Transthyretin stabilizers and methods of use thereof

Abstract

The invention relates to methods of treating, preventing, or ameliorating symptoms associated with one or more conditions associated with metabolic syndrome in a subject having transthyretin (TTR) dysfunction by administration of a TTR stabilizer. Particularly, the methods described herein may be used to treat or prevent in a subject having TTR dysfunction diabetes, insulin resistance, dyslipidemia, or obesity.

Description

[0001]ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT TRANSTHYRETIN STABILIZERS AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS This application claims benefit of the filing date of U.S. provisional application no.63 / 688,346, filed August 29, 2024, which is hereby incorporated by reference in its entirety. BACKGROUND Transthyretin (TTR) is a tetrameric essential protein primarily produced by the liver. The main function of TTR is to serve as a transporter of thyroxin and retinol binding protein. TTR is also expressed in the pancreas, and its metabolic correlates are less understood. The destabilization of the TTR tetramer (whether secondary to TTR mutations or not) is the pathological basis for the clinical manifestations of TTR amyloidosis (ATTR). The destabilization of TTR causes the protein to unfold and misfold, with consequent formation and systemic accumulation of amyloid fibrils in tissues (ATTR amyloidosis), especially the heart (cardiac amyloidosis, that causes the cardiac walls to thicken and stiffen thereby leading to cardiac insufficiency and premature death). TTR misfolding is responsible for TTR dysfunction. TTR dysfunction is associated with a significant occurrence of metabolic complications. Patients with TTR dysfunction, for example, have a significant occurrence of obesity, diabetes, insulin resistance, and dyslipidemia. Given the prevalence of these metabolic comorbidities associated with TTR dysfunction, there remains a need for the development of new therapies that effectively treat, prevent, and / or ameliorate the symptoms associated not only ATTR but also with its metabolic complications. SUMMARY Described herein are methods of treating subjects having TTR (e.g., TTR-related metabolic dysfunction), for one or more diseases or conditions associated with metabolic syndrome by administration of a TTR stabilizer. The methods described herein include treatment of diabetes, insulin resistance, obesity, and / or dyslipidemia in a subject who is also suffering from TTR dysfunction. The disclosure provided herein is based at least in part on Applicant’s surprising discovery that TTR stabilizers result in improved metabolic regulation including, for example, enhanced pancreatic function. As a result, the methods described herein may be used to, for example, reduce body mass of a subject, reduce blood glucose concentrations in a subject, or reduce lipid concentration in the bloodstream of a subject. In an aspect, the disclosure provides a method of treating, preventing, or ameliorating one or more symptoms associated with metabolic syndrome in a subject having Transthyretin (TTR) dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. In another aspect, the disclosure provides a method of treating, preventing, or ameliorating one or more symptoms associated with diabetes in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT In another aspect, the disclosure provides a method of treating or preventing insulin resistance in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. In some embodiments, the subject’s blood glucose concentration is reduced in comparison to the subject’s blood glucose prior to administration of the TTR stabilizer. In some embodiments, the subject’s blood glucose concentration is reduced by at least 10% (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%) in comparison to the subject’s blood glucose prior to administration of the TTR stabilizer. In some embodiments, the subject has been diagnosed with diabetes. In some embodiments, the diabetes is Type II diabetes. In some embodiments, the subject is being treated with one or more compositions for the treatment of diabetes. In some embodiments, the composition for the treatment of diabetes is an anti- diabetic drug. In some embodiments, the anti-diabetic drug is ertugliflozin, bexagliflozin, canagliflozin, dapagliflozin, or empagliflozin. In some embodiments, the anti-diabetic drug is dapagliflozin. In some embodiments, the amount of the composition for the treatment of diabetes is reduced in comparison to the amount of the composition for the treatment of diabetes prior to administration of the TTR stabilizer. In some embodiments, the amount of the composition for treatment of diabetes is reduced by at least 20% (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%) in comparison to the amount of the composition for the treatment of diabetes prior to administration of the TTR stabilizer. In an aspect, the disclosure provides a method of treating, preventing, or ameliorating one or more symptoms associated with dyslipidemia in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. In some embodiments, the subject’s bloodstream lipid concentration is decreased in comparison to the subject’s bloodstream lipid concentration prior to administration of the TTR stabilizer. In some embodiments, the subject’s bloodstream lipid concentration is decreased by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%) in comparison to the subject’s bloodstream lipid concentration prior to administration of the TTR stabilizer. In an aspect, the disclosure provides a method of treating or preventing obesity in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. In some embodiments, the subject’s body mass index (BMI) is reduced in comparison to the subject’s BMI prior to administration of the TTR stabilizer. In some embodiments, the subject's BMI is reduced by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%) in comparison to the subject’s BMI prior to administration of the TTR stabilizer. In some embodiments, the subject has Cardiac Amyloidosis caused by TTR dysfunction (e.g., ATTRCM). In some embodiments, the TTR stabilizer is acoramidis. In some embodiments, the TTR stabilizer is tafamidis. In some embodiments, the TTR stabilizer is administered to the subject in amount of between 500 mg to 2,500 mg (e.g., between 1,000 mg and 2,000 mg, 1,200 mg to 1,800 mg, or about 1,600 mg) per day. ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT In some embodiments, the TTR stabilizer is administered subcutaneously, intramuscularly, intravenously, or orally. In some embodiments, the TTR stabilizer is administered orally. In some embodiments, the TTR stabilizer is administered orally. In some embodiments, the TTR stabilizer is administered once daily. In some embodiments, the TTR stabilizer is administered twice daily. In some embodiments, the TTR stabilizer is administered three times daily. In some embodiments, the TTR stabilizer is administered four times daily. In some embodiments, the subject is a human subject. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1A and FIG.1B are bar graphs that depict the prevalence of hyperlipidemia (FIG.1A) and type 2 diabetes (FIG.1B) in subjects under 45 years old having transthyretin (TTR) amyloidosis (ATTR) or primary (AL) amyloidosis. FIG.2A and FIG.2B are box plots showing expression of complement and complement regulatory proteins at day 1 and day 540, respectively left and right bar (FIG.2A) as well as the upregulation of CD55, CD46, and CD59 matched with complement C7 downregulation (FIG.2B) in patients having TTR dysfunction who were administered acoramidis. FIG.3 is a series of box plots showing the modulation of proteins that are part of the Clathrin- mediated endocytosis signal in plasma that contribute to the TTR internalization into B-cells from plasma in patients having TTR dysfunction who were administered acoramidis. FIG.4A and FIG.4B are box plots showing the modulation of glucose-regulated proteins Grps94 (FIG.4A) and Grps170 (FIG.4B) in patients having TTR dysfunction who were administered acoramidis. FIG.5A and FIG.5B are bar graphs showing the average change in weight, in kg (FIG.5A), and blood glucose concentration (mmol / L) (FIG.5B) in patients having TTR dysfunction who were administered acoramidis for 18 months. FIG.6A and FIG.6B are bar graphs showing the average change in body mass index (BMI) (FIG.6A) and modified BMI (FIG.6B) in patients having TTR dysfunction who were administered acoramidis for 18 months. DETAILED DESCRIPTION The instant disclosure provides methods of treating one or more conditions associated with metabolic syndrome in a subject having TTR dysfunction by administering a TTR stabilizer to the subject. Further provided are methods of treating, preventing, or ameliorating symptoms associated with diabetes, obesity, insulin resistance, and / or dyslipidemia by administration of a TTR stabilizer to a subject. The disclosure is based at least in part on Applicant’s surprising discovery that in subjects having TTR dysfunction, TTR stabilizers may function to improve metabolic regulation by specifically enhancing pancreatic function by stabilizing tetrameric TTR and enhancing pancreatic β-cells uptake. As a result, the administration of TTR stabilizers to a subject having TTR dysfunction stabilizes TTR in selected tissues such as the pancreas, thereby addressing the metabolic dysregulation seen in patients having TTR dysfunction. Metabolic syndromes, such as, for example, hyperlipidemia and type 2 diabetes, are prevalent among TTR amyloidosis patients, as shown by comprehensive analysis using Komodo Health data ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT (FIG.1A and FIG.1B illustrate the notably high prevalence of these metabolic conditions in younger ATTR patients (under 45 years old) compared to those with light chain (AL) amyloidosis, who also experience amyloid deposits in the heart. Definitions As used herein, the terms “about” and “approximately” refer to an amount that is ± 10 % of the recited value and is optionally ± 5 % of the recited value or ± 2 % of the recited value. As used herein, “administering” and “administration” refers to any method of providing a pharmaceutical preparation to a subject. The TTR stabilizers described herein may be administered by any method known to those skilled in the art. Suitable methods for administering a TTR stabilizer may include, for example, orally, by injection (e.g., intravenously, intraperitoneally, intramuscularly, intravitreally and subcutaneously), drop infusion preparations, and the like. TTR stabilizers prepared as described herein may be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the subject, as is known in the art. A preparation can be administered prophylactically; that is, administered to decrease the likelihood of developing a disease or condition. As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like. The term “dyslipidemia” refers to elevation of plasma cholesterol, triglycerides, or low high-density lipoprotein (HDL) cholesterol levels in a subject that may contribute to atherosclerosis. Dyslipidemia may refer to primary or secondary dyslipidemia. For example, an elevated plasma cholesterol level may be greater than 200 mg / dL; an “elevated” triglyceride level may be considered to be greater that 200 mg / dL; and “low” HDL may be below 40 mg / dL. The term “effective amount” refers to an amount of an agent that provides the desired biological, therapeutic, and / or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and / or alleviation of one or more of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. In one example, an “effective amount” is the amount of a transthyretin stabilizer clinically proven to alleviate at least one symptom of metabolic syndrome (e.g., diabetes or obesity). An effective amount can be administered in one or more administrations. As used herein, “effective treatment” refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement over baseline, e.g., an improvement over a measurement or observation made prior to initiation of therapy according to the method. Effective treatment may refer to alleviation of at least one symptom of the disease or condition (e.g., metabolic syndrome). The term “metabolic syndrome” refers to a human or animal condition or disease resulting from abnormal function or control of the metabolic system (e.g., obesity, diabetes, dyslipidemia, insulin resistance, fatty liver disease, PCOS, or elevated blood glucose levels). As used herein, the term “obesity” refers to an adult subject having a body mass index (BMI) of greater than 30. ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT As used herein, “pharmaceutically acceptable” carrier refers to a carrier comprised of a material that is not biologically or otherwise undesirable. The term “carrier” is used generically herein to refer to any components present in the pharmaceutical formulations other than the active agent or agents, and thus includes diluents, binders, lubricants, disintegrants, fillers, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like. Similarly, a “pharmaceutically acceptable” salt or a variant (e.g., ester) of a molecule as provided herein is one that is not biologically or otherwise undesirable. As used herein, the term “salt” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the presently disclosed subject matter. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenyl acetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. The term “pharmaceutically acceptable salt” or a variant thereof, as used herein, refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with subjects (e.g., human subjects) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure. Thus, pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. The term “pharmaceutical composition,” as used herein, refers to a composition containing a compound (e.g., TTR stabilizer) as described herein formulated with a pharmaceutically acceptable ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT excipient, and optionally manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for subcutaneous administration, for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); for intrathecal injection; for intracerebroventricular injections; for intraparenchymal injection; for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment; or in any other pharmaceutically acceptable formulation. The term “small molecule” refers to an organic molecule having a molecular weight less than about 2500 amu, less than about 2000 amu, less than about 1500 amu, less than about 1000 amu, or less than about 750 amu. In some embodiments a small molecule contains one or more heteroatoms. As used herein, the term “subject” or “patient” is a human patient (e.g., a patient having a metabolic syndrome). As used herein, the term “subject” and “patient” are interchangeable. The term “symptom” refers to an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by others, e.g., non-health-care professionals. The term “sign” also refers to an indication that something is not right in the body, which can be seen by a doctor, nurse, or other health care professional. As used herein, the term “treat” refers to the act of providing care to a subject in need thereof, e.g., through the administration a therapeutic agent (e.g., a TTR stabilizer) to the subject, for purposes of improving the health and / or well-being of the subject with respect to an existing condition (e.g., a disease or disorder) or to prevent or decrease the likelihood of the occurrence of a condition. In some embodiments, treatment involves reducing the frequency or severity of at least one sign, symptom, or contributing factor of a condition (e.g., disease or disorder) experienced by a subject. In some embodiments, the TTR stabilizers described herein are used to control the cellular and clinical manifestations of a metabolic syndrome disorder, such as, e.g., diabetes or obesity, disclosed herein. As used herein, the term “transthyretin dysfunction” or “TTR dysfunction” refers to a protein disorder in which tetrameric TTR is destabilized, leading to protein misfolding, and eventually resulting in the formation of fibrils and tissue deposition. TTR disfunction may be hereditary or spontaneous and may be caused by one or more mutation to a TTR subunit. Transthyretin Stabilizers TTR stabilizers may be used in treating, preventing, or ameliorating symptoms associated with metabolic syndrome, diabetes, insulin resistance, dyslipidemia, or obesity in a subject having TTR dysfunction. The TTR stabilizer may bind to and stabilize the tetrameric form of TTR, thus preventing the misfolding and subsequent formation of fibrils. While not being limited by theory, TTR stabilizers can prevent the TTR tetramer from dissociating by binding to the T4-binding site on TTR, for example, or by reproducing the structural stabilizing effect of TTR variant referred to as “T119M” (or the “T119M allele”). Stabilization of tetrameric TTR may result in halting or slowing of a series of molecular events that give rise to ATTR. ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT In some embodiments, the TTR stabilizer may be a small molecule, or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the TTR stabilizer is acoramidis, or a pharmaceutically acceptable salt thereof. Acoramidis consists of the following chemical structure: Acoramidis may stabilize tetrameric TTR by the development of hydrogen bonds between the residues of Ser117 of the TTR monomers and functions by emulating the stabilizing properties of the TTR T119M variant. TTR stabilization is achieved by acoramidis binding the tetrameric form of TTR in the thyroxine binding pockets in a 2:1 ratio. In some embodiments, the TTR stabilizer is a pharmaceutically acceptable salt of acoramidis. Acoramidis may be prepared by any method known in the art. For example, acoramidis may be prepared using the methods described in Internation Patent Publication No. WO 2018 / 151815, which is herein incorporated by reference in its entirety. In some embodiments, the TTR stabilizer is tafamidis, or a pharmaceutically acceptable salt thereof. Tafamidis is an orally bioavailable benzoxazole derivative that inhibits the dissociation of TTR tetramers by binding the T4-binding site. Tafamidis consists of the following chemical structure: In some embodiments, the TTR stabilizer is a pharmaceutically acceptable salt of tafamidis, such as a meglumine salt of tafamidis. Tafamidis may be prepared by any method known in the art. For example, tafamidis may be prepared using the methods described in International Patent Publication Nos.: WO 2021 / 152623 and WO 2016 / 038500. In some embodiments, the TTR stabilizer is diflunisal, or a pharmaceutically acceptable salt thereof. Diflunisal is also known as 2′,4′–difluoro-4-hydroxy-3-byphenylcarboxylic acid. Diflunisal is a salicylate derivative that functions as a non-steroidal anti-inflammatory agent. Diflunisal consists of the following structure: ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT Diflunisal may be prepared by any method known in the art. For example, diflunisal may be prepared using the methods described in Chinese Patent Publication No.: CN110372493n. In some embodiments, the TTR stabilizer is a TTR stabilizer described in International Patent Publication No. WO 2014 / 100227, which is herein incorporated by reference in its entirety. Methods of Treatment Stabilization of TTR is crucial for preventing the misfolding and aggregation of TTR, which leads to amyloid fibril formation and deposition in the heart as well as other tissues and organs. Importantly, it has been discovered, as described herein, that stabilized TTR can act at the local tissue level to improve metabolic pathways. By stabilizing TTR, particularly in the pancreas, TTR stabilizers may ameliorate insulin resistance, dyslipidemia, obesity and overall metabolic syndrome. As a result, administration of TTR stabilizers provides a method of treating ATTR with associated metabolic comorbidities. Serum TTR is a transport protein for thyroxine and, in association with retinol-binding protein, for retinol, mainly exists as a tetramer in vivo, primarily produced by the liver. The misfolding of TTR results in the development of hereditary and wild-type transthyretin amyloidosis (ATTR): cardiac amyloidosis (ATTR-CM) is characterized by the harmful accumulation of TTR amyloid fibrils in the heart, which leads to progressive cardiac dysfunction and potentially fatal outcomes. TTR is also expressed in pancreatic alpha (glucagon) cells in the islets of Langerhans where it plays important roles in glucose homeostasis via regulating the expression of glucagon. At the pancreas level, TTR interferes with Islet amyloid polypeptide (IAPP, amylin) amyloid formation, which has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. In ATTR, the misfolding of TTR results in a decrease of functional circulating TTR, while TTR stabilizers may work to treat or prevent one or more conditions associated with metabolic syndrome by preserving the TTR tetramer structure and function and increasing circulating levels of TTR. A subject suffering from TTR dysfunction has a protein disorder in which faulty TTR proteins form amyloid fibrils in tissues. The faulty TTR proteins may occur as a result of a hereditary mutation, as in the case of hereditary ATTR amyloidosis, or may occur spontaneously, as in the case of wild-type (i.e. non- mutant) ATTR amyloidosis. TTR is a 127-amino-acid, β-sheet-rich protein, which forms a homotetramer that is primarily synthesized by the liver and secreted into the blood. Using orthogonal binding surfaces, TTR binds to both thyroxine (T4) and holo-retinol-binding protein (RBP). TTR is the main carrier of RBP, but due to the presence of two other T4 transport proteins it is only a back-up carrier for T4 in humans ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT (<1% T4 bound). The two TTR T4-binding pockets, which remain largely unoccupied in humans, are formed by the weaker dimer-dimer interface. Each of the two T4 binding sites created by the dimer-dimer interface of the TTR homotetramer consists of an outer binding subsite, an inner binding subsite, and an intervening interface that are composed of pairs of symmetric hydrophobic depressions referred to as halogen binding pockets (HBPs), in which the iodine atoms of T4 reside. Dissociation of the TTR-tetramer at the T4-binding interface, which causes dimers to rapidly dissociate into monomers, is the rate-limiting step of TTR misfolding and amyloid formation. There are more than 100 known amyloidogenic mutations that result in faulty TTR protein that can cause hereditary ATTR amyloidosis. These variants can segregate into ethnic and geographic groupings. Point mutations in TTR promote TTR amyloidogenesis either by lowering the thermodynamic stability of TTR or through decreasing the kinetic barrier for tetramer dissociation, or both. ATTR amyloidosis is an autosomal dominant condition with varying ages of onset and penetrance depending on different factors including the ethnic background. The disease can manifest with various degrees of neurological, cardiac and visceral involvement. One of the most clinically studied TTR mutations is the thermodynamically destabilized Val50Met (also known as V30M) (Coelho, T. Curr. Opin. Neurol., 9:355-9, 1996), which causes a primarily neuropatic phenotype (known as familial amyloid polyneuropathy or FAP) in early-onset cases or a cardiac or mixed cardiac and neurologic phenotype in late-onset cases. The most common TTR variant is the kinetically destabilizing V142I (also known as V122I) mutation, which causes primarily a late onset cardiomyopathy, known as familial amyloid cardiomyopathy (FAC). Although the V122I-TTR monomer has similar stability to the wild type (WT-TTR) monomer, the tetramer dissociates 3-fold faster under physiological conditions. This mutant allele occurs in 3-4% of African- Americans, however the penetrance of the disease is believed to be relatively low. The TTR stabilizer described herein can be administered to a subject having TTR dysfunction. In some embodiments, the subject has ATTR-CM. The TTR stabilizer may be administered to the subject to treat, for example, diabetes, insulin resistance, dyslipidemia, or obesity, where functional, tetrameric TTR is required to treat the metabolic disease or disorder. A TTR stabilizer may be used to treat, prevent, or ameliorate one or more symptoms associated with metabolic syndrome in a subject having TTR dysfunction. Metabolic disorders, diseases, or metabolic syndrome refers to diseases or conditions that increase risk for diseases or disorders associated with, related to, or caused by abnormal metabolism (e.g., diabetes, heart disease, stroke, obesity, or elevated blood sugar). A TTR stabilizer may be used to treat, prevent, or ameliorate one or more symptoms associated with diabetes in a subject having TTR dysfunction or reduce the risk of diabetes progression in a subject. The TTR stabilizer may stabilize tetrameric TTR in the pancreas of the subject. In some embodiments, the TTR stabilizer reduces insulin resistance. As described herein, a TTR stabilizer can be used, for example, to treat or prevent insulin resistance in a subject having TTR dysfunction. Following administration of a TTR stabilizer to the subject, the subject’s blood glucose concentration may be reduced in comparison to the subject’s blood glucose prior to administration of the TTR stabilizer. For example, administration of a TTR stabilizer to a subject having TTR dysfunction may result in reduction of the subject’s blood glucose concentration. In some embodiments, the subject’s blood glucose concentration is reduced by at least 10% in comparison to the subject’s blood glucose prior to ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT administration of the TTR stabilizer. In some embodiments, the subject’s blood glucose concentration is reduced by between 10% and 95% (e.g., between 10% and 90%, 10% and 80%, 10% and 70%, 10% and 60%, 10% and 50%, 10% and 40%, 10% and 30%, 10% and 20%, 20% and 95%, 30% and 95%, 40% and 95%, 50% and 95%, 60% and 95%, 70% and 95%, 80% and 95%, 30% and 50%, 40% and 60%, or 20% and 70%) in comparison to the subject’s blood glucose prior to administration of the TTR stabilizer. In some embodiments, the subject’s blood glucose concentration is measured prior to administration of the TTR stabilizer and at least 5 weeks after administration of the TTR stabilizer. For example, the subject’s blood glucose concentration may be measured between 5 weeks and 25 weeks (e.g., 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or 25 weeks) after the initial administration of the TTR stabilizer. The subject may have been diagnosed with diabetes prior to administration of the TTR stabilizer. The subject’s diabetes may be Type II diabetes. For example, the subject may have been diagnosed with diabetes by a physician. In some embodiments, the subject had been treated for diabetes prior to administration of the TTR stabilizer. In some embodiments, the subject is being treated for diabetes concomitantly with the administration of the TTR stabilizer. The subject may be treated, prior to or concomitantly with one or more compositions for the treatment of diabetes, such as an anti-diabetic drug. In some embodiments, the anti-diabetic drug is a Sodium-Glucose-Co-Transporter-2 (SGLT2) inhibitor. For example, the anti-diabetic drug administered to the subject may be ertugliflozin, bexagliflozin, canagliflozin, dapagliflozin, or empagliflozin. In some embodiments, the subject may be being administered dapagliflozin (marketed under the brand name FORXIGA) prior to or concomitantly with the administration of a TTR stabilizer. The amount of the composition for the treatment of diabetes (e.g., anti- diabetic drug) may be reduced in comparison to the amount of the composition for the treatment of diabetes (e.g., anti-diabetic drug) prior to administration of the TTR stabilizer. In some embodiments, the amount of the composition for treatment of diabetes is reduced by at least 20% in comparison to the amount of the composition for the treatment of diabetes prior to administration of the TTR stabilizer. For example, the amount of the composition for the treatment of diabetes (e.g., anti-diabetic drug) may be reduced by between 20% to 95% (e.g., 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 95%, 40% to 95%, 50% to 95%, 60% to 95%, 70% to 95%, 80% to 95%, 40% to 60%, 30% to 50%, or 50% to 70%) in comparison to the amount of the composition for the treatment of diabetes prior to administration of the TTR stabilizer. In some embodiments, the amount of the composition for the treatment of diabetes administered to the subject is noted prior to administration of the TTR stabilizer and at least 5 weeks after administration of the TTR stabilizer. For example, the amount of the composition for the treatment of diabetes administered to the subject is noted between 5 weeks and 25 weeks (e.g., 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or 25 weeks) after the initial administration of the TTR stabilizer. A TTR stabilizer may be administered to a subject to treat, prevent, or ameliorate one or more symptoms associated with dyslipidemia in a subject having TTR dysfunction. The TTR stabilizer may help ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT in normalizing levels of cholesterol and triglycerides in a subject, thereby reducing the risk of cardiovascular diseases. In some embodiments, administration of the TTR stabilizer to the subject results in the subject’s bloodstream lipid concentration to be decreased in comparison to the subject’s bloodstream lipid concentration prior to administration of the TTR stabilizer. The bloodstream lipid concentration may include the concentration of cholesterol or triglycerides in the bloodstream of the subject. In some embodiments, that subject’s bloodstream lipid concentration is reduced by at least 10% in comparison to the subject’s bloodstream lipid concentration prior to administration of the TTR stabilizer. For example, the subject’s bloodstream lipid concentration may be reduced by between 10% to 95% (e.g., 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 20% to 30%, 30% to 95%, 40% to 95%, 50% to 95%, 60% to 95%, 70% to 95%, 80% to 95%, 40% to 60%, 30% to 50%, or 50% to 70%) in comparison to the subject’s bloodstream lipid concentration prior to administration of the TTR stabilizer. In some embodiments, the subject’s bloodstream lipid concentration is measured prior to administration of the TTR stabilizer and at least 5 weeks after administration of the TTR stabilizer. For example, the subject’s bloodstream lipid concentration may be measured between 5 weeks and 25 weeks (e.g., 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or 25 weeks) after the initial administration of the TTR stabilizer. A TTR stabilizer may be used to treat or prevent obesity in a subject having TTR dysfunction. Stabilization of tetrameric TTR influences pathways involved in weight management and adiposity. For example, administration of a TTR stabilizer to subject may result in the subject’s body mass index (BMI) to be reduced in comparison to the subject’s BMI prior to administration of the TTR stabilizer. In some embodiments, the subject's BMI is reduced by at least 10% in comparison to the subject’s BMI prior to administration of the TTR stabilizer. For example, the subject’s BMI may be reduced by between 10% and 95% (e.g., 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 20% to 30%, 30% to 95%, 40% to 95%, 50% to 95%, 60% to 95%, 70% to 95%, 80% to 95%, 40% to 60%, 30% to 50%, or 50% to 70%) in comparison to subject’s body mass prior to administration of the TTR stabilizer. In some embodiments, the subject’s BMI is measured prior to administration of the TTR stabilizer and at least 5 weeks after administration of the TTR stabilizer. For example, the subject’s BMI may be measured between 5 weeks and 25 weeks (e.g., 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or 25 weeks) after the initial administration of the TTR stabilizer. For the treatment of one or conditions associated with metabolic syndrome, the TTR stabilizer may be administered to the subject subcutaneously, intramuscularly, intravenously, or orally. In some embodiments, the TTR stabilizer is administered to the subject orally. The TTR stabilizer may be administered to the subject in any therapeutically effective amount as determined by a physician. The TTR stabilizer may be administered to the subject in amount of between 500 mg to 2,500 mg (e.g., between 1,000 mg and 2,000 mg, 1,200 mg to 1,800 mg, or about 1,600 mg) per day. ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT The TTR stabilizer may be administered to the subject once daily. The TTR stabilizer may be administered to the subject at least twice daily. For example, TTR stabilizer may be administered to the subject twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times daily. The TTR stabilizer may be administered for 12 to 30 months, or for the remainder of the subject’s life. Pharmaceutical Compositions The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the prevention, treatment or amelioration of one or more of the symptoms of diseases or disorders associated with TTR misfolding, or in which TTR misfolding is implicated, in a pharmaceutically acceptable carrier. Diseases or disorders associated with TTR misfolding include, but are not limited to, familial amyloid polyneuropathy, familial amyloid cardiomyopathy, senile systemic amyloidosis, Alzheimer's disease, spongiform encephalopathy (e.g., Creutzfeldt Jakob disease GSS, fatal familial insomnia), frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Down Syndrome, multiple sclerosis, polyneuropathy, Guillain-Barré syndrome, macular degeneration, vitreous opacities, glaucoma, type II diabetes, or medullary carcinoma of the thyroid. Pharmaceutical carriers suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. For example, the compound may be formulated as a tablet containing 400 mg of the compound, wherein two tablets are administered to the subject orally twice per day as described in Gilmore, J., N. Engl. J. Med.390:132-42, 2024, which is herein incorporated by reference in its entirety. In some embodiments, the compound is acoramidis. In some embodiments, the compound is acoramidis HCl. The compositions contain one or more compounds provided herein. The compounds are, in one embodiment, formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration. In one embodiment, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126). Duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT In some embodiments, the TTR stabilizer is suitable for oral administration. Oral pharmaceutical dosage forms may be solid, gel, or liquid. In certain embodiments, the solid dosage forms are tablets, capsules, granules, or bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated, or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. The compound, or pharmaceutically acceptable derivative thereof, could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient. Kits and Unit Dosage Forms Also provided herein are kits that include a pharmaceutical composition containing the TTR stabilizer and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods. The kits can also optionally include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse or patient) to administer the composition contained therein to administer the composition to a patient having metabolic syndrome. The kit also can include a syringe. Kits can optionally include multiple packages of the single-dose pharmaceutical compositions each containing an effective amount of the TTR stabilizer for a single administration in accordance with the methods provided above. Instruments or devices necessary for administering the pharmaceutical composition(s) also may be included in the kits. A kit may provide one or more pre-filled syringes containing an amount of the TTR stabilizer or one or more bottles containing oral tablets of the TTR stabilizer. EXAMPLES The following are examples of the methods of the invention. It is understood that various other embodiments may be practiced, given the general description provided above. Example 1. Administration of a TTR stabilizer to a subject having TTR dysfunction. Measuring the metabolic changes in patients treated with acoramidis was conducted using a high-throughput proteomic analysis, comparing their metabolic profiles before and after treatment with acoramidis in the Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of AG10 in Subjects with Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTRIBUTE-CM Trial; Protocol Number: Eidos AG10-301). The trial included 25 subjects affected by ATTR amyloidosis with cardiomyopathy. All subjects were administered 800 mg of acoramidis twice a day. The study period was 30 months. A decrease in complement activity was observed (FIG.2A and FIG.2B) alongside an increase in receptors that facilitate the movement of TTR to pancreatic tissue (FIG.3), which suggested enhanced pancreatic function and reduced complement and inflammatory pathway activity. TTR, a plasma protein predominantly produced by the liver and also synthesized in pancreatic endocrine cells, is essential for ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT transporting Vitamin A and Thyroxine. Its effectiveness is attributed to the folded tetrameric form, which is crucial for glucose uptake and insulin release, a function compromised in type I diabetes patients. The presence of TTR in pancreatic β-cells suggests it protects against Type 2 Diabetes Mellitus (T2DM) by preventing IAPP-amyloid elongation, a process leading to T2DM. Moreover, TTR's interaction with specific glucose-regulated proteins (Grps)—Grp78 (also known as HSP90B1), Grp94 and Grp170 (also known as HYOU1)—in the endoplasmic reticulum chaperone family, underscores its multifaceted role in insulin release and β-cell protection. The critical mechanism involves TTR binding to these Grps at the plasma membrane, followed by its clathrin-dependent internalization into β-cells, a process essential for its beneficial impact on β-cell functionality and overall pancreatic physiology. The protein levels increased upon treatment of the Clathrin-mediated and Grp94 and Grp170 of the glucose-regulated pathways, respectively, with acoramidis as shown in FIG.3, and FIG.4A and FIG.4B.4 patients out of 23 were concomitantly treated with anti-diabetes drug. One of these patients (0210-105) stopped FORXIGA treatment. FORXIGA was restarted but this time with 50% dose decrease. The remaining 3 patients continued anti-diabetes treatment. Additionally, the weight and blood glucose concentration were measured after 18 weeks of acoramidis administration (FIG.5A and FIG.5B) as well as BMI and modified BMI (FIG.6A and FIG.6A) for the 23 patients that participated in the clinical trial FIG.5B particularly showed the consistent glucose reduction in almost all patients. This indicates the potential benefit especially for diabetic or metabolic impaired patients. Numbered embodiments 1. A method of treating, preventing, or ameliorating one or more symptoms associated with a metabolic syndrome in a subject having Transthyretin (TTR) dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. 2. A method of treating, preventing, or ameliorating one or more symptoms associated with diabetes in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. 3. A method of treating or preventing insulin resistance in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. 4. The method of any one of embodiments 1-3, wherein the subject’s blood glucose concentration is reduced in comparison to the subject’s blood glucose prior to administration of the TTR stabilizer. 5. The method of embodiment 4, wherein the subject’s blood glucose concentration is reduced by at least 10% in comparison to the subject’s blood glucose prior to administration of the TTR stabilizer. 6. The method of any one of embodiments 1-5, wherein the subject has been diagnosed with diabetes. 7. The method of embodiment 6, wherein the diabetes is Type II diabetes. 8. The method of embodiment 6 or 7, wherein the subject is being treated with one or more compositions for the treatment of diabetes. 9. The method of embodiment 8, wherein the composition for the treatment of diabetes is an anti-diabetic drug. ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT 10. The method of embodiment 9, wherein the anti-diabetic drug is ertugliflozin, bexagliflozin, canagliflozin, dapagliflozin, or empagliflozin. 11. The method of embodiment 10, wherein the anti-diabetic drug is dapagliflozin. 12. The method of any one of embodiments 8-11, wherein the amount of the composition for the treatment of diabetes is reduced in comparison to the amount of the composition for the treatment of diabetes prior to administration of the TTR stabilizer. 13. The method of embodiment 12, wherein the amount of the composition for treatment of diabetes is reduced by at least 20% in comparison to the amount of the composition for the treatment of diabetes prior to administration of the TTR stabilizer. 14. A method of treating, preventing, or ameliorating one or more symptoms associated with dyslipidemia in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. 15. The method of embodiment 14, wherein the subject’s bloodstream lipid concentration is decreased in comparison to the subject’s bloodstream lipid concentration prior to administration of the TTR stabilizer. 16. A method of treating or preventing obesity in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer. 17. The method of embodiment 16, wherein the subject’s body mass index (BMI) is reduced in comparison to the subject’s BMI prior to administration of the TTR stabilizer. 18. The method of embodiment 17, wherein the subject's BMI is reduced by at least 10% in comparison to the subject’s BMI prior to administration of the TTR stabilizer. 19. The method of embodiment 14 or 16, wherein the subject has Cardiac Amyloidosis caused by TTR dysfunction (ATTR-CM). 20. The method of any of embodiments 1-19, wherein the TTR stabilizer is acoramidis. 21. The method of any one of embodiments 1-19, wherein the TTR stabilizer is tafamidis. 22. The method of any one of embodiments 1-21, wherein the TTR stabilizer is administered to the subject in amount of between 500 mg to 2,500 mg per day. 23. The method of embodiment 22, wherein the TTR stabilizer is administered to the subject in amount of between 1,000 mg to 2,000 mg per day. 24. The method of embodiment 22, wherein the TTR stabilizer is administered to the subject in amount of between 1,200 mg to 1,800 mg per day. 25. The method of embodiment 22, wherein the TTR stabilizer is administered to the subject in amount of about 1,600 mg per day. 26. The method of any one of embodiments 1-25, wherein the TTR stabilizer is administered subcutaneously, intramuscularly, intravenously, or orally. 27. The method of embodiment 26, wherein the TTR stabilizer is administered orally. 28. The method of any one of embodiments 1-27, wherein the TTR stabilizer is administered once daily. 29. The method of any one of embodiments 1-27, wherein the TTR stabilizer is administered twice daily. 30. The method of any one of embodiments 1-27, wherein the TTR stabilizer is administered three times daily. ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT 31. The method of any one of embodiments 1-27, wherein the TTR stabilizer is administered four times daily. 32. The method of any one of embodiments 1-31, wherein the subject is a human subject. Additional embodiments All references cited in this specification including database-accessioned information (e.g., in GENBANK, UNIPROT, PUBMED), are herein incorporated by reference as though each reference was specifically and individually indicated to be incorporated by reference. The citation of any reference is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such reference by virtue of prior invention. It will be understood that each of the elements described above, or two or more together may also find a useful application in other types of methods differing from the type described above. Without further analysis, the foregoing will so fully reveal the gist of the present disclosure that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this disclosure set forth in the appended claims. The foregoing embodiments are presented by way of example only.

Claims

ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT CLAIMS What is claimed is:

1. A method of treating, preventing, or ameliorating one or more symptoms associated with a metabolic syndrome in a subject having Transthyretin (TTR) dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer.

2. A method of treating, preventing, or ameliorating one or more symptoms associated with diabetes in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer.

3. A method of treating or preventing insulin resistance in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer.

4. The method of any one of Claims 1-3, wherein the subject’s blood glucose concentration is reduced in comparison to the subject’s blood glucose prior to administration of the TTR stabilizer.

5. The method of Claim 4, wherein the subject’s blood glucose concentration is reduced by at least 10% in comparison to the subject’s blood glucose prior to administration of the TTR stabilizer.

6. The method of any one of Claims 1-3, wherein the subject has been diagnosed with diabetes.

7. The method of Claim 6, wherein the diabetes is Type II diabetes.

8. The method of Claim 6, wherein the subject is being treated with one or more compositions for the treatment of diabetes.

9. The method of Claim 8, wherein the composition for the treatment of diabetes is an anti-diabetic drug.

10. The method of Claim 9, wherein the anti-diabetic drug is ertugliflozin, bexagliflozin, canagliflozin, dapagliflozin, or empagliflozin.

11. The method of Claim 10, wherein the anti-diabetic drug is dapagliflozin.

12. The method of any one of Claims 8-11, wherein the amount of the composition for the treatment of diabetes is reduced in comparison to the amount of the composition for the treatment of diabetes prior to administration of the TTR stabilizer.ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT 13. The method of Claim 12, wherein the amount of the composition for treatment of diabetes is reduced by at least 20% in comparison to the amount of the composition for the treatment of diabetes prior to administration of the TTR stabilizer.

14. A method of treating, preventing, or ameliorating one or more symptoms associated with dyslipidemia in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer.

15. The method of Claim 14, wherein the subject’s bloodstream lipid concentration is decreased in comparison to the subject’s bloodstream lipid concentration prior to administration of the TTR stabilizer.

16. A method of treating or preventing obesity in a subject having TTR dysfunction, wherein the method comprises administering the subject a therapeutically effective amount of a TTR stabilizer.

17. The method of Claim 16, wherein the subject’s body mass index (BMI) is reduced in comparison to the subject’s BMI prior to administration of the TTR stabilizer.

18. The method of Claim 17, wherein the subject's BMI is reduced by at least 10% in comparison to the subject’s BMI prior to administration of the TTR stabilizer.

19. The method of Claim 14 or 16, wherein the subject has Cardiac Amyloidosis caused by TTR dysfunction (ATTR-CM).

20. The method of any one of Claims 1-3, wherein the TTR stabilizer is acoramidis.

21. The method of any one of Claims 1-3, wherein the TTR stabilizer is tafamidis.

22. The method of any one of any one of Claims 1-3, wherein the TTR stabilizer is administered to the subject in amount of between 500 mg to 2,500 mg per day.

23. The method of Claim 22, wherein the TTR stabilizer is administered to the subject in amount of between 1,000 mg to 2,000 mg per day.

24. The method of Claim 22, wherein the TTR stabilizer is administered to the subject in amount of between 1,200 mg to 1,800 mg per day.

25. The method of Claim 22, wherein the TTR stabilizer is administered to the subject in amount of about 1,600 mg per day.ATTORNEY DOCKET NO.: 51196-045WO2 ALEXION REFERENCE NO.: ALXN-2060-METAB-01 PATENT 26. The method of any one of Claims 1-3, wherein the TTR stabilizer is administered subcutaneously, intramuscularly, intravenously, or orally.

27. The method of Claim 26, wherein the TTR stabilizer is administered orally.

28. The method of any one of Claims 1-3, wherein the TTR stabilizer is administered once daily.

29. The method of any one of Claims 1-3, wherein the TTR stabilizer is administered twice daily.

30. The method of any one of Claims 1-3, wherein the TTR stabilizer is administered three times daily.

31. The method of any one of Claims 1-3, wherein the TTR stabilizer is administered four times daily.

32. The method of any one of Claims 1-3, wherein the subject is a human subject.

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