUT, vehicle) mice. By comparison, the control Group 1 (WT, vehicle) mice exhibit a small decrease in wall thickness over the 3 week time period and the Group 4 (MUT, Compound A) mice appear to exhibit an even more significant decrease in wall thickness over the three week period. These data suggest that administration of Compound A was effective in preventing, or at leastdelaying the progression of or onset of left ventricle anterior wall thickness (diastole) increase in the FA mouse model. As an increase in left ventricle anterior wall thickness (diastole) is a hallmark of cardiac hypertrophy, these data suggest that Compound A is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model.

[0181] With reference to Fig. 11, echocardiogram data for left ventricle anterior wall thickness (diastole) is presented for each group of mice using time points at 4 weeks post commencement of first administration of drug and 7 weeks post commencement of first administration of drug. In this figure, mice treated with vatiquinone (Group 3) and Compound B (Group 5) are compared with the WT vehicle (Group 1) and MUT vehicle (Group 2) control groups over the three week treatment period. With reference to the figure, Group 2 (MUT, vehicle) mice exhibit a small increase in wall thickness over the three week treatment period. Similarly, Group 3 (MUT vatiquinone) mice exhibit a small increase in wall thickness, albeit apparently less significant than that observed with the Group 2 (MUT, vehicle) mice. By comparison, the control Group 1 (WT, vehicle) mice exhibit a small decrease in wall thickness over the 3 week time period and the Group 5 (MUT, Compound B) mice appear to exhibit a substantially similar decrease (as compared with Group 1 mice) in wall thickness over the three week period. These data suggest that administration of Compound B was effective in preventing, or at least delaying the progression of or onset of left ventricle anterior wall thickness (diastole) increase in the FA mouse model. As an increase in left ventricle anterior wall thickness (diastole) is a hallmark of cardiac hypertrophy, these data suggest that Compound B is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model.

[0182] With reference to Fig. 12, echocardiogram data for left ventricle anterior wall thickness (systole) is presented for each group of mice using time points at 4 weeks post commencement of first administration of drug and 7 weeks post commencement of first administration of drug. In this figure, mice treated with vatiquinone (Group 3) and Compound A (Group 4) are compared with the WT vehicle (Group 1) and MUT vehicle (Group 2) control groups over the three week treatment period. With reference to the figure, Group 2 (MUT, vehicle) mice exhibited a significant increase in wall thickness over the three week treatment period. Similarly, Group 3 (MUT, vatiquinone) mice exhibit a small increase in wall thickness, albeit apparently less significant than that observed with the Group 2 (MUT, vehicle) mice over the three weektreatment period. By comparison, the control Group 1 (WT, vehicle) mice exhibit a small decrease in wall thickness over the 3 week time period and the Group 4 (MUT, Compound A) mice appear to exhibit an even more significant decrease in wall thickness over the three week period. These data suggest that administration of Compound A was effective in preventing, or at least delaying the progression of or onset of left ventricle anterior wall thickness (systole) increase in the FA mouse model. As an increase in left ventricle anterior wall thickness (systole) is a hallmark of cardiac hypertrophy, these data suggest that Compound A is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model.

[0183] With reference to Fig. 13, echocardiogram data for left ventricle anterior wall thickness (diastole) is presented for each group of mice using time points at 4 weeks post commencement of first administration of drug and 7 weeks post commencement of first administration of drug. In this figure, mice treated with vatiquinone (Group 3) and Compound B (Group 5) are compared with the WT vehicle (Group 1) and MUT vehicle (Group 2) control groups over the three week treatment period. With reference to the figure, Group 2 (MUT, vehicle) mice exhibited a significant increase in wall thickness over the three week treatment period. Similarly, Group 3 (MUT, vatiquinone) mice exhibit an increase in wall thickness, albeit apparently substantially less significant than that observed with the Group 2 (MUT, vehicle) mice. By comparison, the control Group 1 (WT, vehicle) mice exhibit a small decrease in wall thickness over the 3 week time period and the Group 5 (MUT, Compound B) mice appear to exhibit a substantially similar decrease (as compared with Group 1 mice) in wall thickness over the three week period. These data suggest that administration of Compound B was effective in preventing, or at least delaying the progression of or onset of left ventricle anterior wall thickness (systole) increase in the FA mouse model. As an increase in left ventricle anterior wall thickness (systole) is a hallmark of cardiac hypertrophy, these data suggest that Compound B is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model.

[0184] With reference to Fig. 14, echocardiogram data for left ventricle anterior wall thickness (diastole) is presented in bar graph format for each group of mice using the data at 7 weeks post commencement of first administration of drug. With reference to the figure, there is a statistically significant increase in left ventricle anterior wall thickness (diastole) between Group 1 (WT, vehicle) and Group 2 (MUT, vehicle) mice. This would be expected for the mutant miceas compared with the wild type mice based on the known phenotype of the FA mouse model. Further, there is a statistically significant decrease in left ventricle anterior wall thickness (diastole) between Group 2 (MUT, vehicle) mice and Group 4 (MUT, Compound A) mice. Moreover, there is no statistically significant difference between the Group 1 (WT, vehicle) and Group 4 (MUT, Compound A). These data further support the conclusion that Compound A is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model. These data may even suggest that Compound A is able to reverse remodel the heart of the FA mouse model.

[0185] With reference to Fig. 15, echocardiogram data for left ventricle anterior wall thickness (systole) is presented in bar graph format for each group of mice using the data at 7 weeks post commencement of first administration of drug. With reference to the figure, there is not a statistically significant increase in left ventricle anterior wall thickness (systole) between Group 1 (WT, vehicle) and Group 2 (MUT, vehicle) mice. However, there is a statistically significant decrease in left ventricle anterior wall thickness (systole) between Group 2 (MUT, vehicle) mice and Group 4 (MUT, Compound A) mice. Moreover, there is a statistically significant difference between the Group 1 (WT, vehicle) and Group 4 (MUT, Compound A), strongly suggesting that Compound A is protective against increases in in left ventricle anterior wall thickness (systole) and possibly possessing the ability to reverse remodel heart tissue (i.e., reversing cardiac hypertrophy). These data further support the conclusion that Compound A is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model and may even be suitable for reverse remodeling heart tissue (i.e., reversing cardiac hypertrophy).

[0186] With reference to Fig. 16, echocardiogram data for left ventricle anterior wall thickness (diastole) is presented in bar graph format for each group of mice using the data at 7 weeks post commencement of first administration of drug. With reference to the figure, there is a statistically significant increase in left ventricle anterior wall thickness (diastole) between Group 1 (WT, vehicle) and Group 2 (MUT, vehicle) mice as would be expected for the mutant vs. wild type mouse. Further, there is a statistically significant decrease in left ventricle anterior wall thickness (diastole) between Group 2 (MUT, vehicle) mice and Group 5 (MUT, Compound B) mice. Moreover, there is no statistically significant difference between the Group 1 (WT, vehicle) and Group 5 (MUT, Compound B). These data further support the conclusion thatCompound B is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model.

[0187] With reference to Fig. 17, echocardiogram data for left ventricle anterior wall thickness (systole) is presented in bar graph format for each group of mice using the data at 7 weeks post commencement of first administration of drug. With reference to the figure, there is not a statistically significant increase in left ventricle anterior wall thickness (systole) between Group 1 (WT, vehicle) and Group 2 (MUT, vehicle) mice. However, there is a statistically significant decrease in left ventricle anterior wall thickness (systole) between Group 2 (MUT, vehicle) mice and Group 5 (MUT, Compound B) mice. These data further support the conclusion that Compound B is useful for treating, preventing, delaying the onset of or delaying the progression of cardiac hypertrophy in the FA mouse model and may even be suitable for reverse remodeling heart tissue (i.e., reversing cardiac hypertrophy).Example 3; Efficacy Study of Small Molecule Compounds (Compound A, and a comparator compound Omaveloxolone) in a Friedreich’s Ataxia (FA) Mouse Model a) Disease Characteristics and Mouse Model

[0188] Same mouse model as used in Example 2. This study was performed substantially as described in Example 2, with the following modifications. For purposes of this Example 3, the results from heart tissue from only groups 1, 2 and 4 (described below) are presented and discussed below. b) Study Purpose

[0189] The present study was designed to evaluate efficacy in a cardiac-specific FA mouse model after chronic exposure to novel small molecule therapeutics (i.e., Compound A) administered by subcutaneous injection. Omaveloxolone was also studied as a comparator molecule (but administered orally as it is typically administered), because omaveloxolone was recently approved by the FDA for use in the treatment of Friedreich’s ataxia.c) Test Articles, Vehicles, Formulations

[0190] Stock solutions of Compound A (stock at 6 mg / mL) were prepared as shown below. Compound A was obtained as described in Example 1, above. Omavel oxoIone was purchased from a commercially available source.Table 9d) Basic Study & Experimental DesignTable 10: Basic Study InformationTable 11: Grouping of Mice for StudySC = subcutaneous administration; PO = administration by oral gavage. Omaveloxolone was included in this study as a comparator molecule since it is currently an FDA-approved therapy for Friedreich’s ataxia patients aged 16 and older.

[0191] For purposes of this Example 3, the results from heart tissue from only groups 1, 2 and 4 are presented and discussed below. e) SC Dosing

[0192] Frequency: Daily for ~8 weeks (until mice meet endpoint) - Groups 1, 2, 4, and 5.

[0193] Procedure: Injections using a 27G needle were made in the flanks. Animals were restrained and the syringe held parallel to the mouse. The needle was inserted just under the skin of the flank of the mouse. The needle was lifted and if the skin “tents” over the needle then the needle was in a subcutaneous position. If / when the needle did not lift easily, the needle was withdrawn slightly, as it likely penetrated the muscle mass underneath. The desired dose volume(1 OmL / kg (BWxl 0)) per mouse was injected. Proper injection was indicated by a bleb or “bubble” forming under the skin. The mouse was then returned to its home cage. f) Oral Gavage (PO) Dosing

[0194] Frequency: Daily for ~8 weeks (until mice meet endpoint) - Groups 3 & 5

[0195] Procedure: Injections using a 22 or 23G needle was used for animals 21-27 days of age and 20 or 22 G needle was used for animals 28 days and older.

[0196] Animals were restrained vertically so that the ball, syringe and the mouse’s mouth are visible to the individual restraining the mouse. Holding syringe firmly, the needle was inserted into the mouse’s mouth and followed the roof of the mouth with the needle. Once the ball of the needle reached the back of the throat, the nose of the mouse was gently raised upwards, by moving the syringe vertically such that it was parallel with the spine, until the mouse swallowed and then the needle slides easily down the esophagus. The needle would then empty of its own accord. Once the needle stopped moving, the syringe plunger was slowly depressed (without moving the syringe or needle) until the desired amount of liquid was administered to the mouse. The needle was then gently removed from the animal’s mouth. Between pens, reusable gavage needles were wiped with a paper towel (or similar) moistened with 70%ethanol. Desired dose volume was lOmL / kg (BWxlO) per mouse. After proper test article / vehicle administration, the mouse was returned to its home cage. g) Tissue Collection

[0197] Heart was collected and then snap frozen for further analysis when desired. h) Preparation of Heart Tissue and TEM analysis thereof

[0198] Heart tissue that was collected from the mice was dissected and immediately placed into 2.5% glutaraldehyde / 2.5% paraformaldehyde in 0.1 M sodium cacodylate buffer (pH 7.4). Tissue samples were cut into small pieces (approx. 1-2 mm in size). Samples were preserved at 4°C until processed as described below.

[0199] Fixed tissue samples were washed in 0. IM cacodylate buffer and postfixed with 1% osmiumtetroxide (OsO4) / 1.5% potassiumferrocyanide(KFeCN6) for 1 hours, then washed in water 2x, lx in 50mM maleate buffer pH 5.15 (MB) and incubated in 1% uranyl acetate in MB for 1 hour followed by 1 wash in MB, 2 washes in water and subsequent dehydration in grades ofalcohol (10 minutes each in; 50%, 70%, 90%, 2xl0min 100%). The samples were then put in propyleneoxide for 1 hour and infiltrated overnight in a 1 : 1 mixture of propyleneoxide and TAAB Epon (TAAB Laboratories Equipment Ltd, https: / / taab.co.uk). The following day the samples were embedded in TAAB Epon and polymerized at 60°C for 48 hours.

[0200] Ultrathin sections (approx. 50-80nm) were cut on a Reichert Ultracut-S microtome, picked up on to copper grids and stained with 1% Uranyl Acetate in acetone (5 min) followed by 0.2% lead citrate (20 seconds) and examined in a JEOL 1200EX Transmission electron microscope (TEM) and TEM images were recorded with an AMT 2k CCD camera. Approximately 10 images per sample were taken at a magnification of 9300x.

[0201] Mitochondrial cross-sectional area was determined using ImageJ open-source program (National Institutes of Health). ImageJ was used to convert pixel size to metric unit based on the image scale bar to obtain final measurements in unified scale. Regions of interest were then manually outlined for mitochondria in ImageJ to determine mitochondrial cross-sectional area. Only mitochondrial that appeared fully in frame were quantified. Mitochondria were quantified from n=3 mice per group. >150 mitochondria were measured from transgenic treatment groups, and >80 mitochondria were measured from wildtype mice. Data was plotted both as a bar graph (Fig. 18A) and as a violin plot (Fig. 18B) and statistical analysis was performed using GraphPad Prism. Statistical outliers were removed, and significance was determined using One-Way ANOVA (P<0.0001). TEM Images taken can be found in Figs. 19A-19C. Dark areas in the TEM images (see the pointers) of the mitochondria were observed and believed to be caused by deposition / accumulation of iron as is known from images available in literature (See: Martelli et al. and Chiang et al. discussed above). i) Results & Discussion

[0202] With reference to Fig. 18A, the cross sectional area (in nm2) of the mitochondria in the cardiac tissue is presented in a bar graph format. There is a steep (statistically significant) reduction in cross-sectional area in mitochondria of the MUT (vehicle treated) cohort as compared with the WT (vehicle treated) cohort. There is also a statistically significant increase (improvement) in cross-sectional area of the mitochondria of the MUT (Compound A treated) cohort as compared to the MUT (vehicle treated) cohort. This data suggests that treatment withCompound A improved or helped to normalize the mitochondria; making them more comparable to the mitochondria of the wildtype mouse.

[0203] This inference is further supported by the data presented in Fig. 18B. In Fig. 18B, the same data is plotted in a violin plot. The violin plot presents the size distribution of the individual mitochondria in the sample. As can be seen in Fig. 18B, there is a large distribution of size of the mitochondria in the WT cohort. However, the size distribution of the mitochondria in the MUT (untreated cohort) is much smaller and the individual mitochondria are also much smaller. Albeit not commensurate with the data for the WT cohort, by comparison to the MUT (untreated cohort), the MUT (Compound A treated) cohort shows a significantly larger size distribution in the mitochondria and on average overall larger mitochondria. In this sense, these data also support the conclusion that treatment with Compound A improves or normalizes the mitochondria of the cardiomyocytes of the subject organism exhibiting a cardiac condition - at least so far as it is associated with Friedreich’s ataxia - as compared to those of an untreated control subject or control group.

[0204] With respect to Fig. 19A, there are essentially no dark spots seen in the mitochondria of the WT, vehicle treated mice. By comparison, in the TEM image presented in Fig. 19B for the MUT, vehicle treated mice, myriad dark spots are observed. These dark spots are believed to be iron deposits in the mitochondria. These iron deposits would be consistent with the disease state of the mutant mouse line as described in the literature. By comparison, in the TEM image for the MUT, Compound A treated mice, while still present, these dark spots appear to be far less numerous and smaller than those seen in the TEM image for the MUT, vehicle treated mice. This data further supports the conclusion that treatment with Compound A can improve or normalize the mitochondrial health of the cardiomyocytes of the subject organism exhibiting a cardiac condition - at least so far as it is associated with Friedreich’s ataxia.EQUIVALENTS

[0205] The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, inaddition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present technology is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0206] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0207] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a nonlimiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.

[0208] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0209] Other embodiments are set forth within the following claims.

Claims

CLAIMSWhat is claimed is:

1. A method for treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy, in a mammalian subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:

2. The method of claim 1, wherein the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia.

3. The method of claims 1 or 2, wherein the cardiomyopathy is hypertrophic cardiomyopathy.

4. The method of any one of claims 1 to 3, wherein the subject is human.

5. The method of any one of claims 1 to 4, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group.

6. The method of any one of claims 1 to 4, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group.

7. The method of any one of claims 1 to 5, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis (e.g., myocardial fibrosis) in the subject’s heart tissue.

8. The method of any one of claims 1 to 7, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject results in reverse remodeling of the subject’s heart.

9. The method of any one of claims 1 to 8, wherein administration of Compound A, Compound B or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group.

10. The method of any one of claims 1 to 8, wherein administration of Compound A, Compound B or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group.11 . The method of any one of claims 1 to 10, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves hearing and / or vision of the subject.

12. The method of any one of claims 1 to 11, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject increases the lifespan of the subject.

13. The method of any one of claims 1 to 12, wherein Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

14. A composition, medicament or formulation comprising Compound A, Compound B, or a mixture of Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, for use in treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy in a mammalian subject in need thereof, wherein Compound A and Compound B have the following structures:

15. The composition, medicament or formulation of claim 14, wherein the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia.

16. The composition, medicament or formulation of claims 14 or 15, wherein the cardiomyopathy is hypertrophic cardiomyopathy.

17. The composition, medicament or formulation of any one of claims 14 to 16, wherein the subject is human.

18. The composition, medicament or formulation of any one of claims 14 to 17, wherein administration of the composition, medicament or formulation to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group.

19. The composition, medicament or formulation of any one of claims 14 to 18, wherein administration of the composition, medicament or formulation to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group.

20. The composition, medicament or formulation of any one of claims 14 to 19, wherein administration of the composition, medicament or formulation to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis in the subject’s heart tissue.21 . The composition, medicament or formulation of any one of claims 14 to 20, wherein administration of the composition, medicament or formulation to the subject results in reverse remodeling of the subject’s heart.

22. The composition, medicament or formulation of any one of claims 14 to 21, wherein administration of the composition, medicament or formulation to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group.

23. The composition, medicament or formulation of any one of claims 14 to 21, wherein administration of the composition, medicament or formulation to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group.

24. The composition, medicament or formulation of any one of claims 14 to 23, wherein administration of the composition, medicament or formulation to the subject improves hearing and / or vision of the subject.

25. The composition, medicament or formulation of any one of claims 14 to 24, wherein administration of the composition, medicament or formulation to the subject increases the lifespan of the subject.

26. The composition, medicament or formulation of any one of claims 14 to 25, wherein the composition, medicament or formulation is prepared for administration to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

27. Use of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, in treating, preventing, delaying the progression of or delaying the onset of cardiomyopathy in a mammaliansubject in need thereof, wherein Compound A and Compound B have the following structures:

28. The use of claim 27, wherein the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia.

29. The use of claims 27 or 28, wherein the cardiomyopathy is hypertrophic cardiomyopathy.

30. The use of any one of claims 27 to 29, wherein the subject is human.

31. The use of any one of claims 27 to 30, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle mass of the subject relative to an untreated control subject or an untreated control group.

32. The use of any one of claims 27 to 31, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces left ventricle anterior wall thickness (both diastolic and systolic) of the subject relative to an untreated control subject or an untreated control group.

33. The use of any one of claims 27 to 32, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject treats, prevents, delays the progression of or delays the onset of cardiac fibrosis in the subject’s heart tissue.

34. The use of any one of claims 27 to 33, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject results in reverse remodeling of the subject’s heart.

35. The use of any one of claims 27 to 34, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject reduces iron accumulation in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group.

36. The use of any one of claims 27 to 34, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves or normalizes the size of mitochondria in the subject’s cardiomyocytes relative to an untreated control subject or an untreated control group.

37. The use of any one of claims 27 to 36, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject improves hearing and / or vision of the subject.

38. The use of any one of claims 27 to 37, wherein administration of Compound A, Compound B, or a mixture comprising Compound A and Compound B, orpharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, to the subject increases the lifespan of the subject.

39. The use of any one of claims 27 to 38, wherein Compound A, Compound B, or a mixture comprising Compound A and Compound B is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

40. A method for reducing iron accumulation in the cardiomyocytes of a mammalian subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:

41. The method of claim 40, wherein the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia.

42. The method of claim 40 or 41, wherein the subject is human.

43. A method for improving or normalizing the size of mitochondria in the cardiomyocytes of a mammalian subject in need thereof, comprising administering to said subject atherapeutically effective amount of Compound A, Compound B, or a mixture comprising Compound A and Compound B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein Compound A and Compound B have the following structures:

44. The method of claim 43, wherein the subject has been diagnosed with, or is suspected of having, Friedreich’s ataxia.

45. The method of claim 43 or 44, wherein the subject is human.

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