Methods for treating heparin-induced thrombocytopenia

Abstract

Provided herein are methods for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof comprising administering to the subject by intravenous infusion a dose of about 50 mg to about 600 mg of Compound 1 having the structure: (1), or a pharmaceutically acceptable salt thereof. The dosing regimen can include administering Compound 1 or a pharmaceutically acceptable salt thereof over about 30 minutes to about 2 hours, e.g., every 12 hours, with the treatment period ranging from 1 day to 30 days.

Description

METHODS FOR TREATING HEPARIN-INDUCED THROMBOCYTOPENIACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of and priority to U.S. Provisional Application No. 63 / 570,574, filed March 27, 2024, which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates to methods for treating heparin-induced thrombocytopenia (HIT) by administering to a subject by intravenous infusion over about 30 minutes to about 2 hours a dose of about 50 mg to about 600 mg of Compound 1 or a pharmaceutically acceptable salt thereof.BACKGROUND

[0003] Compound 1 is a highly potent and selective 12-lipoxygenase (12-LOX) inhibitor having the following structural formula:

[0004] Compound 1 is under development to address a clinical need for a safe, more effective therapy for heparin-induced thrombocytopenia (HIT). It was discovered that Compound 1 blocks the 12-LOX pathway that is believed to be responsible for platelet activation in HIT. In animal models of HIT, Compound 1 can prevent or treat HIT and halt the development of both thrombocytopenia and abnormal blood clots. Advantageously, Compound 1 has not been associated with increased bleeding in either animals or healthy human volunteers.

[0005] In view of its potential to address serious medical needs across of variety of indications, including HIT, Compound 1 is being evaluated in clinical trials.SUMMARY

[0006] In some aspects, the present disclosure relates to methods for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering to the subject a compound having the structurepharmaceutically acceptable salt thereof, wherein the compound is administered to the subject at a dose of about 200 mg. In some embodiments, the compound is administered by intravenous infusion. In some embodiments, the compound is administered by intravenous infusion over about 30 minutes to about 2 hours. In some embodiments, the compound is administered by intravenous infusion over about 1 hour.

[0007] In other aspects, the present disclosure provides methods for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering to the subject a compound having the structurepharmaceutically acceptable salt thereof, wherein the compound is administered to the subject by intravenous infusion over about 30 minutes to about 2 hours at a dose in the range of about 50 mg to about 600 mg. In some embodiments, the dose of the compound is in the range of about 100 mg to about 300 mg. In some embodiments, the dose of the compound is about 200 mg. In some embodiments, the intravenous infusion is performed over about 1 hour.

[0008] In embodiments of the present methods, the compound is administered twice a day. In some embodiments, the compound is administered every 12 hours. In some embodiments, the compound is administered every 9 to 15 hours.

[0009] Accordingly, in further aspects, the present disclosure provides methods for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering to the subject by intravenous infusion over a period of about 1 hour about 200 mg a compound having the structurepharmaceutically acceptable salt thereof, wherein the compound is administered to the subject every 12 hours. In some embodiments, Compound1 or a pharmaceutically acceptable salt thereof is administered over a treatment period that is between 7 days and 14 days.

[0010] In some embodiments, the methods disclosed herein further comprise administering to the subject another pharmaceutically active agent. In some embodiments, the subject undergoes therapy with another pharmaceutically active agent. In some embodiments, the therapy is standard of care anticoagulation. In some embodiments, the other pharmaceutically active agent is a thrombin inhibitor, e.g., a direct thrombin inhibitor (DTI). In some embodiments, the other pharmaceutically active agent is an anticoagulant. In some embodiments, the other pharmaceutically active agent is argatroban or bivalirudin.

[0011] In some embodiments, the methods disclosed herein comprise a treatment period that is between 1 day and 30 days. In some embodiments, the treatment period is up to 14 days. In some embodiments, the treatment period of the method is between 1 day and 14 days. In some embodiments, the treatment period of the method is between 1 day and 7 days. In some embodiments, the treatment period of the method is between 7 day and 14 days.

[0012] In some embodiments, the methods disclosed herein are repeated until the subject’s platelet count is 150,000 / pL or greater. In some embodiments, the method is repeated until the subject’s platelet count is 150,000 / pL or greater for 2 consecutive days.

[0013] In some embodiments, the subject has a positive serotonin release assay (SRA+). In some embodiments, the subject is 18 years old or older.

[0014] In some embodiments, the HIT is suspected HIT. In some embodiments, the HIT is an acute HIT.DETAILED DESCRIPTIONOverview

[0015] The present disclosure relates generally to the demonstration that Compound 1 or a pharmaceutically acceptable salt thereof of administered to a subject in need at a dose of from about 200 mg to 600 mg is useful for treating heparin-induced thrombocytopenia (HIT).Definitions

[0016] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that acomplex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0017] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied (+) or (-) by increments of 1.0 or 0.1, as appropriate, or alternatively by a variation of + / - 15 %, or alternatively 10%, or alternatively 5%, or alternatively 2%. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”. It is to be understood that such range format is used for convenience and brevity and should be understood flexibly to include numerical values explicitly specified as limits of a range, but also to include all individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly specified. For example, a ratio in the range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0018] Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0019] The term “a” or “an” refers to one or more of that entity, i.e., can refer to plural referents. As such, the terms “a,” “an,” “one or more,” and “at least one” are used interchangeably herein. In addition, reference to “an element” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there is one and only one of the elements.

[0020] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device or the method being employed to determine the value, or the variation that exists among the samples being measured. Unless otherwise stated or otherwise evident from the context, the term “about” means within 10% above or below the reported numerical value (except where such number would exceed 100% of a possible value or go below 0%). When used in conjunction with a range or series of values, the term “about” applies to the endpoints of the range or each of the values enumerated in the series, unlessotherwise indicated. As used in this application, the terms “about” and “approximately” are used as equivalents.

[0021] As used herein, the term “treating” refers to acting upon a disease, disorder, or condition with an agent to reduce or ameliorate harmful or any other undesired effects of the disease, disorder, condition and / or their symptoms.

[0022] As used herein, the term “preventing” refers to reducing the incidence or risk of developing, or delaying the development of, harmful or any other undesired effects of the disease, disorder, condition and / or symptoms

[0023] “Administration,” “administering” and the like, refer to administration to a subject by a medical professional or by self-administration by the subject, as well as to indirect administration, which may be the act of prescribing a composition of the invention. Typically, an effective amount is administered, which amount can be determined by one of skill in the art. Any method of administration may be used. Administration to a subject can be achieved by, for example, oral administration, in liquid or solid form, e.g., in capsule or tablet form; intravascular injection; intramyocardial delivery; or other suitable forms of administration.

[0024] As used herein, the term “effective amount” or “therapeutically effective amount” refers broadly to an amount of a compound disclosed herein, that is effective for preventing, ameliorating, treating or delaying the onset of a disease or condition. The expression “prophylactically effective amount” refers to an amount of a compound disclosed herein, that is effective for inhibiting the onset or progression of a disorder. An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period which the individual dosage unit is to be used, the bioavailability of the composition, the route of administration, etc. It is understood, however, that specific amounts of the compositions for any particular subject depends upon a variety of factors including the activity of the specific agent employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the composition combination, severity of the particular disease being treated and form of administration.

[0025] As used herein, the terms “subject” or “patient”, which can be used interchangeably, refer to a human subject or human patient. Specific examples of “subjects” and “patients” include, but are not limited to, individuals with heparin-induced thrombocytopenia.

[0026] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0027] The term “pharmaceutically acceptable salt” includes that which is obtained by reacting the active compound, i.e., Compound 1, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of Compound 1 with the appropriate inorganic or organic acid via any of a number of known methods.

[0028] As used herein, the term “restores” refers to increasing the level of biochemical or physiological parameter to a level observed in the subject prior to development of disease or condition, or to the level observed in a subject not having the disease or condition.

[0029] As used herein, the term “reduces” refers to decreasing the level of biochemical or physiological parameter.

[0030] The detailed description of the disclosure is divided into various sections only for the reader’s convenience and disclosure found in any section may be combined with that in another section. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.Compound 1

[0031] Compound l is a highly potent and specific small molecule inhibitor of 12-LOX having the structural formula:The synthesis and evaluation of Compound 1 as a potent and selective inhibitor of 12-LOX is provided in U.S. Patent Nos. 10,266,488, 10,752,581, and 11,274,077, which are incorporated herein by reference in their entirety. Preclinical studies, including the evaluation of Compound 1 in various in vitro assays, cellbased systems, and an animal pharmacokinetic model, have demonstrated that Compound 1 is effective in treating a variety of diseases and disorders associated with 12-LOX activity or responsive to 12-LOX inhibition, such as heparin-induced thrombocytopenia (HIT).Methods of Treatment

[0032] In some aspects, the present disclosure provides methods for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering to the subject a compound having the structureor a pharmaceutically acceptable salt thereof, wherein the compound is administered to the subject at a dose in the range of about 50 mg to about 1000 mg, e.g., about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg, including all ranges and values therebetween. In some embodiments of the present methods, about 200 mg to about 600 mg of Compound 1, e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg or about 1000 mg, is administered to the subject. In some embodiments of the present methods, about 200 mg to about 600 mg of Compound 1, e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg, is administered to the subject. In some embodiments, about 200 mg of Compound 1 is administered to the subject. In some embodiments, about 300 mg of Compound 1 is administered to the subject. In some embodiments, about 400 mg of Compound 1 is administered to the subject. In someembodiments, about 500 mg of Compound 1 is administered to the subject. In some embodiments, about 600 mg of Compound 1 is administered to the subject.

[0033] In some aspects, the present disclosure provides methods for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering to the subject a compound having the structureor a pharmaceutically acceptable salt thereof, wherein the compound is administered to the subject at a dose of about 200 mg.

[0034] In some aspects, the present disclosure provides methods for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering by intravenous infusion to the subject over a period of about 30 minutes to about 2 hours a compound having the structureor a pharmaceutically acceptable salt thereof, wherein the compound is administered to the subject at a dose in the range of about 50 mg to about 1000 mg, e.g., about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg, including all ranges and values therebetween.. In some embodiments, the compound or composition is administered over a period of about 1 hour to about 2 hours. In some embodiments, the compound is administered over a period of about 1 hour. In some embodiments, the compound is administered over period of about 1.5 hours. In some embodiments, the compound is administered over period of about 2 hours. In some embodiments of the present methods, about 200 mg to about 600 mg of Compound 1, e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg, is administered to the subject. In some embodiments, about 200 mg of Compound 1 is administered to the subject. In some embodiments, about 300 mg of Compound 1 is administered to the subject. In some embodiments, about 400 mg of Compound 1 is administered to the subject. In some embodiments, about 500 mg of Compound1 is administered to the subject. In some embodiments, about 600 mg of Compound 1 is administered to the subject.

[0035] In other aspects, the present disclosure provides methods for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering by intravenous infusion to the subject over a period of about 30 minutes to about 2 hours a compound having the structureor a pharmaceutically acceptable salt thereof, wherein the compound is administered to the subject at a dose of about 200 mg. In some embodiments, the compound is administered over a period of about 1 hour to about 2 hours. In some embodiments, the compound is administered over period of about 1 hour. In some embodiments, the compound is administered over period of about 1.5 hours. In some embodiments, the compound is administered over period of about 2 hours.

[0036] In further aspects, the methods for treating HIT disclosed herein comprise administering by intravenous infusion to a subject in need thereof a pharmaceutical composition comprising 50 mg to 1000 mg of Compound 1, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the composition comprises about 100 mg, about 150 mg, about, 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg, including all ranges and values therebetween, of Compound 1 or a pharmaceutically acceptable salt thereof. In a specific embodiment, the composition comprises about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is administered over a period of about 30 minutes to about 2 hours. In some embodiments, the composition is administered over a period of about 1 hour to about 2 hours. In some embodiments, the composition is administered over period of about 1 hour. In some embodiments, the composition is administered over period of about 1.5 hours. In some embodiments, the composition is administered over period of about 2 hours.

[0037] In some embodiments, the HIT is suspected HIT. In other embodiments, the HIT is an acute HIT.

[0038] A serotonin release assay, which detects platelet activating antibodies, can be used to diagnose a subject with HIT, e.g., HIT type II, which is considered a medical complication that requires treatment. In some embodiments, a subject in need of treatment for HIT has a positive serotonin release assay (SRA+). In some embodiments, a subject in need of treatment for HIT is determined by their 4T test score (thrombocytopenia, timing of platelet count fall, thrombosis or other sequelae, and other causes of thrombocytopenia). Scores of 1-3, 4-5, and 6-8 are considered to correspond to a low, intermediate, and high probability of HIT, respectively. In some embodiments, a subject in need of treatment for HIT is determined by a heparin-PF4 immunoassay.Administration and Treatment Period

[0039] In some embodiments, Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered to the subject by intravenous infusion. In some embodiments, Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered by intravenous infusion over about 1 to 12 hours, about 1 to 6 hours, or about 1 to 4 hours. In some embodiments, Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered by intravenous infusion over about 30 minutes to about 2 hours, e.g., about 30 minutes about 45 minutes, about 1 hour, about 1.5 hours, or about 2 hours. In some embodiments, Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered by intravenous infusion over about 1 hour. The time period for infusion can be adjusted within the specified ranges or values, e.g., for safety and or efficacy reasons. In other embodiments of the present methods, Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered to the subject by a bolus injection.

[0040] In some embodiments, Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is continuously infused over a time period disclosed herein. For example, about 400 mg of Compound a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be continuously infused over about 4 hours. In some embodiments, about 200 mg of Compound a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is continuously infused over about 1 hour.

[0041] In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered every 3 hours to 24 hours. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof is administered every 3 hours. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered every 6 hours. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered every 12 hours. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered every 18 hours. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered every 24 hours. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered every 12 hours ± 3 hours, e.g., every 9 to 15 hours, including every 9 hours, every 12 hours, or every 15 hours. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered once daily. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered twice daily. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered three times daily. In some embodiments, a dose of Compound 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered four times daily.

[0042] The methods for treating HIT disclosed herein can comprise any treatment period suitable for treating HIT in a subject in need thereof. In some embodiments, the treatment period is from 1 day to 30 days. In some embodiments, the treatment period is up to 7 days, up to 14 days, or up to 21 days. In some embodiments, the treatment period is up to 14 days. In some embodiments, the treatment period is between 1 day and 21 days. In some embodiments, the treatment period is between 1 day and 14 days. In some embodiments, the treatment period is between 1 day and 7 days. In some embodiments, the treatment period is between 7 days and 21 days. In some embodiments, the treatment period is between 7 days and 14 days. In some embodiments, the treatment period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.Other Active Agents

[0043] The methods disclosed herein can further comprise administering to the subject another pharmaceutically active agent. In some embodiments the other pharmaceutically active agent is a thrombin inhibitor including, but not limited to, argatroban, fondaparinux, bivalirudin, danaparoid and drotrecogin alfa. In some embodiments, the other pharmaceutically active agentis argatroban, bivalirudin, or fondaparinux. In some embodiments, the other pharmaceutically active agent is argatroban or bivalirudin. In some embodiments, the other pharmaceutically active agent is argatroban. In other embodiments, the other pharmaceutically active agent is bivalirudin. In further embodiments, the other pharmaceutically active agent is fondaparinux. In some embodiments, the other pharmaceutically active agent is an anticoagulant. In some embodiments, the anticoagulant is apixaban, betrixaban, dabigatran, rivaroxaban, or edoxaban. In some embodiments, the other pharmaceutically active agent is standard of care anti coagulation therapy.

[0044] In embodiments of the present methods, the other pharmaceutically active agent is administered concurrently with, prior to, or after administering Compound 1 or a pharmaceutically acceptable salt thereof.Outcomes and Clinical Endpoints

[0045] In some embodiments, the methods for treating HIT disclosed herein are repeated until the subject’s platelet count is 150,000 / pL or greater. In other embodiments, the method is repeated until the subject’s platelet count is 150,000 / pL or greater for 2-7 consecutive days. In specific embodiments, the method is repeated until the subject’s platelet count is 150, 000 / pL or greater for 2 consecutive days.Pharmaceutical Compositions and Formulations

[0046] Parenterally administered aqueous pharmaceutical compositions and formulations suitable for the disclosed methods of treating HIT are described in WO2023 / 122472, which is incorporated herein by reference in its entirety.

[0047] In some embodiments, the pharmaceutical compositions disclosed herein comprise a 2- hydroxyalkylated P-cyclodextrin including, but not limited to, 2-hydroxypropyl -P-cyclodextrin (HP-P-CD), 2-hydroxyethyl-P-cyclodextrin (HE-P-CD) and 2-hydroxybutyl-P-cyclodextrin (HB-P-CD). In some embodiments, the aqueous pharmaceutical compositions comprise HP-P- CD.

[0048] The pharmaceutically acceptable 2-hydroxyalkylated P-cyclodextrin, such as HP-P- CD, may be present in any suitable amount within the aqueous parenteral pharmaceutical compositions described herein. The pharmaceutically acceptable 2-hydroxyalkylated P- cyclodextrin such as HP-P-CD may be present in amount of between about 5% and 50% w / v. For example, the pharmaceutically acceptable solubilizer, optionally HP-P-CD, may be in an amount of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, or about 50% w / v. In specific embodiments, the HP-P-CD may be present in amount from about 10% to about 40%, from about 20% to about 40%, from about 30% to about 40%, from about 10% to about 30%, or from about 10% to about 20% of the total composition. In one embodiment, the 2-hydroxyalkylated P-cyclodextrin, optionally, HP-P-CD may present in amount of about 25% of the total composition w / v.

[0049] The 2-hydroxyalkylated P-cyclodextrin, optionally, HP-P-CD, may be present in the aqueous parenteral pharmaceutical composition in amount of at least 100 mg / mL, at least 150 mg / mL, at least 200 mg / mL, at least 225 mg / mL, at least 250 mg / mL, at least 275 mg / mL, at least 280 mg / mL, or at least 300 mg / mL. The HP-P-CD may be present in the pharmaceutical composition in amount from about 100 mg / mL to about 300 mg / mL, from about 200 mg / mL to about 300 mg / mL, from about 220 mg / mL to about 260 mg / mL, from about 200 mg / mL to about 275 mg / mL, or from about 210 mg / mL to about 255 mg / mL of the total composition.

[0050] HE-P-CD may be present in any suitable amount within the aqueous parenteral pharmaceutical compositions described herein. In some embodiments, HE-P-CD is present in amount of between about 5% and 50% w / v. For example, the pharmaceutically acceptable solubilizer, optionally HE-P-CD, may be in an amount of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% w / v. In specific embodiments, the HE-P-CD may be present in amount from about 10% to about 40%, from about 20% to about 40%, from about 30% to about 40%, from about 10% to about 30%, or from about 10% to about 20% of the total composition. In one embodiment, the 2- hydroxyalkylated P-cyclodextrin, optionally, HE-P-CD may present in amount of about 25% of the total composition w / v.

[0051] HE-P-CD may be present in the aqueous parenteral pharmaceutical composition in amount of at least 100 mg / mL, at least 150 mg / mL, at least 200 mg / mL, at least 225 mg / mL, at least 250 mg / mL, at least 275 mg / mL, at least 280 mg / mL, or at least 300 mg / mL. In some embodiments, the HE-P-CD is present in the pharmaceutical composition in amount from about 100 mg / mL to about 300 mg / mL, from about 200 mg / mL to about 300 mg / mL, from about 220 mg / mL to about 260 mg / mL, from about 200 mg / mL to about 275 mg / mL, or from about 210 mg / mL to about 255 mg / mL of the total composition.

[0052] HB-P-CD may be present in any suitable amount within the aqueous parenteral pharmaceutical compositions described herein. In some embodiments, HB-P-CD is present in amount of between about 5% and 50% w / v. For example, the pharmaceutically acceptablesolubilizer, optionally HB-P-CD, may be in an amount of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% w / v. In specific embodiments, the HB-P-CD may be present in amount from about 10% to about 40%, from about 20% to about 40%, from about 30% to about 40%, from about 10% to about 30%, or from about 10% to about 20% of the total composition. In one embodiment, the 2- hydroxyalkylated P-cyclodextrin, optionally, HB-P-CD may present in amount of about 25% of the total composition w / v.

[0053] HB-P-CD may be present in the aqueous parenteral pharmaceutical composition in amount of at least 100 mg / mL, at least 150 mg / mL, at least 200 mg / mL, at least 225 mg / mL, at least 250 mg / mL, at least 275 mg / mL, at least 280 mg / mL, or at least 300 mg / mL. In some embodiments, the HB-P-CD is present in the pharmaceutical composition in amount from about 100 mg / mL to about 300 mg / mL, from about 200 mg / mL to about 300 mg / mL, from about 220 mg / mL to about 260 mg / mL, from about 200 mg / mL to about 275 mg / mL, or from about 210 mg / mL to about 255 mg / mL of the total composition.

[0054] The aqueous parenteral pharmaceutical compositions described herein may comprise Compound 1 or a pharmaceutically acceptable salt thereof in an amount between about 1.0 mg / mL and 20 mg / mL, 2-hydroxyalkylated P-cyclodextrin, optionally, HP-P-CD, in an amount between about 1% and 30% w / v, a base (e.g., sodium hydroxide) and / or an acid (e.g., HC1). For example, the aqueous parenteral pharmaceutical compositions described herein may comprise Compound 1 or a pharmaceutically acceptable salt thereof in an amount between about 1.5 and 20 mg / mL and 2-hydroxyalkylated P-cyclodextrin, optionally, HP-P-CD, sodium hydroxide, and hydrochloric acid. The pharmaceutical compositions described herein may comprise Compound 1 or a pharmaceutically acceptable salt thereof in an amount of 15 mg / mL 2-hydroxyalkylated P-cyclodextrin, optionally, HP-P-CD, sodium hydroxide, and hydrochloric acid.

[0055] The pH of the aqueous parenteral pharmaceutical compositions described herein may be between about pH 6.0 and pH 10.0. The pH of the pharmaceutical compositions described herein may be at about pH 6.0, about pH 6.1, about pH 6.2, about pH 6.3, about pH 6.4, about pH 6.5, about pH 6.6, about pH 6.7, about pH 6.8, about pH 6.9, about pH 7.0, about pH 7.1, about pH 7.2, about pH 7.3, about pH 7.4, about pH 7.5, about pH 7.6, about pH 7.7, about pH 7.8, about pH 7.9, about pH 8.0, about pH 8.1, about pH 8.2, about pH 8.3, about pH 8.4, about pH 8.5, about pH 8.6, about pH 8.7, about pH 8.8, about pH 8.9, about pH 9.0, about pH 9.1, about pH 9.2, about pH 9.3, about pH 9.4, about pH 9.5, about pH 9.6, about pH 9.7, about pH9.8, about pH 9.9, or about pH 10.0. In a preferred embodiment, the pH of the aqueous parenteral pharmaceutical compositions described herein may be between about pH 7.4 and about pH 9.0. In an embodiment, the pH of the aqueous parenteral pharmaceutical compositions described herein may be at about pH 8.0, about pH 8.1, about pH 8.2, about pH 8.3, about pH 8.4, about pH 8.5, about pH 8.6, about pH 8.7, about pH 8.8, about pH 8.9, or about pH 9.0. The pH of the pharmaceutical compositions described herein may be at about pH 8.4, about pH 8.5, about pH 8.6, or about pH 8.7. In another preferred embodiment, the pH of the aqueous parenteral pharmaceutical compositions described herein may be between a pH of about 8.4 and about 8.7.

[0056] The solubility of Compound 1 or a pharmaceutically acceptable salt thereof in the aqueous parenteral pharmaceutical composition may increase with increasing pH. In one embodiment, the aqueous pharmaceutical composition comprises 20 mg / mL of Compound 1 or a pharmaceutically acceptable salt thereof at about pH 8.0. In another embodiment, the aqueous parenteral pharmaceutical composition comprises 40 mg / mL of Compound 1 or a pharmaceutically acceptable salt thereof at about pH 9.5. pH can be adjusted to provide a composition comprising a desired dose.

[0057] In one embodiment, the aqueous parenteral pharmaceutical compositions described herein comprise Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable solubilizer, namely HP-P-CD.

[0058] In another embodiment, the pharmaceutically acceptable solubilizer is 2-hydroxyethyl- P-cyclodextrin (HE-P-CD) or 2-hydroxybutyl-P-cyclodextrin (HB-P-CD). In a specific embodiment, the pharmaceutically acceptable solubilizer is 2-hydroxypropyl-P-cyclodextrin (HP-P-CD).

[0059] The aqueous parenteral pharmaceutical compositions disclosed herein may further comprise other acceptable liquid carriers in an amount that does not alter the aqueous nature of the formulation, including, vegetable oils such as peanut oil, cotton seed oil, sesame oil, as well as organic solvents, PEG, propylene glycol, glycerol, and surfactants.

[0060] In one embodiment, the aqueous parenteral pharmaceutical compositions comprise at least 50% water, preferably 70% or more of water.

[0061] The compounds described herein may be present in any suitable amount within the aqueous parenteral pharmaceutical compositions described herein. Those of skill in the art can readily determine suitable concentrations of compound to include in the aqueous parenteralpharmaceutical compositions depending on various factors including dosage and route of administration. The aqueous parenteral pharmaceutical compositions useful in the present invention can contain a quantity of a compound described herein in an amount effective to treat or prevent the condition, disorder or disease of the subject being treated.

[0062] Compound 1 or a pharmaceutically acceptable salt thereof may be present in the aqueous parenteral pharmaceutical composition in an amount of at least 0.1 mg / mL, at least 0.5 mg / mL, at least 1 mg / mL, at least 1.5 mg / mL, at least 2 mg / mL, at least 5 mg / mL, at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 23 mg / mL, at least 25 mg / mL, at least 26 mg / mL, at least 28 mg / mL, or at least 30 mg / mL.

[0063] Compound 1 or a pharmaceutically acceptable salt thereof may be present in the aqueous parenteral pharmaceutical composition in an amount from about 0.1 mg / mL to about 50 mg / mL, from about 0.5 mg / mL to about 100 mg / mL, from about 1 mg / mL to about 100 mg / mL, from about 15 mg / mL to about 60 mg / mL, from about 20 mg / mL to about 40 mg / mL, from about 50 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 50 mg / mL, from about 15 mg / mL to about 30 mg / mL, from about 25 mg / mL to about 75 mg / mL, or from about 50 mg / mL to about 100 mg / mL.

[0064] Compound 1 or a pharmaceutically acceptable salt thereof may be present in the aqueous parenteral pharmaceutical composition in an amount from about 0.1 mg / mL to about 50 mg / mL, from about 0.1 mg / mL to about 25 mg / mL, from about 0.1 mg / mL to about 20 mg / mL, from about 0.1 mg / mL to about 15 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, from about 0.1 mg / mL to about 3 mg / mL, from about 0.1 mg / mL to about 2 mg / mL, from about 0.1 mg / mL to about 1.5 mg / mL, or from about 0.1 mg / mL to about 1 mg / mL. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in amount from about 1 mg / mL to about 20 mg / mL or from about 1.5 mg / mL to about 30 mg / mL.

[0065] Compound 1 or a pharmaceutically acceptable salt thereof may be present in the aqueous parenteral pharmaceutical composition in an amount of about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 50 mg / mL or about 100 mg / mL. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is present in the aqueous parenteral pharmaceutical composition in an amount of about 15 mg / mL. Dilution of an aqueous parenteral pharmaceutical compositiondisclosed herein up to 5X or up to 10X can be carried out with IV fluids or a hydroxyalkyl -P- cyclodextrin (e.g., HP-P-CD). In some embodiments, the IV fluid is saline (e.g., 0.9% NaCl), dextrose in water (e.g., D5W), Ringer’s solution, or lactated Ringer’s solution with or without dextrose. In some embodiments, the IV fluid is saline. In some embodiments, the IV fluid is 0.9% NaCl saline solution. In some embodiments, an aqueous parenteral pharmaceutical composition comprising 15 mg / mL of Compound 1 or a pharmaceutically acceptable salt thereof is diluted 1 :5 (5X) to obtain a composition comprising 3 mg / mL of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, an aqueous parenteral pharmaceutical composition comprising 15 mg / mL of Compound 1 or a pharmaceutically acceptable salt thereof is diluted 1 : 10 (10X) to obtain a composition comprising 1.5 mg / mL of Compound 1 or a pharmaceutically acceptable salt thereof.

[0066] In addition to Compound 1 or a pharmaceutically acceptable salt thereof, the aqueous parenteral pharmaceutical compositions disclosed herein may further comprise at least one of any suitable auxiliaries including, but not limited to, diluents, crystal inhibitors, tonicifiers, water structure forming agents or disruptors, polymers, ion pairing agents, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants or the like. Pharmaceutically acceptable auxiliaries are preferred. Examples and methods of preparing such sterile solutions are well known in the art and can be found in well-known texts such as, but not limited to, REMINGTON’S PHARMACEUTICAL SCIENCES (Adejare, Ed., 23rd Edition, Academic Press. (2020); Handbook of Pharmaceutical Excipients, 9thEdition, Pharmaceutical Press (2020)). Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and / or stability of the compound.

[0067] Pharmaceutical excipients and additives useful in the aqueous parenteral pharmaceutical compositions described herein can also include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination in ranges of 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, and casein. Representative amino acid components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, and aspartame.

[0068] Carbohydrate excipients suitable for use in the aqueous parenteral pharmaceutical compositions described herein include but are not limited to monosaccharides such as dextrose, fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides, such as lactose, sucrose, trehalose, and cellobiose; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, and starches; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), and myoinositol.

[0069] The pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof can also a pH adjusting agent. The pH adjusting agent may be a base, optionally sodium hydroxide.

[0070] The present disclosure provides stable aqueous parenteral pharmaceutical compositions as well as preserved solutions and compositions containing a preservative, as well as multi-use preserved compositions suitable for pharmaceutical or veterinary use, comprising at least one compound disclosed herein in a pharmaceutically acceptable composition. Pharmaceutical compositions in accordance with the present disclosure may optionally comprise at least one known preservative. Preservatives include, but are not limited to, phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl paraben (methyl, ethyl, propyl, butyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent. Any suitable concentration or mixture can be used as known in the art, such as 0.001-5%, or any range or value therein. Non-limiting examples include, no preservative, 0.1-2% m-cresol, 0.1-3% benzyl alcohol, 0.001-0.5% thimerosal, 0.001-2.0% phenol, 0.0005-1.0% alkyl paraben(s).

[0071] Other excipients, e.g., isotonicity agents, buffers, antioxidants, preservative enhancers, can be optionally added. When used, the amount of tonicity modifier used most often ranges from 0.1 to 1% (w / v). Non-limiting examples of suitable tonicity modifiers include sodium chloride, glycerin, boric acid, calcium chloride, dextrose, and potassium chloride. The compositions can include a local anesthetic to reduce the potential of pain during injection. A physiologically tolerated buffer can be added to provide improved pH control if necessary. The pharmaceutical compositions can cover a wide pH range, such as from about pH 4 to about pH 10, specifically, a range from about pH 5 to about pH 9, and more specifically, a range of about 7.0 to about 9.0. In one aspect, the compositions described herein have a pH between about 8.4 and about 8.7.

[0072] Aqueous pharmaceutical compositions suitable for parenteral administration include aqueous sterile injection solutions which may comprise anti-oxidants, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient. The compositions may be presented in unit-dose or multi-dose containers, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, e.g., water for injections, saline, dextrose in water (D5W), lactated Ringer’s solution, immediately prior to use. Extemporaneous inj ection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0073] For parenteral administration, sterile solutions and suspensions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous, administration is desired. The aqueous pharmaceutical compositions may be administered parenterally via injection of a pharmaceutical composition comprising a compound dissolved in an inert liquid carrier, such as sterile water or other pharmaceutically acceptable diluents. The term “parenteral,” as used herein, includes, but is not limited to, subcutaneous injections, intravenous, intramuscular, intraperitoneal injections, or infusion techniques, including bolus.

[0074] Methods of preparing aqueous pharmaceutical compositions with a certain amount of active ingredients are known, or will be apparent in light of this disclosure, to those skilled in the art. Methods of preparing said pharmaceutical compositions can incorporate other suitable pharmaceutical excipients and their compositions as described in REMINGTON’S PHARMACEUTICAL SCIENCES, above.

[0075] WO2023 / 122472, which is incorporated herein by reference in its entirety, provides methods of preparing the parenterally administered aqueous pharmaceutical compositions disclosed herein.

[0076] In some embodiments, the cyclodextrin is dissolved in water while being subjected to a first pH adjustment with a base to bring the pH up to about 9.5 to about 12.5 to enhance dissolution of the compound. This is followed by addition of the compound. Once the compound is completely in solution, the pH is brought down to a physiological range with acid to the physiological pH of e.g., between about 8.4-8.7.

[0077] The combination of Compound 1 and 2-hydroxypropyl-P-cyclodextrin (HP-P-CD) in a high pH, e.g., between about 8.4 and about 8.7, resulted in increased solubility of the compounds. Related 2-hydroxyalkyl-P-cyclodextrins such as HE-P-CD and HB-P-CD may also be useful.

[0078] In some embodiments, the cyclodextrin is dissolved in water along with a base to bring the pH up to about 9.5 to about 12.5, followed by addition of the compound. Once the compound is completely in solution, the pH is lowered to a physiological range with an acid to a pH of e.g., between about 8.4 to about 8.7. In a specific embodiment, HP-P-CD, or a related 2-hydroxyalkyl-P-cyclodextrin, or combinations thereof, is dissolved in water with agitation, e.g., vigorous stirring, until a clear solution is obtained. Dilute sodium hydroxide is then slowly added to the e.g., HP-P-CD solution while continuously stirring. The resulting basic pH of between about 9.5 to about 12.5 facilitates the dissolution of the compounds described herein. A compound described above, e.g, Compound 1 or pharmaceutically acceptable salt thereof is then slowly added to the cyclodextrin under vigorous stirring. Stirring is continued for e.g., an additional 10 min followed by 10 min of sonication. Alternate stirring and sonication cycles are repeated at least three (3) times until the active ingredient is dissolved. For example, 3 cycles of 10 minutes of stirring and 10 minutes of sonication. Under continuous stirring, dilute hydrochloric acid is slowly added to a target pH range of about 8.4 to about 8.7. Water may be added to achieve the target concentration of the compound per mL, e.g., 30 mg / mL, 15 mg / mL, or 1.5 mg / mL. The solution may be filtered through a0.45 pm and / or a 0.22 pm filter and stored at 2-8°C. Prior to administration, the solution is sterile filtered under aseptic processing into syringes, vials, or ampules of appropriate size. In one embodiment, dissolution is performed at room temperature, i.e., about 20-25 °C or lower.

[0079] In some embodiments, the present disclosure provides a vial comprising about 200 mg of Compound in about 13.3 mL of water at pH 8.4-8.7. In some embodiments, the vial further comprises about 3.33 g of HP-P-CD.

[0080] In some embodiments, the present disclosure provides a vial comprising about 219 mg of Compound 1 and about 3.65 g of HP-P-CD in about 14.6 mL of water at pH 8.4-8.7.

[0081] In some embodiments, the present disclosure provides a single-dose vial comprising Compound 1 and HP-P-CD in water at pH 8.4-8.7, wherein Compound 1 is present at a concentration of about 15 mg / mL.

[0082] Although embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.Further, to the extent not already indicated, it will be understood by those of ordinary skill in the art that any one of the various embodiments herein described and illustrated can be further modified to incorporate features shown in any of the other embodiments disclosed herein.Example 1: Evaluation of Compound 1 in Patients with Suspected Heparin-Induced Thrombocytopenia

[0083] Background: Over 12 million patients are treated with heparin each year in the United States. Heparin induced thrombocytopenia (HIT) is a recognized complication of heparin therapy and is characterized by the formation of antibodies to heparin and platelet factor 4 (PF4). The scale of the clinical problem is illustrated by cardiopulmonary bypass patients, half of whom develop antibodies to PF4 / heparin complexes. In a significant proportion of such seropositive HIT patients, these antibodies will bind to and activate platelets, resulting in a drop in the number of platelets (thrombocytopenia) and activation of the coagulation (clotting) system. Formation of clots in this manner can lead to stroke, heart attacks, damage to internal organs or to limbs, and even death.

[0084] The current standard of care with anticoagulants such as argatroban or bivalirudin have not proven effective in reducing poor outcomes in HIT : major morbidity and death rates remain high (> 20%). In addition, these anticoagulants increase the risk of major bleeding (-20%), which can prove to be a fatal complication of such therapy.

[0085] Compound 1 has been developed to address the major unmet clinical need for safer, more effective therapy for HIT. Compound 1 is a drug that blocks the 12-lipoxygenase (12- LOX) pathway that is believed to be responsible for platelet activation in HIT. In animal models of HIT, Compound 1 can prevent or treat HIT and halt the development of both thrombocytopenia and abnormal blood clots. The drug has not been associated with increased bleeding in either animals or healthy human volunteers.

[0086] Study Overview: The purpose of this study is to evaluate the efficacy and safety of Compound 1, a 12-lipoxygenase (12-LOX) enzyme inhibitor in treating heparin-induced thrombocytopenia (HIT). Participants with suspected HIT will receive the usual standard of care and will be assigned randomly to either Compound 1 or placebo treatment. The study will measure important outcomes including platelet count, stroke, pulmonary embolus (clot to the lungs) and bleeding.

[0087] The study will enroll patients suspected of having HIT by clinical measures (4T score) and by laboratory testing (heparin-PF4 immunoassay). Patients will be randomly assigned in adouble-blind fashion to receive either Compound 1 intravenously or placebo. All patients will receive current guideline mandated therapy for HIT that will include the standard of care anti coagulation - either argatroban or bivalirudin. Patients will be treated for 7 to 14 days until the platelet count has recovered into the normal range. The study will measure important outcomes including platelet count recovery time, stroke, pulmonary embolus, deep vein thrombosis, myocardial infarction, limb and organ injury, and major bleeding.

[0088] Study Drug, Dosage, and Mode of Administration - Compound 1 injection (15 mg / mL) is a sterile solution intended for IV infusion. Compound 1 will be administered as twice-daily (Q12H) IV infusion in doses of 200 mg / 13.33 mL. Sample dilution is permitted at the discretion of each center, up to 5X with normal saline (e.g., 0.9% NaCl).

[0089] Study Design: Compound 1 will be administered twice-daily by IV infusion in doses of 200 mg every 12 hours ± 3 hours + standard-of-care (SoC) (argatroban or bivalirudin).

[0090] Specifically, participants randomized to the active treatment group will receive Compound 1 injection 200 mg / 13.33 mL (15 mg / mL), twice daily Q12H from the Day 1 dose time with a + / - 3-hour window. Compound 1 injection is a sterile solution for IV infusion, supplied in single-dose vials. Each vial of Compound 1 injection will be administered via IV infusion into a peripheral line, a central catheter, or a peripherally inserted catheter (PICC line) over 60 minutes. Infusion will take place at steady rate using, e.g., a syringe pump or IV pump.

[0091] Placebo will be administered twice-daily by IV infusion + SoC (argatroban or bivalirudin). The placebo includes inactive ingredients to match the content and tonicity of the active product. The placebo product is a sterile solution for IV infusion supplied in single-dose vials. Each vial of placebo will be administered via IV infusion over 60 minutes.

[0092] Primary Objective: To evaluate the effects of Compound 1 compared to placebo on platelet count recovery, a clinical outcome in patients with a positive serotonin release assay confirmed HIT, on a background of SoC anti coagulation. Time to recovery of pl telet count to > 150 X 10y / L in patients with a positive serotonin release assay (up to 14 days). In the presentstudy, time to platelet count recovery is defined as the time from the first dose of Compound 1 to the time of the first of 2 consecutive platelet count recoveries to > 150 X 109 / L in patients with positive serotonin release assay (SRA+) confirmed HIT.

[0093] Primary Endpoint Analysis: The time to event will be analyzed for the modified Intent-to-Treat (mITT) Analysis Set using Kaplan-Meier analysis, with a stratified log-rank test including the randomization stratification factors. Participants who have not reached the targeted platelet recovery level before discontinuing the study will be censored at the time of their last platelet result. The number and proportion of participants with an event, the median and corresponding 95% confidence interval (CI), and quartiles from the survival analysis will be presented.

[0094] Secondary Objectives:(1) to evaluate the efficacy of Compound 1• composite of death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, skin necrosis, limb gangrene, organ ischemia or infarction;• incidence of death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, organ ischemia or infarction;• time from the first dose of Compound 1 to change to oral anti-coagulant treatment;• time from Compound 1 initiation to each element of the composite as a separate endpoint: death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, organ ischemia or infarction;• proportion of participants with any element of the composite as a separate endpoint: death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis or pulmonary embolism, organ ischemia or infarction;• time from study drug initiation to occurrence of any incidence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding; and• proportion of participants with incidence of major bleeding as defined by ISTH criteria.(2) to evaluate the time to onset of any incidence of major bleeding following treatment with Compound 1 - time from study drug initiation to occurrence of any incidence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding;(3) to evaluate the incidence of major bleeding following treatment with Compound 1 - proportion of participants with incidence of major bleeding as defined by ISTH criteria;(4) to evaluate the pharmacokinetics (PK) of Compound 1 - PK sampling (10 samples) will be performed to inform a population PK model as further described in the PK analysis plan.

[0095] Secondary Endpoint Analysis: Secondary endpoint analyses will be performed on both efficacy and safety endpoints. The analysis of efficacy endpoints will be performed using the mITT population. Safety will be assessed by collection and review of AEs, laboratory parameters, physical examination, vital signs, and ECG parameters throughout the duration of the study. Unless otherwise noted, the Safety Analysis Set will be used for the safety analyses.

[0096] Exploratory Objective: to evaluate pharmacodynamic (PD) biomarkers of 12- hydroxy eicosatetraenoic acid (12-HETE), thrombin generation (prothrombin fragment 1+2[F1.2], thrombin-antithrombin complete [TAT]), fibrin formation (fibrin d-dimer [d- dimer]).• Change from baseline to Day 7 of 12-HETE levels;• Change from baseline to study drug discontinuation of 12-HETE levels;• Change from baseline to Day 7 of d-dimer levels;• Change from baseline to study drug discontinuation of d-dimer levels;• Change from baseline to Day 7 of TAT levels;• Change from baseline to study drug discontinuation of TAT levels;• Change from baseline to Day 7 of fibrin split levels;• Change from baseline to study drug discontinuation of fibrin split levels;• Change from baseline to Day 7 of Fl.2 levels;• Change from baseline to study drug discontinuation of Fl.2 levels;

[0097] Exploratory samples will be collected daily, in the morning, for research purposes.

[0098] Methodology / Patient Eligibility

[0099] Participants who have had recent unfractionated heparin or low-molecular-weight heparin exposure and who have suspected heparin induced thrombocytopenia (HIT) based on clinically obtained laboratory results are eligible for this study. After confirming a 4T score > 4 and a positive PF4 immunoassay (e.g., enzyme-linked immunosorbent assay [ELISA], line immunoassay [LIA], or chemiluminescence immunoassay [CLIA]), a participant may be consented to this study. A confirmatory SRA test will also be performed, but participants will be randomized once the test is drawn; they will not await the test results.

[0100] Following screening and baseline assessments, participants will be required to receive background SoC for HIT (argatroban or bivalirudin) and will be stratified by qualifying platelet count (QPC; the last platelet count obtained prior to randomization) (> 75,000 X 109 / L or < 75,000 X 109 / L) and randomized 1 : 1 to either Compound 1 + SoC or placebo + SoC. Treatment with study drug (Compound 1 or placebo) will commence for a minimum of 7 days, with blood drawn for platelets twice daily (BID). If 2 consecutive tests yield platelet counts > 150 x 109 / L after Day 7, treatment with study drug can be stopped. Participants whose platelet counts remain < 150 x 109 / L will continue receiving study drug until 2 consecutive tests yield platelet counts > 150 x 109 / L up to a maximum treatment period of 14 days. The primary endpoint of the study is the time to platelet count recovery, defined as the time from the first dose of study drug to the time of the first of 2 consecutive platelet count recoveries to > 150 X 109 / L. All participants will be followed for a 30-day safety follow-up period. Participants should have SoC managed in accordance with guideline mandated therapy.

[0101] Enrollment Plan- It is the intention to enroll and randomize up to 60 participants until there are at least 4 SRA-positive participants in each of the 4 strata. Participants will be stratified by QPC (> 75,000 X 109 / L or < 75,000 X 109 / L) and randomized to either Compound 1 + SoC or placebo + SoC.• Compound 1 + SoC; QPC (> 75,000 X I 09 / L)• Placebo + SoC; QPC (> 75,000 X 109 / L)• Compound 1 + SoC; QPC (< 75,000 X 109 / L)• Placebo + SoC; QPC (< 75,000 X 109 / L)

[0102] An unblinded statistician will monitor treatment / strata under the supervision of the Data Monitoring Committee (DMC) to determine when enrollment is complete.

[0103] Main Inclusion Criteria - Participants who have had recent unfractionated heparin or low molecular-weight heparin exposure and who have suspected HIT based on clinically obtained laboratory results are eligible for this study. After confirming a 4T score > 4 and a positive PF4-immunoassay (e.g., ELISA, LIA, CLIA), a participant may be consented to this study.

[0104] Treatment Duration - Up to 14 days; participants will be treated with study drug for a minimum of 7 days; platelet counts will be evaluated BID. If two consecutive tests yield platelet counts >150 X 109 / L after 7 days of dosing, treatment with study drug can be stopped.

[0105] Criteria for Evaluation

[0106] Serotonin release assay for confirmation of HIT status by sponsor’s specialty laboratory SRA.

[0107] Efficacy:• platelet count - platelet count will be evaluated Q12H. If 2 consecutive tests yield platelet counts > 150 X 109 / L, treatment with study drug can be stopped after 7 days of treatment. If after 7 days of treatment, the platelet count remains < 150 x 109 / L, Compound 1 administration may be continued for up to a maximum of 14 days of treatment• clinical thrombotic or thromboembolic events: death, amputation, new thrombosis, stroke, systemic embolism, myocardial infarction, deep vein thrombosis, pulmonary embolism, skin necrosis, limb gangrene, organ ischemia or infarction• thrombosis identified on ultrasound• PD biomarkers - 12-HETE level; prothrombin fragment 1+2 (Fl.2); thrombin-antithrombin complex (TAT); fibrin split products; fibrin d-dimer (d-dimer).

[0108] Safety:• major bleeding (as defined by ISTH)• all bleeding• adverse events (other than bleeding)• clinical laboratory test abnormalities (hematology, chemistry, cardiac enzymes)• vital signs• physical examination• 12-lead electrocardiogram (ECG)

[0109] An ultrasound of extremities will be performed to evaluate for blood clots.

[0110] Pharmacokinetics[OHl] Plasma sample concentrations of Compound 1 will be determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. These data will be evaluated by population PK methods.

[0112] Previous PK studies with Compound 1 indicated that after IV administration of single doses from 10 mg to 600 mg over 1 hour and 600 mg over 4 hours, there were dose-related increases in geometric mean plasma concentrations. Geometric mean values for Cmax and AUC(O-24) also increased with dose and AUC(o-24) vs. dose was reasonably dose proportional over the 60-fold range of doses. After IV administration of 100 mg, 200 mg, and 400 mg over 1 hour and 400 mg over 4 hours once-daily for 5 days, there were dose-related increases ingeometric mean plasma concentrations. Geometric mean values for Cmax and AUC(o-24) increased with dose in a linear but slightly less than dose proportional manner. There was little to no change in Cmax and AUC(o-24) from Day 1 to Day 5 indicating minimal accumulation of Compound 1. The median time to maximum concentration (Tmax) was concordant with the infusion times of 1 hour and 4 hours. The geometric mean values for clearance (CL), apparent volume of distribution (Vz), and half-life (U) were consistent among the single IV doses and multiple dose IV treatments and across study days.Example 2: Exemplary Intravenous Formulation of Compound 1 and Preparation Thereof

[0113] Compound 1 Solution (15 mg / mL) for IV infusion

[0114] 61.25-63.75 g of hydroxypropyl- 3 -cyclodextrin (HP- 3 -CD) is dissolved in 125 mL of sterile water with continuous stirring. Mixing is continued until a clear solution is obtained.

[0115] Dilute (e.g., 0.5 N) sodium hydroxide at a target 1.6: 1 NaOH:Compound 1 molar ratio is slowly added to the HP-P-CD solution while continuously stirring. The resulting basic pH of about 9.5 to 12 facilitates the dissolution of the active ingredient (Compound 1).

[0116] The active ingredient (e.g., 3.675 to 3.825 g) Compound 1) is slowly added under vigorous stirring. Stirring is continued for an additional 10 min followed by 10 min of sonication. Alternate stirring and sonication cycles are repeated at least three (3) times until the active ingredient is dissolved.

[0117] Under continuous stirring, dilute hydrochloric acid (0.2 N) is slowly added to a target pH range of 8.4 to 8.7 if necessary.

[0118] Water is added to achieve the target concentration of 15 mg of Compound 1 per mL.

[0119] The solution is filtered through a 0.22 pm filter and stored at 2-8°C. Prior to administration, the solution is sterile filtered under aseptic processing into syringes of appropriate size.

[0120] The resulting Compound 1 Solution (15 mg / mL) can be used as-is or further diluted with HP-P-CD solution for IV administration. For example, the Compound 1 Solution (15 mg / mL) can be diluted 1 : 10 to obtain a 1.5 mg / mL Compound 1 IV formulation or 1 :5 to obtain a 3 mg / mL Compound 1 IV formulation.

[0121] Additionally, a Compound 1 solution as described herein can alternatively been made with other molar ratios of dilute NaOH:Compound 1.EXAMPLE 3: EXEMPLARY FORMULATION OF COMPOUND 1 WITH NaOHTITRATION

[0122] Compound 1 Solution (15 mg / mL) for IV infusion

[0123] 2.5 g of hydroxypropyl-P-cyclodextrin (HP-P-CD) is dissolved in 20 mL of sterile water with continuous stirring. Mixing is continued until a clear solution is obtained.

[0124] Dilute (e.g., 0.5 N) sodium hydroxide at a target 1.6: 1 NaOH: Compound 1 molar ratio is added in two portions; one to the HP-P-CD solution while continuously stirring and a second portion after API addition. The first portion added to the HP-P-CD solution before addition of the active ingredient is 1.9 mL.

[0125] The active ingredient (e.g., 746.25 to 753.75 mg Compound 1) is then slowly added under vigorous stirring. Stirring is continued is continued until API is wetted and dispersed. The second portion of NaOH (about 3.1 mL) is added until the pH is increased sufficiently to attain complete API dissolution.

[0126] Under continuous stirring, dilute hydrochloric acid (0.2 N) is slowly added to a target pH range of 8.4 to 8.7.

[0127] Water is added to achieve the target concentration of 15 mg of Compound 1 per mL.

[0128] The solution is filtered through a 0.22 pm filter and stored at 2-8°C.EXAMPLE 4: EXEMPLARY FORMULATION OF COMPOUND 1 WITHOUT SONICATION

[0129] Compound 1 Solution (15 mg / mL) for IV infusion

[0130] 750 g of hydroxypropyl-P-cyclodextrin (HP-P-CD) is dissolved in 1200 mL of sterile water with continuous stirring. Mixing is continued until a clear solution is obtained.

[0131] Dilute (e.g., 0.5 N) sodium hydroxide at a target 1.6: 1 NaOH:Compound 1 molar ratio is slowly added to the HP-P-CD solution while continuously stirring. The resulting basic pH of about 9.5 to 12 facilitates the dissolution of the active ingredient (Compound 1).

[0132] The active ingredient (e.g., 45.0 g) Compound 1) is slowly added under vigorous stirring. Stirring is continued without sonication for up to one hour until API is dissolved.

[0133] Under continuous stirring, dilute hydrochloric acid (0.2 N) is slowly added to a target pH range of 8.4 to 8.7.

[0134] Water is added to achieve the target concentration of 15 mg of Compound 1 per mL. The total solution volume is 3 liters.

[0135] The solution is filtered through a 0.22 pm filter and stored at 2-8°C.EXAMPLE 5: EXEMPLARY FORMULATION OF COMPOUND 1 WITH LOWER SODIUM HYDROXIDE RATIO

[0136] Compound 1 Solution (15 mg / mL) for IV infusion

[0137] 62.5 g of hydroxypropyl-P-cyclodextrin (HP-P-CD) is dissolved in 125 mL of sterile water with continuous stirring. Mixing is continued until a clear solution is obtained.

[0138] 21.2 mL of dilute (e.g., 0.5 N) sodium hydroxide is slowly added to the HP-P-CD solution while continuously stirring. The resulting basic pH of about 9 to 11 facilitates the dissolution of the active ingredient (Compound 1).

[0139] The active ingredient (e.g., 3.675 to 3.825 g) Compound 1) is slowly added under vigorous stirring. Stirring is continued for an additional 10 min followed by 10 min of sonication. Alternate stirring and sonication cycles are repeated at least three (3) times until the active ingredient is dissolved.

[0140] Under continuous stirring, 27.3 mL of dilute hydrochloric acid (0.2 N) is slowly added resulting in a pH of 6.5-8. Additional NaOH (about 6 mL) is added to attain the target pH range of 8.4 to 8.7.

[0141] Water is added to achieve the target concentration of 15 mg of Compound 1 per mL.

[0142] The solution is filtered through a 0.22 pm filter and stored at 2-8°C.INCORPORATION BY REFERENCE

[0143] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

What is claimed is:

1. A method for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering to the subject a compound having the structurepharmaceutically acceptable salt thereof, wherein the compound is administered to the subject at a dose of about 200 mg.

2. The method of claim 1, wherein the compound is administered every 12 hours.

3. The method of claim 1 or 2, wherein the compound is administered by intravenous infusion.

4. The method of claim 3, wherein the compound is administered by intravenous infusion over about 30 minutes to about 2 hours.

5. The method of claim 3, wherein the compound is administered by intravenous infusion over about 1 hour.

6. The method of any one of claims 1-5, further comprising administering to the subject another pharmaceutically active agent.

7. The method of any one of claims 1-5, wherein the subject undergoes a therapy with another pharmaceutically active agent.

8. The method of claim 6 or 7, wherein the other pharmaceutically active agent is a thrombin inhibitor.

9. The method of claim 6 or 7, wherein the other pharmaceutically active agent is an anticoagulant.

10. The method of any one of claims 6-9, wherein the other pharmaceutically active agent is argatroban, bivalirudin, or fondaparinux.

11. The method of claim 7, wherein the therapy is standard of care anti coagulation.

12. The method of any one of claims 1-11, wherein a treatment period of the method is between 1 day and 30 days.

13. The method of any one of claims 1-11, wherein a treatment period of the method is between 1 day and 7 days or between 1 day and 14 days.

14. The method of any one of claims 1-11, wherein a treatment period of the method is between 7 day and 14 days.

15. The method of any one of claims 1-14, wherein the method is repeated until the subject’s platelet count is 150,000 / pL or greater.

16. The method of any one of claims 1-14, wherein the method is repeated until the subject’s platelet count is 150,000 / pL or greater for 2 consecutive days.

17. The method of any one of claims 1-16, wherein the subject has a positive serotonin release assay (SRA+) prior to treatment.

18. The method of any one of claims 1-17, wherein the HIT is suspected HIT.

19. The method of any one of claims 1-18, wherein the HIT is an acute HIT.

20. A method for treating heparin-induced thrombocytopenia (HIT) in a subject in need thereof, comprising administering to the subject a compound having the structurepharmaceutically acceptable salt thereof, wherein the compound is administered to the subject by intravenous infusion over about 30 minutes to about 2 hours at a dose in the range of about 50 mg to about 600 mg.

21. The method of claim 20, wherein the dose of the compound is in the range of about 100 mg to about 300 mg.

22. The method of claim 20, wherein the dose of the compound is about 200 mg.

23. The method of any one of claims 21-22, wherein the intravenous infusion is performed over about 1 hour.

24. The method of any one of claims 20-23, wherein the compound is administered twice a day.

25. The method of any one of claims 20-23, wherein the compound is administered every 12 hours.

26. The method of any one of claims 20-25, further comprising administering to the subject another pharmaceutically active agent.

27. The method of any one of claims 20-25, wherein the subject undergoes a therapy with another pharmaceutically active agent.

28. The method of claim 26 or 27, wherein the other pharmaceutically active agent is a thrombin inhibitor.

29. The method of claim 26 or 27, wherein the other pharmaceutically active agent is an anticoagulant.

30. The method of any one of claims 26-29, wherein the other pharmaceutically active agent is argatroban, bivalirudin, or fondaparinux.

31. The method of claim 27, wherein the therapy is standard of care anti coagulation.

32. The method of any one of claims 20-31, wherein a treatment period of the method is between 1 day and 30 days.

33. The method of any one of claims 20-31, wherein a treatment period of the method is between 1 day and 7 days or between 1 day and 14 days.

34. The method of any one of claims 20-31, wherein a treatment period of the method is between 7 day and 14 days.

35. The method of any one of claims 20-34, wherein the method is repeated until the subject’s platelet count is 150,000 / pL or greater.

36. The method of any one of claims 20-34, wherein the method is repeated until the subject’s platelet count is 150,000 / pL or greater for 2 consecutive days.

37. The method of any one of claims 20-36, wherein the subject has a positive serotonin release assay (SRA+) prior to treatment.

38. The method of any one of claims 20-37, wherein the HIT is suspected HIT.

39. The method of any one of claims 20-38, wherein the HIT is an acute HIT.

Images