Treatment of hypertriglyceridemia with 2-hydroxypropyl-β-cyclodextrin

Abstract

Disclosed herein is a method for treating hypertriglyceridemia by administering to a subject a therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin, optionally an amount effective to reduce the amount of serum triglycerides after said administration by at least 10% compared to the amount before said administration.

Description

[Technical field]

[0001] Hypertriglyceridemia is a disease in which there is an elevated amount of triglycerides in the blood. [Background technology]

[0002] Hypertriglyceridemia occurs in various physiological conditions and in various diseases, and high triglyceride levels are associated with atherosclerosis, heart disease, and pancreatitis. Hypertriglyceridemia is a major burden for our modern society. There are preclinical data suggesting that 2-hydroxypropyl-β-cyclodextrin has profound beneficial effects on the pathological mechanisms involved in the development of hypertriglyceridemia and may halt or reverse the progression of hypertriglyceridemia. Therefore, 2-hydroxypropyl-β-cyclodextrin may provide a novel treatment option for hypertriglyceridemia. Summary of the Invention

[0003] There is a need for a safe and effective treatment for hypertriglyceridemia, and the present disclosure addresses this unmet need.

[0004] The present disclosure provides methods of treating hypertriglyceridemia in a subject, the methods comprising administering to the subject a therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin to treat hypertriglyceridemia and / or reduce or prevent symptoms of hypertriglyceridemia. In some embodiments, hypertriglyceridemia is caused by high triglyceride levels, overeating, obesity, diabetes and / or insulin resistance, excessive alcohol intake, renal failure, nephrotic syndrome, genetic predisposition, lipoprotein lipase deficiency, lysosomal acid lipase deficiency, hypothyroidism, lupus, glycogen storage disease, propofol, and / or HIV medications in the subject. In one aspect, the disclosure provides a method of reducing a symptom of hypertriglyceridemia or inhibiting the development of hypertriglyceridemia in a subject, the method comprising administering to the subject a therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin, the therapeutically effective amount being an amount effective to (a) increase circulating and / or systemic levels of one or more oxysterols in the subject after said administration by at least about 10% compared to before said administration, (b) increase cholesterol crystal solubility (CCDC) of plasma by at least about 10% after said administration, and (c) increase cholesterol crystal solubility (CCDC) of at least about 10% after said administration. (c) an amount effective to increase the level of ABCA1 and / or ABCG1 after said administration by at least about 10% compared to before said administration, (d) about 50 mg / kg to about 2,000 mg / kg, (e) an amount effective to decrease the amount of serum triglycerides after said administration by at least 10% compared to before said administration, or (f) any combination thereof, thereby reducing or inhibiting the onset of hypertriglyceridemia in said subject. In some embodiments, the therapeutically effective amount is about 2 g to about 250 g of said 2-hydroxypropyl-β-cyclodextrin.

[0005] In some embodiments, the therapeutically effective amount is an amount sufficient to achieve a serum, plasma, and / or whole blood concentration of 2-hydroxypropyl-β-cyclodextrin of about 0.6 mM to about 3 mM. In some embodiments, the therapeutically effective amount is an amount effective to increase the circulating and / or systemic levels of one or more oxysterols in the subject by at least about 10% after the administration compared to before the administration. In some embodiments, the circulating and / or systemic levels include serum, plasma, and / or whole blood levels. In some embodiments, the one or more oxysterols are selected from the group consisting of 27-hydroxycholesterol and 24-hydroxycholesterol. In some embodiments, the at least about 10% includes at least about 15%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0006] In some embodiments, the therapeutically effective amount is an amount effective to increase circulating and / or systemic levels of one or more oxysterols to about 40 ng / mL or greater. In some embodiments, the therapeutically effective amount is an amount effective to increase circulating and / or systemic levels of one or more oxysterols to at least about 40 ng / mg of circulating and / or systemic total cholesterol. In some embodiments, the one or more oxysterols include 27-hydroxycholesterol. In some embodiments, the therapeutically effective amount is an amount effective to increase circulating and / or systemic levels of 27-hydroxycholesterol to at least about 100 ng / mL. In some embodiments, the therapeutically effective amount is an amount effective to increase circulating and / or systemic levels of 27-hydroxycholesterol to at least about 90 ng / mg of circulating and / or systemic total cholesterol. In some embodiments, the therapeutically effective amount is an amount sufficient to sustain circulating and / or systemic levels of the one or more oxysterols for at least 24 hours. In some embodiments, the therapeutically effective amount is an amount effective to increase the cholesterol crystal dissolving capacity (CCDC) of plasma by at least about 10% after the administration compared to before the administration. In some embodiments, the therapeutically effective amount is an amount effective to increase the level of ABCA1 and / or ABCG1 by at least about 10% after the administration compared to before the administration. In some embodiments, the therapeutically effective amount is an amount effective to decrease the amount of serum triglycerides by at least 10% after the administration compared to before the administration. In some embodiments, the therapeutically effective amount is about 50 mg / kg to about 2,000 mg / kg. In some embodiments, the therapeutically effective amount is at least about 100 mg / kg. In some embodiments, the therapeutically effective amount is at least about 250 mg / kg. In some embodiments, the therapeutically effective amount is at least about 500 mg / kg. In some embodiments, the therapeutically effective amount is at least about 1,000 mg / kg. In some embodiments, the therapeutically effective amount is at least about 1,500 mg / kg.In some embodiments, the therapeutically effective amount is about 500 mg / kg to about 1,500 mg / kg, or about 800 mg / kg to about 1,200 mg / kg. In some embodiments, the subject is a human individual.

[0007] In another embodiment of the invention, the administering further comprises: (i) administering a first therapeutically effective dose of 2-hydroxypropyl-β-cyclodextrin to the subject at a first time point; and (ii) administering a second therapeutically effective dose of 2-hydroxypropyl-β-cyclodextrin to the subject at a second time point. In some embodiments, the second time point is at least one week after the first time point. In some embodiments, the second time point is at least two weeks after the first time point. In some embodiments, the second time point is at least one month after the first time point. In some embodiments, the treating comprises reducing or preventing the progression and / or development of hypertriglyceridemia in the subject. In some embodiments, the treating comprises mediating the regression of high serum triglyceride levels in the subject. In some embodiments, the treating leads to one or more of the following: a) liver enzyme (e.g., ALT, AST) levels less than 2.5 times normal, b) serum creatinine levels less than 0.3 mg / dl, or c) substantially no sensorineural hearing loss. In some embodiments, the administering is by intravenous administration.

[0008] Provided in various embodiments herein is a pharmaceutical composition comprising an amount of 2-hydroxypropyl-β-cyclodextrin effective to treat hypertriglyceridemia in a subject and a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises about 4 g to about 250 g of 2-hydroxypropyl-β-cyclodextrin and a pharma- ceutically acceptable excipient. In some embodiments, the amount of 2-hydroxypropyl-β-cyclodextrin is effective to increase circulating and / or systemic levels of one or more oxysterols in the subject by at least about 10% after administration of the pharmaceutical composition to the subject. In some embodiments, the amount of 2-hydroxypropyl-β-cyclodextrin is effective to increase plasma cholesterol crystal dissolving capacity (CCDC) by at least about 10% after administration of the pharmaceutical composition to the subject. In some embodiments, the amount of 2-hydroxypropyl-β-cyclodextrin is effective to increase the level of ABCA1 and / or ABCG1 by at least about 10% after administration of the pharmaceutical composition to the subject. In some embodiments, the pharmaceutical composition is formulated for single administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration.

[0009] In another embodiment, the present disclosure provides a kit comprising (a) one or more containers and (b) a pharmaceutical composition disclosed herein, the pharmaceutical composition being contained within the one or more containers. In some embodiments, the kit further comprises (c) instructions for use of the pharmaceutical composition for treating hypertriglyceridemia in a subject and / or reducing or inhibiting the onset or symptoms of hypertriglyceridemia in a subject. In some embodiments, at least one of the one or more containers is an intravenous infusion bag. In some embodiments, the one or more containers comprise a single container comprising the pharmaceutical composition and one or more additional active pharmaceutical ingredients. In some embodiments, the one or more containers comprise a first container housing the pharmaceutical composition and a second container housing one or more additional active pharmaceutical ingredients. In some embodiments, the kit further comprises one or more additional components selected from the group consisting of an intravenous infusion bag, a catheter, a tube, a needle, a syringe, a solution, and any combination thereof.

[0010] Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0011] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description that sets forth illustrative modes in which the principles of the invention are utilized, and the accompanying drawings in which: [Brief description of the drawings]

[0012] [Figure 1A] 1 shows a non-limiting example of the administration details of 2-hydroxypropyl-β-cyclodextrin (HPBCD) to a Western Diet (WD) fed mouse model. [Figure 1B] A non-limiting example of the details of administration of HPBCD to a mouse model fed a normal diet (NC) is provided. [Figure 2A] A representative graph of triglyceride levels obtained from a Western chow-fed (WD)-fed mouse model treated with 2 g / kg HPBCD as a function of post-administration time of HPBCD is shown. [Figure 2B] Representative triglyceride levels obtained from a normal chow (NC) fed mouse model treated with 2 g / kg HPBCD as a function of post-administration time of HPBCD are shown. [Figure 3A] 1 shows a graph of triglyceride levels obtained from volunteers receiving 50 mg / kg, 250 mg / kg, 500 mg / kg, 1000 mg / kg or 1500 mg / kg of HPBCD immediately prior to injection and 24 and 48 hours after administration of HPBCD. [Figure 3B] 1 shows a graph of the mean change in triglyceride levels 24 and 48 hours after dosing from volunteers receiving placebo, 500 mg / kg, 1000 mg / kg or 1500 mg / kg of HPBCD. [Figure 3C] 1 shows a graph of the mean change in triglyceride levels 24 and 48 hours post-dose from volunteers with baseline triglyceride levels above 100 mg / dL who received placebo, 500 mg / kg, 1000 mg / kg or 1500 mg / kg of HPBCD. [Figure 3D] 1 shows a graph of the mean change in triglyceride levels 24 and 48 hours after dosing from volunteers with baseline triglyceride levels below 100 mg / dL who received placebo, 500 mg / kg, 1000 mg / kg or 1500 mg / kg of HPBCD. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Disclosed herein is a method for the treatment of hypertriglyceridemia. In some embodiments, the method may include administering a therapeutically effective amount of cyclodextrin to a subject in need thereof (e.g., a subject suffering from, suspected of suffering from, or at risk of developing hypertriglyceridemia). Optionally, the therapeutically effective amount is an amount effective to increase the circulating and / or systemic levels of one or more sterols and / or oxysterols in the subject compared to baseline (e.g., before treatment with cyclodextrin). In certain embodiments, the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.

[0014] In some aspects, disclosed herein are methods for reducing the amount and / or size of circulating (e.g., blood, plasma, serum) cholesterol crystals (and / or blood clots containing cholesterol crystals) and / or altering the shape of said crystals (and / or blood clots) in an individual (e.g., a human) suffering from, having, or likely to develop hypertriglyceridemia.

[0015] In some embodiments, disclosed herein is a method for preventing or reducing the risk of hypertriglyceridemia in an individual (e.g., a human).Further disclosed herein is a method for preventing or reducing the risk of hypertriglyceridemia in an individual (e.g., a human suffering from or suspected of suffering from hypertriglyceridemia) increasing the amount of serum triglycerides.In certain embodiments, the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.

[0016] The following terms are discussed to explain the meaning of the terms as used herein, as well as the understanding of these terms by those skilled in the art. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended to serve as a precondition for the use of exclusive terms such as "solely," "only," and the like in connection with the description of claim elements or the use of "negative" limitations.

[0017] As used herein, the term "about" + a number refers to the number in question + / - 10% of the number in question. The term "about" + a range refers to the range in question minus 10% of the lowest value and +10% of the highest value.

[0018] As used herein, the terms "subject," "individual," and "patient" are used interchangeably. None of these terms should be construed as requiring the supervision of a medical professional (e.g., physician, nurse, physician's assistant, nursing assistant, hospice worker). As used herein, a subject can be any animal, including mammals (e.g., human or non-human animals) and non-mammals. In one embodiment, the subject is a human.

[0019] As used herein, the terms "treat," "treating," or "treatment," and other grammatical equivalents include ameliorating or preventing the underlying cause of one or more symptoms of a disease or disorder; alleviating, relieving, or ameliorating one or more symptoms of a disease or disorder; ameliorating, preventing, or reducing the appearance, severity, or frequency of one or more symptoms of a disease or disorder; inhibiting a disease or disorder, for example, preventing the onset of a disease or disorder, relieving a disease or disorder, causing regression of a disease or disorder, alleviating a condition caused by a disease or disorder, or inhibiting a symptom of a disease or disorder, either prophylactically and / or therapeutically. Therapeutic methods disclosed herein include disclosure of the use of the (e.g., pharmaceutical) compositions provided herein for the treatment of any of the indications described herein, including disclosure of the (e.g., pharmaceutical) compositions provided herein for use in the treatment of any of the indications described herein.

[0020] The term "pharmaceutical acceptable" generally refers to the attributes of a material useful in preparing a pharmaceutical composition that is safe, non-toxic, and not biologically or otherwise undesirable, and that is acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable" can refer to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, e.g., the material can be administered to an individual without producing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is included.

[0021] As used herein, "pharmaceutically acceptable excipient" refers to any pharmaceutically acceptable ingredient in a pharmaceutical composition, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, excipient, preservative, or lubricant, used in formulating a pharmaceutical product, which has no therapeutic activity and is non-toxic to a subject to which it is administered.

[0022] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered to alleviate to some extent one or more symptoms of the disease or disorder being treated, or to reduce the underlying cause of the disease or disorder being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to clinically significantly reduce the symptoms of the disease or the underlying cause of the disease (e.g., without undue adverse side effects). In some embodiments, the appropriate "effective amount" in any individual case is determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein may be an amount effective to achieve a desired effect or therapeutic improvement (e.g., without undue adverse side effects). An "effective amount" of a compound disclosed herein may be an amount effective to achieve one or more desired outcomes (e.g., systemic and / or circulating levels of sterols or oxysterols as described herein). In some cases, it should be understood that the "effective amount" or "therapeutically effective amount" will vary from subject to subject due to differences in metabolism of the composition, the subject's age, weight, general condition, concomitant medications the subject may be taking, the disease being treated, the severity of the disease being treated, and the prescribing physician's judgment. In some cases, the disease or condition being treated is hypertriglyceridemia. The underlying cause of hypertriglyceridemia may be high triglyceride levels, overeating, obesity, diabetes and / or insulin resistance, excessive alcohol intake, renal failure, nephrotic syndrome, genetic predisposition, lipoprotein lipase deficiency, lysosomal acid lipase deficiency, hypothyroidism, lupus, glycogen storage disease, propofol, HIV drugs, and / or ischemia in the subject.

[0023] Methods for Treating Hypertriglyceridemia

[0024] Disclosed herein is a method for treating a subject suffering from, suspected of, or at risk of developing hypertriglyceridemia. Optionally, treating a subject as described herein may inhibit, prevent, or reduce the high serum triglyceride level in the subject. Optionally, treating a subject as described herein may mediate, promote, enhance, or increase the regression of hypertriglyceridemia that has already developed. Optionally, treating a subject as described herein may reduce the serum triglyceride level in the subject. Optionally, reducing the serum triglyceride level in the subject may improve, prevent, or alleviate one or more symptoms associated with hypertriglyceridemia.

[0025] In various embodiments, the method includes administering cyclodextrin to the subject. Cyclodextrins are a family of cyclic oligosaccharides consisting of rings (e.g., macrocycles) of glucose subunits linked by α-1,4 glycosidic bonds. Cyclodextrins contain multiple glucose monomers in the ring structure. Common cyclodextrins include α-cyclodextrin (six glucose monomers), β-cyclodextrin (seven glucose monomers), γ-cyclodextrin (eight glucose monomers), and δ-cyclodextrin (nine glucose monomers). The outer portion of the ring structure is hydrophilic, and the inner cavity of the ring structure is hydrophobic, so cyclodextrins are generally water-soluble (e.g., due to the hydrophilic exterior) and can incorporate hydrophobic molecules into the cavity (e.g., due to the hydrophobic cavity). The water solubility of parent cyclodextrin is limited, therefore, several chemically modified cyclodextrins have been synthesized, in which hydroxyl groups are replaced with other chemical moieties to improve solubility. In various embodiments, the methods provided herein include administering cyclodextrin to a subject (e.g., a human) in need thereof (e.g., suffering from hypertriglyceridemia, suspected of suffering from hypertriglyceridemia, or at risk of developing hypertriglyceridemia). In some cases, the subject has atherosclerotic plaque (e.g., cholesterol-rich plaque and / or lipid-rich plaque), is suspected of having atherosclerotic plaque, or is at risk of developing atherosclerotic plaque.

[0026] In certain embodiments, the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. Optionally, the 2-hydroxypropyl-β-cyclodextrin is Kleptose® HP Parenteral Grade (Roquette Freres, #346114; available at roquette.com / - / media / roquette-sharepoint-libraries / sdol_product-specification-sheet / roquette_quality_specification-sheet_kleptose-hp-parenteral-grade_50_346114_en.pdf (as of August 26, 2020)), Kleptose® HPB Parenteral Grade (Roquette Freres, #346111; available at roquette.com / - / media / roquette-sharepoint-libraries / sdol_product-specification-sheet / roquette_quality_specification-sheet_kleptose-hpb-parenteral-grade_50_346111_en.pdf (as of August 26, 2020)), Kleptose® HPB-LB parenteral grade (Roquette Freres, #346115; available at roquette.com / - / media / roquette-sharepoint-libraries / sdol_product-specification-sheet / roquette_quality_specification-sheet_kleptose-hpb-lb-parenteral-grade_50_346115_en.pdf (as of August 26, 2020)), Cavitron® W7 HP5 Pharma Cyclodextrin (Ashland;ashland.com / file_source / Ashland / Product / Documents / Pharmaceutical / PC_11734_Cavitron_Cavasol.pdf (as of August 26, 2020)), Cavitron® W7 HP7 Pharma cyclodextrin, (Ashland; accessible at ashland.com / file_source / Ashland / Product / Documents / Pharmaceutical / PC_11734_Cavitron_Cavasol.pdf (as of August 26, 2020)), Trappsol® Cyclo™ (Cyclo Therapeutics, Inc.; accessible at cyclotherapeutics.com / cyclodextrins / trappsol-cyclo (as of August 26, 2020)), and VTS-270 / adorabetadex.

[0027] In certain embodiments, the cyclodextrin provided or used in the (e.g., pharmaceutical) compositions or methods or other applications herein is a mixture of cyclodextrins, for example, in some embodiments, the 2-hydroxypropyl-β-cyclodextrin provided herein comprises a mixture of 2-hydroxypropyl-β-cyclodextrins. In some embodiments, the cyclodextrin molecules provided herein are optionally substituted with one or more chemical groups, each independently being a hydroxypropyl group, a hydroxyethyl group, a methyl group, an ethyl group, a carboxymethyl group, a heptakis(2,6)-di-O-methyl group, a sulfoethyl group, a sulfopropyl group, and / or a sulfobutylethyl group, or are oligomers thereof. In some preferred embodiments, the cyclodextrin is a hydroxypropyl-β-cyclodextrin, such that one or more hydroxyls of the cyclodextrin are substituted with a hydroxypropyl group (e.g., a 2-hydroxypropyl group). For example, one or more hydroxyl positions are substituted with one or more hydroxypropyl groups by replacing the H of the hydroxyl (OH) with a -CH2CH2(OH)CH3 group, as shown in Formula I below: In some embodiments, the 2-hydroxypropyl-β-cyclodextrin comprises a plurality of cyclodextrins having a variety of different degree of substitution (DS) values ​​and / or molar substitution (MS) values. [ka]

[0028] In some embodiments, the β-cyclodextrin molecules in a β-cyclodextrin (a mixture of β-cyclodextrin molecules) are characterized by an average molar substitution. "Molar substitution," or "MS," is the average number of substituents per glucose unit in the β-cyclodextrin molecules. In some embodiments, MS is measured according to the procedures described in the USP Monograph for Hydroxypropyl Betadex (USP NF 2015) ("USP Hydroxypropyl Betadex Monograph"), which is incorporated herein by reference in its entirety. In some embodiments, the (e.g., pharmaceutical) compositions provided herein include a plurality of β-cyclodextrin molecules having an average MS of at least about 0.3. In some embodiments, the (e.g., pharmaceutical) compositions provided herein include a plurality of β-cyclodextrin molecules having an average MS of about 0.3 to 1.2. In some embodiments, the (e.g., pharmaceutical) compositions provided herein include a plurality of β-cyclodextrin molecules having an average MS of about 0.8 to 1.2.

[0029] In some embodiments, the plurality of β-cyclodextrin molecules is characterized by an average degree of substitution. The term "degree of substitution", or "DS", refers to the total number of substituents substituted directly or indirectly on a β-cyclodextrin molecule. In some embodiments, the β-cyclodextrin molecule may have one or more glucose units substituted by a substituent at a hydroxyl position. Thus, the average DS refers to the total number of substituents in a population of β-cyclodextrin divided by the number of β-cyclodextrin molecules. In some embodiments, the average DS of the molecules is measured using electrospray ionization mass spectrometry (ESI-MS) analysis (e.g., HPLC-ESI-MS, etc.). In some embodiments, the average DS of the molecules is measured by the peak height of an electrospray MS spectrum. In some embodiments, the average DS of the molecules is determined by multiplying the MS by 7. In some embodiments, the (e.g., pharmaceutical) compositions provided herein include a plurality of β-cyclodextrin molecules having an average DS of about 2.0 to 9.0. In some embodiments, the (eg, pharmaceutical) compositions provided herein comprise a plurality of β-cyclodextrin molecules having an average DS of about 6.0 to 8.0.

[0030] In some aspects, any atom of the cyclodextrins described herein (e.g., 2-hydroxypropyl-β-cyclodextrin) may be substituted with any suitable isotope. In certain embodiments, any one or more hydrogen atoms of the cyclodextrins described herein (e.g., 2-hydroxypropyl-β-cyclodextrin) may be substituted or replaced with a deuterium atom. Such cyclodextrins are expected to have similar or improved properties compared to the original cyclodextrins that do not contain deuterium. Deuterium is a safe and stable non-radioactive isotope of hydrogen. Deuterium forms stronger bonds with carbon compared to hydrogen. In some cases, the increased bond strength imparted by deuterium can positively affect the properties of the cyclodextrin, creating the possibility of improving the efficacy, safety, and / or tolerability of drugs. Furthermore, deuteration can reduce metabolic clearance in vivo, thereby increasing the half-life and circulation of the compound. At the same time, because the size and shape of deuterium is essentially identical to the size and shape of hydrogen, the replacement of hydrogen with deuterium is not expected to affect the biochemical potency and selectivity of the compound compared to the parent chemical containing only hydrogen.

[0031] In various embodiments, the subject is administered a therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin. In some embodiments, administration of a therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin increases the circulating and / or systemic levels of one or more cholesterol derivatives compared to baseline. In some embodiments, the one or more cholesterol derivatives are by-products of cholesterol biosynthesis. In some embodiments, the one or more cholesterol derivatives include products that include hydrogenated products, products that are differently hydrogenated 1H-cyclopenta[a]phenanthren-3-ol products, or products formed with hydroxyl groups, epoxy groups, or keto groups. Optionally, the one or more cholesterol derivatives are oxysterols or sterols.

[0032] A therapeutically effective amount can be an amount of 2-hydroxypropyl-β-cyclodextrin effective to increase the circulating and / or systemic amount of one or more sterols and / or oxysterols in the subject compared to baseline. The circulating and / or systemic amount of sterols and / or oxysterols can be the amount present in a biological sample from the subject (e.g., blood (e.g., whole blood), plasma, serum, etc.). In some cases, the circulating and / or systemic sterol and / or oxysterol levels can be increased by at least about 10% (e.g., at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more) compared to baseline (e.g., 24 hours after treatment). In some cases, the circulating and / or systemic sterol and / or oxysterol levels may be elevated to at least about 40 ng / mL (e.g., at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, or more). In another embodiment, the circulating and / or systemic sterol and / or oxysterol levels may be elevated to at least about 40 ng per mg of circulating and / or systemic total cholesterol (e.g., at least about 40 ng, at least about 50 ng, at least about 60 ng, at least about 70 ng, at least about 80 ng, at least about 90 ng, or at least about 100 ng per mg of circulating and / or systemic total cholesterol). Generally, circulating and / or systemic levels of sterols and oxysterols (e.g., after treatment with 2-hydroxypropyl-β-cyclodextrin) are compared to baseline levels (e.g., circulating and / or systemic levels of the sterols and / or oxysterols in the subject prior to treatment with the 2-hydroxypropyl-β-cyclodextrin).Non-limiting examples of sterols and oxysterols that may exhibit increased levels (e.g., in whole blood, plasma, and / or serum) upon administration of 2-hydroxypropyl-β-cyclodextrin include 27-hydroxycholesterol, 24-hydroxycholesterol, and 25-hydroxycholesterol. In various embodiments, the therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin may be an amount sufficient to maintain or sustain the systemic and / or circulating levels of the sterol and / or oxysterol for at least 24 hours (e.g., at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours) following treatment.

[0033] In certain embodiments, the therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin is an amount effective to increase the circulating and / or systemic amount of 27-hydroxycholesterol compared to baseline.In some cases, the circulating and / or systemic 27-hydroxycholesterol level may be increased by at least about 10% compared to baseline (e.g., 24 hours after treatment), e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more.In some cases, the circulating and / or systemic 27-hydroxycholesterol level may be increased by at least about 40ng / mL, e.g., at least about 50ng / mL, at least about 60ng / mL, at least about 70ng / mL, at least about 80ng / mL, at least about 90ng / mL, at least about 100ng / mL, or more. In certain embodiments, the circulating and / or systemic 27-hydroxycholesterol levels may be elevated to at least about 100 ng / mL. In another embodiment, the circulating and / or systemic 27-hydroxycholesterol levels may be elevated to at least about 40 ng per mg of circulating and / or systemic total cholesterol, e.g., at least about 50 ng, at least about 60 ng, at least about 70 ng, at least about 80 ng, at least about 90 ng, or at least about 100 ng per mg of circulating and / or systemic total cholesterol. In certain embodiments, the circulating and / or systemic 27-hydroxycholesterol levels may be elevated to at least about 90 ng per mg of circulating and / or systemic total cholesterol.

[0034] Additionally or alternatively, a therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin may be an amount effective to increase the circulating and / or systemic amount of 24-hydroxycholesterol compared to baseline. In some cases, the circulating and / or systemic 24-hydroxycholesterol level may be increased by at least about 10%, e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more compared to baseline (e.g., 24 hours after treatment). In some cases, the circulating and / or systemic 24-hydroxycholesterol level may be increased by at least about 40ng / mL, e.g., at least about 50ng / mL, at least about 60ng / mL, at least about 70ng / mL, at least about 80ng / mL, at least about 90ng / mL, at least about 100ng / mL, or more. In certain embodiments, the circulating and / or systemic 24-hydroxycholesterol levels may be elevated to at least about 50 ng / mL. In another aspect, the circulating and / or systemic 24-hydroxycholesterol levels may be elevated to at least about 40 ng per mg of circulating and / or systemic total cholesterol, e.g., at least about 50 ng, at least about 60 ng, at least about 70 ng, at least about 80 ng, at least about 90 ng, or at least about 100 ng per mg of circulating and / or systemic total cholesterol. In certain embodiments, the circulating and / or systemic 24-hydroxycholesterol levels may be elevated to at least about 40 ng per mg of circulating and / or systemic total cholesterol.

[0035] A therapeutically effective amount can be an amount of 2-hydroxypropyl-β-cyclodextrin effective to increase plasma cholesterol crystal dissolving capacity (CCDC) after administration (e.g., 1 hour after said administration) compared to before said administration. Optionally, said therapeutically effective amount is an amount of 2-hydroxypropyl-β-cyclodextrin effective to increase plasma CCDC after administration by at least about 10% (e.g., at 1 hour) compared to before said administration, e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more.

[0036] A therapeutically effective amount can be an amount of 2-hydroxypropyl-β-cyclodextrin effective to increase the mRNA level of one or more genes (e.g., ABCA1, ABCG1) regulated by an LXR transcription factor after said administration (e.g., 24 hours after said administration) compared to before said administration. Optionally, the therapeutically effective amount is an amount of 2-hydroxypropyl-β-cyclodextrin effective to increase the mRNA level of ABCA1 and / or ABCG1 after said administration by at least about 10% (e.g., at 24 hours) compared to before said administration, e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more.

[0037] A therapeutically effective amount can be an amount of 2-hydroxypropyl-β-cyclodextrin effective to reduce serum triglyceride levels in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to before treatment with the 2-hydroxypropyl-β-cyclodextrin composition. In some embodiments, a therapeutically effective amount can be an amount of 2-hydroxypropyl-β-cyclodextrin effective to reduce serum triglyceride levels in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% 24 hours, 48 ​​hours, 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks after administration. In some embodiments, a therapeutically effective amount can be an amount of 2-hydroxypropyl-β-cyclodextrin effective to reduce serum triglyceride levels in said subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, and to maintain reduced serum triglyceride levels during and / or after administration for at least 24 hours, at least 48 hours, at least 72 hours, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks.

[0038] In some embodiments, the therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin may be an amount of 2-hydroxypropyl-β-cyclodextrin effective to maintain reduced serum triglyceride levels after treatment with 2-hydroxypropyl-β-cyclodextrin. In these maintenance embodiments, the therapeutically effective amount may be an amount effective to maintain serum triglyceride levels at least below 250 mg / dL, such as at least below 200 mg / dL, at least below 150 mg / dL, at least below 100 mg / dL, or at least below 50 mg / dL. In embodiments for maintaining reduced serum triglyceride levels, the therapeutically effective amount may be an amount effective to maintain serum triglyceride levels at least below 250 mg / dL. In another embodiment for maintaining reduced serum triglyceride levels, the therapeutically effective amount may be an amount effective to maintain serum triglyceride levels at least below 200 mg / dL. In another embodiment of maintaining reduced serum triglyceride levels, the therapeutically effective amount can be an amount effective to maintain serum triglyceride levels below at least 150 mg / dL. In another embodiment of maintaining reduced serum triglyceride levels, the therapeutically effective amount can be an amount effective to maintain serum triglyceride levels below at least 100 mg / dL. In another embodiment of maintaining reduced triglyceride levels, the therapeutically effective amount can be an amount effective to maintain serum triglyceride levels below at least 50 mg / dL.

[0039] In a maintenance embodiment, the reduced serum triglyceride levels can be maintained for at least 24 hours, at least 48 hours, at least 72 hours, at least one week, at least two weeks, at least three weeks, at least four weeks during and / or after administration. In an embodiment for maintaining reduced serum triglyceride levels, the reduced serum triglyceride levels are maintained for at least 24 hours during and / or after administration. In another embodiment for maintaining reduced serum triglyceride levels, the reduced serum triglyceride levels are maintained for at least 48 hours during and / or after administration. In another embodiment for maintaining reduced serum triglyceride levels, the reduced serum triglyceride levels are maintained for at least 72 hours during and / or after administration. In another embodiment for maintaining reduced serum triglyceride levels, the reduced serum triglyceride levels are maintained for at least one week during and / or after administration. In another embodiment for maintaining reduced serum triglyceride levels, the reduced serum triglyceride levels are maintained during and / or for at least 2 weeks after administration. In another embodiment for maintaining reduced serum triglyceride levels, the reduced serum triglyceride levels are maintained during and / or for at least 3 weeks after administration. In another embodiment for maintaining reduced serum triglyceride levels, the reduced serum triglyceride levels are maintained during and / or for at least 4 weeks after administration.

[0040] In some embodiments, the therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin is an amount suitable for achieving the therapeutic effect described herein. In some embodiments, the therapeutically effective amount is at least about 50 mg / kg, at least about 100 mg / kg, at least about 200 mg / kg, at least about 300 mg / kg, at least about 400 mg / kg, at least about 500 mg / kg, at least about 600 mg / kg, at least about 700 mg / kg, at least about 800 mg / kg, at least about 900 mg / kg, at least about 1000 mg / kg, at least about 1100 mg / kg, at least about 1200 mg / kg, at least about 1300 mg / kg, at least about 1400 mg / kg, at least about 1500 mg / kg, at least about 1600 mg / kg, at least about 1700 mg / kg, at least about 1800 mg / kg, at least about 1900 mg / kg, or at least about 2000 mg / kg. In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is at least about 100 mg / kg. In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is at least about 250 mg / kg. In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is at least about 500 mg / kg. In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is at least about 1000 mg / kg. In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is at least about 1500 mg / kg.

[0041] In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is an amount suitable for achieving the therapeutic effect described herein. In some embodiments, the therapeutically effective amount is about 50 mg / kg to about 2000 mg / kg (e.g., about 50 mg / kg to about 1000 mg / kg, about 500 mg / kg to about 1000 mg / kg, about 500 mg / kg to about 1500 mg / kg, about 800 mg / kg to about 1500 mg / kg, about 800 mg / kg to about 1200 mg / kg, about 1000 mg / kg to about 1500 mg / kg, about 1000 mg / kg to about 2000 mg / kg). In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is about 500 mg / kg to about 1500 mg / kg. In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is about 800 mg / kg to about 1200 mg / kg.

[0042] In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin is an amount suitable for achieving the therapeutic effect described herein. In some embodiments, the therapeutically effective amount is at least about 4 g (e.g., at least about 10 g, at least about 25 g, at least about 50 g, at least about 75 g, at least about 100 g, at least about 125 g, at least about 150 g, at least about 175 g, at least about 200 g, at least about 250 g). In some embodiments, the therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin may be about 4 g to about 250 g (e.g., about 4 g to about 200 g, about 4 g to about 150 g, about 4 g to about 100 g, about 4 g to about 50 g, about 50 g to about 250 g, about 50 g to about 200 g, about 50 g to about 150 g, about 50 g to about 100 g, about 100 g to about 250 g, about 100 g to about 200 g). The total amount of 2-hydroxypropyl-β-cyclodextrin administered (e.g., in a single dose, e.g., in a therapeutically effective amount) may depend on a number of factors, including, but not limited to, the age, sex, weight, etc., of the subject.

[0043] In some embodiments, the therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin is an amount sufficient to achieve a whole blood, serum, and / or plasma concentration of 2-hydroxypropyl-β-cyclodextrin suitable for achieving a therapeutic effect described herein. In some embodiments, the whole blood, serum, and / or plasma concentration is at least about 0.1 mM (e.g., at least about 0.2 mM, at least about 0.3 mM, at least about 0.4 mM, at least about 0.5 mM, at least about 0.6 mM, at least about 0.7 mM, at least about 0.8 mM, at least about 0.9 mM, at least about 1.0 mM, at least about 1.5 mM, at least about 2.0 mM, at least about 2.5 mM, or at least about 3 mM). The therapeutically effective amount of the 2-hydroxypropyl-β-cyclodextrin may be an amount sufficient to achieve a whole blood, serum, and / or plasma concentration of 2-hydroxypropyl-β-cyclodextrin of about 0.6 mM to about 3 mM (e.g., about 0.6 mM to about 2 mM, about 0.6 mM to about 1 mM, about 1 mM to about 3 mM, about 1 mM to about 2 mM, about 2 mM to about 3 mM).

[0044] The methods disclosed herein may further include administering a first therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin to the subject at a first time point, and administering a second therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin to the subject at a second time point. The second time point may be at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, or at least 6 days after the first time point. The second time point may be at least 1 week after the first time point (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks after the first time point). Optionally, the second time point is 1 week or more after the first time point, 2 weeks after the first time point, or 1 month or more after the first time point. In some embodiments, the administering may be by intravenous administration.

[0045] Optionally, the second time point may be determined based on one or more indicators that additional administration of the drug is beneficial for the subject.For example, the second time point may be administered after the therapeutic benefit of the first administration has decreased or begins to decrease. The second time point may be determined based on, for example, circulating and / or systemic 27-hydroxycholesterol levels, circulating and / or systemic 24S-hydroxycholesterol levels, ATP-binding cassette subfamily A member 1 (ABCA1) transcription levels, ATP-binding cassette subfamily G member 1 (ABCG1) transcription levels, epigenetic (chromatin) signatures of peripheral blood mononuclear cells (PBMCs), triglyceride levels, total cholesterol levels, very low density lipoprotein (vLDL) levels, low density lipoprotein (LDL) levels, high density lipoprotein (HDL) levels, serum or plasma cholesterol crystal lysis, pro-inflammatory mediators (e.g., interleukin-1b (IL-1b), interleukin-6 (IL-6), interleukin-18 (IL-18)).

[0046] In various embodiments, the subject may be a human. In some cases, the subject may be of any age at risk of developing or more susceptible to developing hypertriglyceridemia. The subject may be at least 30 years old (e.g., at least 40 years old, at least 50 years old, at least 60 years old, at least 70 years old, at least 80 years old, at least 90 years old). The subject may be less than 30 years old (e.g., less than 20 years old, less than 15 years old, less than 10 years old, or less than 5 years old). The subject may be diagnosed with hypertriglyceridemia. For example, the subject may be diagnosed with hypertriglyceridemia if the subject has more than 100 mg / dL, more than 150 mg / dL, or more than 200 mg / dL of triglycerides in the blood. For example, the subject may be diagnosed with hypertriglyceridemia if the subject has more than 100 mg / dL of triglycerides in the blood. For example, the subject may be diagnosed with hypertriglyceridemia if the subject has more than 150 mg / dL (1.7 millimoles / liter) of triglycerides in blood. For example, the subject may be diagnosed with hypertriglyceridemia if the subject has more than 200 mg / dL of triglycerides in blood. The subject may be diagnosed with acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) (e.g., as defined by the European Society of Cardiology). Hypertriglyceridemia can be diagnosed through blood tests (e.g., fasting triglyceride levels greater than 200 mg / dL without elevated LDL-C). In some cases, the symptoms of hypertriglyceridemia-related or related diseases can be diagnosed by angiography, cholesterol test, computed tomography (CT) scan, duplex scan, echocardiogram, electrocardiogram (ECG or EKG), exercise stress test, intravascular ultrasound, magnetic resonance imaging (MRI) scan, positron emission tomography (PET) scan, optical coherence tomography (OCT) scan, pharmacological stress test, symptoms / medical history (e.g., patient-reported symptoms), fat attenuation index (FAI), blood test, or a combination thereof. The subject may have a symptom associated with hypertriglyceridemia.The symptoms associated with hypertriglyceridemia may be chest pain (e.g., angina), shortness of breath, fatigue, confusion, muscle weakness, skin symptoms (e.g., eruptive xanthomas), eye abnormalities (e.g., lipemia retinalis), hepatosplenomegaly (e.g., enlargement of the liver and spleen), neurological symptoms, abdominal pain, or a combination thereof. The subject may be at risk for developing hypertriglyceridemia. A subject at risk for developing hypertriglyceridemia may have at least one risk factor for hypertriglyceridemia. In some embodiments, the subject may have a hypertriglyceridemia. Risk factors for triglyceridemia include, but are not limited to, being overweight or obese, high blood pressure, high cholesterol levels, diabetes, lack of physical activity, one or more comorbidities (e.g., smoking, renal disease, rheumatic disease), excessive alcohol intake, renal failure, nephrotic syndrome, genetic predisposition, lipoprotein lipase deficiency, lysosomal acid lipase deficiency, hypothyroidism, lupus, glycogen storage disease, use of propofol, HIV drugs and chemotherapy agents. The subject may have 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% stenosis. The subject may have at least 50% stenosis in an artery and / or vein. The artery may be, for example, a coronary artery, a cerebral artery, a peripheral artery, or an aorta. The subject may have one or more atherosclerotic plaques with high cholesterol and / or lipid content (e.g., as measured by optical coherence tomography (OCT)). The subject may have one or more atherosclerotic plaques with high cholesterol and / or lipid content (e.g., as measured by computed tomography (CT)). The subject may have one or more plaques with a low calcium score (measured by a vascular endothelial stenosis (VESA) scan). The subject may have stable or unstable CAD, or hypertriglyceridemia. The subject may have acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) (as defined, for example, by the European Society of Cardiology). The subject may be treated (e.g., by a method described herein) after (e.g., shortly after) having suffered a myocardial infarction. The subject may have thickening of the arterial wall (tunica media).The subject may be treated (e.g., by a method described herein) after undergoing chemotherapy (e.g., the subject may be at increased risk of or have developed hypertriglyceridemia due to the use of chemotherapeutic agents).

[0047] The methods disclosed herein can be used to treat and / or prevent hypertriglyceridemia. The methods disclosed herein can be used to treat and / or prevent atherosclerosis or cardiovascular disease caused by hypertriglyceridemia.

[0048] In some embodiments, the methods described herein reduce the size of atherosclerotic plaques (e.g., cholesterol-rich plaques and / or lipid-rich plaques) in the subject with or suspected of having hypertriglyceridemia. The plaques may have high cholesterol and / or lipid content. The cholesterol and / or lipid content may be measured, for example, by optical coherence tomography (OCT). The plaques may have low calcium content. The plaques may have a low calcium score by computed tomography (CT) scan. Optionally, the size of the atherosclerotic plaque may be reduced compared to the size of the atherosclerotic plaque prior to the treatment. In some embodiments, the size of the atherosclerotic plaque may be reduced by at least about 0.5%. In some embodiments, the size of atherosclerotic plaques may be reduced by at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or more.

[0049] In some embodiments, the methods described herein reduce and / or prevent the progression and / or onset of hypertriglyceridemia in the subject. In some embodiments, the methods described herein prevent the progression of hypertriglyceridemia. For example, the methods described herein prevent the increase in size of atherosclerotic plaque, prevent the increase in volume of plaque, prevent the increase in the amount of coronary artery surface covered by plaque, prevent the thickening of atherosclerotic plaque, prevent the increase in stenosis of arteries or veins, prevent or reduce the thickening of arterial walls, and / or prevent or reduce calcification of blood vessels. In some cases, the methods described herein mediate the regression of atherosclerotic plaques that have already developed in the subject. For example, the methods described herein reduce the size and / or number of atherosclerotic plaques that have already developed in the subject, and / or reduce the size of the necrotic core of atherosclerotic plaques.

[0050] The treatment may increase flow-mediated vasodilation (FMD) of the brachial artery. The increase in flow-mediated vasodilation (FMD) may occur at least 7 days after the treatment. Flow-mediated vasodilation (FMD) may be measured, for example, by ischemia-induced endothelium-dependent vasodilation. In some embodiments, flow-mediated vasodilation (FMD) is measured by high-resolution ultrasound. Optionally, the treatment may increase sterol and / or oxysterol levels (e.g., 27-hydroxycholesterol, 24-hydroxycholesterol) in whole blood, serum, plasma, or any combination thereof. Optionally, the treatment may dissolve cholesterol crystals present, for example, in atherosclerotic plaques. Dissolution of cholesterol crystals may be measured, for example, by cholesterol crystal dissolution assay. Optionally, the treatment may increase gene expression of genes regulated by liver X receptors (LXRs). The increase in genes regulated by LXRs may be, for example, in peripheral blood mononuclear cells (PBMCs) of the subject. The gene regulated by the LXR may be, for example, ATP-binding cassette subfamily A member 1 (ABCA1), ATP-binding cassette subfamily G member 1 (ABCG1), fatty acid synthase (FAS), apolipoprotein E (APOE), or a combination thereof. Optionally, the treatment may increase the phagocytic activity of PBMCs. Optionally, the treatment may increase or decrease lipid levels in the biological sample from the subject. The lipid may be triglyceride, LDL cholesterol, HDL cholesterol, or apolipoprotein A1 (ApoA1). The treatment may decrease the level of triglyceride in the biological sample. The treatment may decrease LDL cholesterol in the biological sample. The treatment may increase the level of HDL cholesterol in the biological sample. The treatment may increase the level of ApoAl in the biological sample.The biological sample may be blood (e.g., whole blood, serum, plasma). Optionally, the treatment may reduce serum markers of inflammation and myocardial damage and / or increase serum markers of anti-inflammation. The serum markers may be interleukin (IL)-1β (IL-1β), interleukin-1 receptor antagonist (IL-1ra), interleukin-1α (IL-1a), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), troponin, creatine kinase (CK), creatine kinase-MB (CK-MB), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP). Optionally, the treatment may reduce complement activation. Optionally, the treatment may reduce the risk of death and / or all-cause mortality (ACM) of the subject. In some embodiments, the risk of death of the subject is reduced by 25%, 50%, 75%, or 90%. In some embodiments, the subject's risk of death is reduced for at least 1 year, 2 years, or 3 years after the administration. Optionally, the treating may reduce the risk of myocardial infarction in the subject. In some embodiments, the risk of myocardial infarction in the subject is reduced by 25%, 50%, 75%, or 90%. In some embodiments, the risk of myocardial infarction in the subject is reduced for at least 1 year, 2 years, or 3 years after the administration. Optionally, the treating may reduce the risk of severe or mild stroke in the subject. In some embodiments, the risk of severe or mild stroke in the subject is reduced by 25%, 50%, 75%, or 90%. In some embodiments, the risk of severe or mild stroke in the subject is reduced for at least 1 year, 2 years, or 3 years after the administration. Optionally, the treating may reduce blood pressure in the subject. In some embodiments, the blood pressure in the subject is reduced by at least 5%, 10%, 15%, 20%, 25%, or 30%. The reduction in blood pressure may include a reduction in systolic blood pressure, diastolic blood pressure, or a combination thereof.Optionally, the treatment may reduce the risk of major adverse cardiovascular events (MACE) in the subject. In some embodiments, major adverse cardiovascular events include heart failure, reinfarction, recurrent angina pain, rehospitalization due to cardiovascular-related disease, repeat percutaneous coronary intervention (PCI), coronary artery bypass graft, coronary revascularization, stroke, all-cause mortality (ACM), or combinations thereof. In some embodiments, the risk of MACE in the subject is reduced by 25%, 50%, 75%, or 90%. In some embodiments, the risk of MACE in the subject is reduced for at least 1 year, 2 years, or 3 years after the administration. Optionally, the treatment may improve erectile dysfunction in correlation with the severity of CAD or hypertriglyceridemia.

[0051] Optionally, the treatment may result in a liver enzyme level that is less than 2.5-fold elevated relative to normal liver enzyme levels. The liver enzyme may be alanine aminotransferase (ALT), aspartate aminotransferase (AST), or a combination thereof. The liver enzyme may be alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), 5' nucleotidase, gamma-glutamyl transpeptidase (GGT), or a combination thereof. In some embodiments, the normal liver enzyme level is the level of the liver enzyme in the absence of liver damage. Optionally, the treatment may result in a serum creatinine level of less than 0.3 mg / dl. The treatment may result in a serum creatinine level of less than 1.3, 1.0, 0.75, 0.5, or 0.3 mg / dl. Optionally, the treatment may result in a substantial elimination of sensorineural hearing loss.

[0052] Pharmaceutical Compositions

[0053] Disclosed herein, in certain embodiments, is a pharmaceutical composition comprising 2-hydroxypropyl-β-cyclodextrin in an amount effective to treat hypertriglyceridemia in a human, and an excipient, which may be a pharma- ceutically acceptable excipient.

[0054] The pharmaceutical composition may comprise an amount of 2-hydroxypropyl-β-cyclodextrin effective to increase circulating and / or systemic levels of one or more oxysterols in a subject by at least about 10% (e.g., over a 24 hour period), e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more, following administration of the pharmaceutical composition.

[0055] The pharmaceutical composition may comprise an amount of 2-hydroxypropyl-β-cyclodextrin effective to increase the cholesterol crystal dissolving capacity (CCDC) of plasma by at least about 10% (e.g., at 1 hour), e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more, after administration of the pharmaceutical composition to the subject.

[0056] The pharmaceutical composition may comprise an amount of 2-hydroxypropyl-β-cyclodextrin effective to increase the mRNA level of one or more genes regulated by an LXR transcription factor (e.g., ABCA1 and / or ABCG1) by at least about 10% (e.g., at 24 hours), e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more, after administration of the pharmaceutical composition to the subject.

[0057] The pharmaceutical composition may comprise an amount of 2-hydroxypropyl-β-cyclodextrin effective to reduce serum triglyceride levels by at least about 10% (e.g., in 24 hours), e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more, after administration of the pharmaceutical composition to the subject.

[0058] The pharmaceutical composition may comprise an amount of 2-hydroxypropyl-β-cyclodextrin effective to maintain serum triglyceride levels reduced by at least about 10% (e.g., at 24 hours), e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more, for at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 7 days, or at least 2 weeks after administration of the pharmaceutical composition to the subject.

[0059] The excipient may include a tonicity adjuster, a preservative, a solubilizer, a buffer, a solution (e.g., an intravenous solution), or any combination thereof. The tonicity adjuster may be dextrose, glycerol, sodium chloride, glycerin, mannitol, or a combination thereof. The preservative may be an antioxidant, an antibacterial agent, a chelating agent, or a combination thereof. The antioxidant may be ascorbic acid, acetylcysteine, a sulfite (e.g., bisulfite, metabisulfite), monothioglycerol, or a combination thereof. The antibacterial agent may be phenol, meta-cresol, benzyl alcohol, paraben, benzalkonium chloride, chlorobutanol, thimerosal, a phenylmercuric salt (e.g., acetate, borate, nitrate), or a combination thereof. The chelating agent may be calcium disodium ethylenediaminetetraacetic acid (EDTA), disodium EDTA, sodium EDTA, calcium vertamide sodium, cartelidol, diethylenetriaminepentaacetic acid (DTPA), or a combination thereof. The solubilizing agent may be a surfactant or a co-solvent. The surfactant may be polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, polyoxyethylene-polyoxypropylene copolymer (Pluronics), or a combination thereof. The co-solvent may be propylene glycol, glycerin, ethanol, polyethylene glycol (PEG), sorbitol, dimethylacetamide, Cremophor EL, or a combination thereof. The polyethylene glycol may be PEG 300, PEG 400, PEG 600, PEG 3350, or PEG 4000.The buffer may include sodium acetate, acetic acid, glacial acetic acid, ammonium acetate, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzenesulfonic acid, sodium benzoate, benzoic acid, sodium bicarbonate, boric acid, sodium borate, sodium carbonate, citric acid, sodium citrate, disodium citrate, trisodium citrate, diethanolamine, glucono-delta-lactone, glycine, glycine HCl, histidine, histidine HCl, hydrochloric acid, hydrobromic acid, lysine, maleic acid, meglumine, methanesulfonic acid, monoethanolamine, phosphate acid, monobasic potassium, dibasic potassium, monosodium phosphate, disodium phosphate, trisodium phosphate, sodium hydroxide, sodium succinate, sulfuric acid, sodium tartrate, tartaric acid, tromethamine (Tris), or combinations thereof.

[0060] The pharmaceutical composition may comprise at least about 4 g, at least about 10 g, at least about 50 g, at least about 100 g, at least about 150 g, at least about 200 g, or at least about 250 g of 2-hydroxypropyl-β-cyclodextrin. In some embodiments, the pharmaceutical composition comprises at least about 4 g of 2-hydroxypropyl-β-cyclodextrin. In some embodiments, the pharmaceutical composition comprises at least about 50 g of 2-hydroxypropyl-β-cyclodextrin. In some embodiments, the pharmaceutical composition comprises at least about 100 g of 2-hydroxypropyl-β-cyclodextrin. In some embodiments, the pharmaceutical composition comprises at least about 200 g of 2-hydroxypropyl-β-cyclodextrin. In some embodiments, the pharmaceutical composition contains about 4 g to about 250 g of 2-hydroxypropyl-β-cyclodextrin (e.g., about 4 g to about 100 g, about 4 g to about 50 g, about 50 g to about 150 g, about 50 g to about 250 g, about 100 g to about 200 g, about 100 g to about 250 g, about 150 g to about 250 g).

[0061] The pharmaceutical composition may be formulated for single unit administration. The pharmaceutical composition may be formulated for intravenous administration. The pharmaceutical composition may be formulated to be isotonic.

[0062] kit

[0063] Further provided herein is a kit. Optionally, the kit comprises one or more containers (e.g., vials, flasks, jars, ampoules, etc.) containing one or more pharmaceutical compositions provided herein (e.g., 2-hydroxypropyl-β-cyclodextrin and a pharma- ceutically acceptable excipient). Optionally, the kit comprises a plurality of containers (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more containers). Optionally, at least one of the one or more containers is an intravenous infusion bag. The one or more containers may contain a single dose of the pharmaceutical composition, or multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of the pharmaceutical composition. Optionally, the one or more containers contain a concentrated amount of the pharmaceutical composition, which is then diluted prior to administration to obtain an effective dose. The dosage may be any amount described herein that is effective for treating one or more of the indications described herein. The kit may further comprise one or more additional components for intravenous infusion of the pharmaceutical composition. Optionally, the kit comprises an intravenous infusion bag. Optionally, the kit comprises one or more solutions (e.g., physiological saline) for mixing and / or diluting the pharmaceutical composition. Optionally, the kit comprises one or more of a catheter, a tube, a syringe, and a needle. The kit may further comprise instructions for administering the pharmaceutical composition to a subject, for example, for use in treating any of the indications described herein (e.g., for treating hypertriglyceridemia in a subject (e.g., a human individual) and / or for reducing or inhibiting the development of cholesterol-rich plaques in a subject (e.g., a human individual) suffering from or suspected of suffering from hypertriglyceridemia). The kit may be provided in a box, a bag, or any other suitable container.

[0064] In some embodiments, the kit may include one or more additional active pharmaceutical ingredients (e.g., therapeutic compounds, drugs, etc.). In some cases, the kit may include a single container that contains the pharmaceutical composition of the present disclosure (e.g., 2-hydroxypropyl-β-cyclodextrin and a pharma- ceutically acceptable excipient) and one or more additional active pharmaceutical ingredients. In other cases, the kit may include a first container that contains the pharmaceutical composition of the present disclosure (e.g., 2-hydroxypropyl-β-cyclodextrin and a pharma- ceutically acceptable excipient) and a second container that contains one or more additional active pharmaceutical ingredients. EXAMPLES

[0065] Example 1. 2-Hydroxypropyl-β-cyclodextrin (HPBCD) is a LDLR - / - Effectively reduces serum triglyceride levels in mouse models LDL receptor deficiency (LDLR - / - ) Mice were divided into six groups. Group 1 was fed a normal diet (NC) for 5 weeks, and groups 2 to 6 were fed a high-fat (42%), high-cholesterol (1.2%) Western diet (WD) for various periods up to 9 weeks before administration of 2 g / kg HPBCD. The experimental scheme and schedule are described in Figure 1A.

[0066] Mice in group 1 were further divided into three subgroups (eg, group 1.1, group 1.2, and group 1.3) according to the administration of HPBCD as shown in FIG. 1B.

[0067] After 5 weeks of feeding, blood samples were taken from the mouse models at specific times (e.g., 1 week, 2 weeks, 3 weeks, and 4 weeks after 2 g / kg HPBCD treatment) to measure triglyceride levels in each model group. Compared with NC-fed controls (group 1), whose triglyceride levels were at steady state, WD-fed mice (groups 2-6) showed elevated triglyceride levels. However, the triglyceride levels of WD-fed mice decreased over time after HPBCD administration, suggesting that HPBCD can be administered to treat hypertriglyceridemia and / or reduce or prevent symptoms of hypertriglyceridemia (Figure 2A). A similar trend in triglyceride levels was observed in NC-fed mice (Figure 2B). Triglyceride levels of NC-fed mice also decreased starting 24 hours after HPBCD administration.

[0068] Example 2. 2-Hydroxypropyl-β-cyclodextrin (HPBCD) safely and effectively reduces serum triglyceride levels in humans Twenty-nine volunteers were divided into five groups. As shown in FIG. 3A, each group was administered 50 mg / kg, 250 mg / kg, 500 mg / kg, 1000 mg / kg, or 1500 mg / kg of HPBCD intravenously. Blood samples were taken immediately before injection to establish baseline triglyceride concentrations, and 24 hours (D2) and 48 hours (D3) after injection for measurement of triglyceride levels. There was no significant increase in triglyceride levels after administration at any of the test doses, confirming the safety of HPBCD. In general, participants' triglyceride levels were reduced, which was especially evident in participants with higher baseline triglyceride concentrations.

[0069] In another study, volunteers were divided into four groups. Each group was intravenously administered placebo or 500 mg / kg, 1000 mg / kg, or 1500 mg / kg HPBCD, as shown in Figure 3B. Blood samples were taken immediately before injection and 24 hours (left bar) and 48 hours (right bar) after injection to establish baseline triglyceride concentrations. Triglyceride levels are shown as the mean median percent change from baseline. Consistent with the data shown in Figure 3A, triglyceride levels did not increase after administration at any of the doses tested.

[0070] The data in FIG. 3B was divided into two groups for further analysis. Group 1 consisted of the portion of the cohort with baseline triglyceride levels above 100 mg / dL, and Group 2 had baseline triglyceride levels below 100 mg / dL. The mean percent change in triglyceride levels from baseline for Groups 1 and 2 are shown in FIG. 3C and FIG. 3D, respectively. A greater reduction in triglyceride levels was observed in participants in Group 1 than in Group 2. This is consistent with the larger reduction in triglyceride levels (about 30%) observed in one participant in FIG. 3A with a baseline triglyceride level of about 425 mg / dL. Overall, the data demonstrate that HPBCD effectively reduces serum triglyceride levels in humans, especially those with higher baseline triglyceride levels.

[0071] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein can be employed in the practice of the present disclosure. It is intended that the appended claims define the scope of the present disclosure, and that methods and structures within the scope of these claims, and their equivalents, be covered thereby.

Claims

1. A pharmaceutical for treating hypertriglyceridemia in a subject, comprising a therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin, said pharmaceutical being administered to said subject to treat hypertriglyceridemia and / or to reduce or prevent symptoms of hypertriglyceridemia.

2. 2. The pharmaceutical composition of claim 1, wherein the hypertriglyceridemia is caused by high triglyceride levels in the subject, overeating, obesity, diabetes and / or insulin resistance, excessive alcohol consumption, renal failure, nephrotic syndrome, genetic predisposition, lipoprotein lipase deficiency, lysosomal acid lipase deficiency, hypothyroidism, lupus, glycogen storage disease, propofol, and / or HIV medication.

3. A medicament for reducing symptoms of hypertriglyceridemia or inhibiting the development of hypertriglyceridemia in a subject, comprising a therapeutically effective amount of 2-hydroxypropyl-β-cyclodextrin, wherein the medicament is administered to the subject, and the therapeutically effective amount is: (a) an amount effective to increase the circulating and / or systemic levels of one or more oxysterols in the subject by at least about 10% after said administration compared to before said administration; (b) an amount effective to increase the cholesterol crystal dissolving capacity (CCDC) of plasma by at least about 10% after said administration compared to before said administration; (c) an amount effective to increase the level of ABCA1 and / or ABCG1 by at least about 10% after said administration compared to before said administration; (d) about 50 mg / kg to about 2,000 mg / kg; (e) an amount effective to reduce the amount of serum triglycerides by at least 10% after said administration compared to before said administration; or (f) any combination thereof; thereby reducing the symptoms of hypertriglyceridemia or inhibiting the development of hypertriglyceridemia in the subject. (a) the 2-hydroxypropyl-beta-cyclodextrin maintains reduced serum triglyceride levels below at least 250 mg / dL for at least 24 hours, at least 48 hours, at least 72 hours, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after administration, and optionally the 2-hydroxypropyl-beta-cyclodextrin maintains reduced serum triglyceride levels below at least 150 mg / dL for at least 2 weeks; (b) the therapeutically effective amount is from about 2 g to about 250 g of the 2-hydroxypropyl-β-cyclodextrin; (c) the therapeutically effective amount is sufficient to achieve a serum, plasma, and / or whole blood concentration of 2-hydroxypropyl-β-cyclodextrin of about 0.6 mM to about 3 mM; (d) and / or said therapeutically effective amount is an amount effective to increase circulating and / or systemic levels of one or more oxysterols in said subject by at least about 10% after said administration compared to before said administration, and optionally: (d)(i) the circulating and / or systemic levels include serum, plasma, and / or whole blood levels; (d)(ii) the one or more oxysterols are selected from the group consisting of 27-hydroxycholesterol and 24-hydroxycholesterol; (d)(iii) said at least about 10% comprises at least about 15%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%; (d)(iv) the therapeutically effective amount is an amount effective to increase circulating and / or systemic levels of one or more oxysterols to about 40 ng / mL or greater; (d)(v) the therapeutically effective amount is an amount effective to increase circulating and / or systemic levels of one or more oxysterols to at least about 40 ng per mg of circulating and / or systemic total cholesterol; (d)(vi) the one or more oxysterols comprise 27-hydroxycholesterol, and optionally the therapeutically effective amount is an amount effective to raise circulating and / or systemic levels of 27-hydroxycholesterol to at least about 100 ng / mL, and / or the therapeutically effective amount is an amount effective to raise circulating and / or systemic levels of 27-hydroxycholesterol to at least about 90 ng per mg of circulating and / or systemic total cholesterol; and / or (d)(vii) the therapeutically effective amount is sufficient to sustain circulating and / or systemic levels of the one or more oxysterols for at least 24 hours. The pharmaceutical composition according to claim 1 or 3. (a) the therapeutically effective amount is an amount effective to increase plasma cholesterol crystal dissolving capacity (CCDC) by at least about 10% after said administration compared to before said administration; (b) the therapeutically effective amount is an amount effective to increase the level of ABCA1 and / or ABCG1 by at least about 10% after said administration compared to the level before said administration; (c) the therapeutically effective amount is an amount effective to reduce the amount of serum triglycerides by at least 10% after said administration compared to the amount before said administration; (d) the therapeutically effective amount is from about 50 mg / kg to about 2,000 mg / kg, and optionally: (d)(i) the therapeutically effective amount is at least about 100 mg / kg; (d)(ii) the therapeutically effective amount is at least about 250 mg / kg; (d)(iii) the therapeutically effective amount is at least about 500 mg / kg; (d)(iv) the therapeutically effective amount is at least about 1,000 mg / kg; (d)(v) the therapeutically effective amount is at least about 1,500 mg / kg; (d)(vi) the therapeutically effective amount is from about 500 mg / kg to about 1,500 mg / kg; or (d)(vii) the therapeutically effective amount is from about 800 mg / kg to about 1,200 mg / kg; and / or (e) the subject is a human individual; The pharmaceutical composition according to claim 1 or 3.

6. The method of claim 1, wherein the administering comprises: (i) administering to said subject at a first time point a first therapeutically effective dose of 2-hydroxypropyl-β-cyclodextrin; (ii) and, at a second time point, administering to the subject a second therapeutically effective dose of 2-hydroxypropyl-β-cyclodextrin, optionally further comprising: (a) the second time point is at least one week after the first time point; (b) the second time point is at least two weeks after the first time point; and / or (c) The pharmaceutical composition of claim 1 or 3, wherein the second time point is at least one month after the first time point.

7. (a) the 2-hydroxypropyl-β-cyclodextrin reduces or prevents the progression and / or onset of hypertriglyceridemia in the subject; (b) said 2-hydroxypropyl-β-cyclodextrin mediates a reduction in high serum triglyceride levels in said subject; (c) The 2-hydroxypropyl-β-cyclodextrin is selected from the group consisting of: i) liver enzyme (e.g., ALT, AST) levels less than 2.5 times normal; ii) a serum creatinine level of less than 0.3 mg / dl; or iii) Virtually no sensorineural hearing loss; and / or (d) the administering is by intravenous administration; The pharmaceutical composition according to claim 1 or 3.

8. A pharmaceutical composition comprising an amount of 2-hydroxypropyl-β-cyclodextrin effective to treat hypertriglyceridemia in a subject, and a pharmaceutically acceptable excipient.

9. A pharmaceutical composition comprising about 4 g to about 250 g of 2-hydroxypropyl-β-cyclodextrin and a pharmaceutically acceptable excipient.

10. (a) the amount of 2-hydroxypropyl-β-cyclodextrin is effective to increase circulating and / or systemic levels of one or more oxysterols in the subject by at least about 10% after administration of the pharmaceutical composition to the subject; (b) the amount of 2-hydroxypropyl-β-cyclodextrin is effective to increase the cholesterol crystal dissolving capacity (CCDC) of plasma by at least about 10% after administration of the pharmaceutical composition to the subject; (c) the amount of 2-hydroxypropyl-β-cyclodextrin is effective to increase the level of ABCA1 and / or ABCG1 by at least about 10% after administering the pharmaceutical composition to the subject; (d) the amount of 2-hydroxypropyl-β-cyclodextrin is effective to reduce serum triglyceride levels by at least 10% after administering the pharmaceutical composition to the subject; (e) the amount of 2-hydroxypropyl-β-cyclodextrin is effective to maintain a reduced serum triglyceride level below at least 250 mg / dL for at least 24 hours, at least 48 hours, at least 72 hours, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after administration of the pharmaceutical composition to the subject; and / or (f) the amount of 2-hydroxypropyl-β-cyclodextrin is effective to maintain a reduced serum triglyceride level below at least 150 mg / dL for at least two weeks after administering the pharmaceutical composition to the subject. The pharmaceutical composition according to claim 8 or 9.

11. A pharmaceutical composition according to claim 8 or 9, formulated for single dose administration and / or intravenous administration.

12. (a) one or more containers; and (b) a pharmaceutical composition according to claim 8 or 9, wherein the pharmaceutical composition is contained in the one or more containers.

13. The kit described in claim 12, further comprising instructions for use of the pharmaceutical composition for treating hypertriglyceridemia in a subject and / or reducing or inhibiting the onset of hypertriglyceridemia or its symptoms in a subject.

14. (a) at least one of the one or more containers is an intravenous infusion bag; (b) the one or more containers comprise a single container containing the pharmaceutical composition and one or more additional active pharmaceutical ingredients; and / or (c) The kit of claim 12, wherein the one or more containers comprise a first container containing the pharmaceutical composition and a second container containing one or more additional active pharmaceutical ingredients.

15. 13. The kit of claim 12, further comprising one or more additional components selected from the group consisting of an intravenous infusion bag, a catheter, a tubing, a needle, a syringe, a solution, and any combination thereof.

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