GB2620543A

GB2620543A - Composition for use

Info

Publication number: GB2620543A
Application number: GB2206659.1A
Authority: GB
Inventors: Climax John; Hamza Moayed
Original assignee: Afimmune Ltd
Current assignee: Afimmune Ltd
Priority date: 2022-05-06
Filing date: 2022-05-06
Publication date: 2024-01-17

Abstract

A method of treating and/or preventing a hematologic disorder comprising administering eicosapentaenoic acid (EPA), or a derivative or metabolite thereof, or a composition comprising EPA, or a derivative or a metabolite thereof, to a subject. A method of treating and/or preventing a hemoglobin disorder, a red blood cell disorder, hemolytic anemia, thrombophilia or a venous thromboembolism are included. The haematologic disorder may be nutritional or non-nutritional anaemia, blood cancers such as lymphoma, leukaemia or myeloma, or coagulation defects such as thrombophilia, hemophilia, Von Wilebrand disease or thrombocytopenia. The haemoglobin or red blood cell disorder may be inherited or acquired haemolytic anaemia, Fanconi anaemia, iron deficiency anaemia, folate deficiency, B12 deficiency or myelodysplastic syndrome. The EPA metabolite may be 5-HEPE, 8-HEPE, 9-HEPE, 11-HEPE, 12-HEPE, 18-HEPE, 20-HEPE, RvE1, RvE2, RvE3 or 18S-RvE1 and is preferably not 15-hydroxyeicosapentaenoic acid (15-HEPE) and. The derivative may be a salt, conjugate or ester, preferably methyl or ethyl ester. The composition may be at least 50% EPA or may comprise up to 2 g of EPA. The EPA may be at least 90% of the fatty acids in the composition. The composition may be administered orally as 1-8 capsules per day and may provide 5-500 mg/Kg EPA.

Description

USE OF COMPOSITIONS COMPRISING EPA FOR TREATING OR PREVENTING

HEMATOLOGIC DISORDERS AND DISEASES

TECHNICAL FIELD

The present application relates generally to use of compositions comprising eicosapentaenoic acid (EPA) for treating hematologic disorders.

BACKGROUND

[0001] Hematologic disorders include red blood cell disorders and thrombophilia.

Red blood cell disorders are a class of conditions that affect the production, life-span, and shape of red blood cells (RBCs) and its oxygen transport molecule, hemoglobin. These conditions inhibit the transport of oxygen from the lungs to the rest of the body. Thrombophilia is a class of disorders that increase a subject's risk of developing blood clots in veins and arteries. These clots can break loose from the blood vessel and travel through the blood stream to an organ thereby preventing blood flow to that organ resulting in ischemia. These conditions lead to an increased risk of stroke and/or pulmonary embolism.

SUMMARY

[0002] The application relates to use of compositions comprising eicosapentaenoic acid (EPA), a derivative of EPA, and/or a metabolite of EPA, in the treatment of a variety of hematologic diseases and disorders.

[0003] In some aspects, the present disclosure provides methods of treating and/or preventing a hematologic disorder in a subject in need thereof, the methods comprising administering to the subject eicosapentaenoic acid (EPA), a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.

[0004] In some aspects, the present disclosure provides methods of treating and/or preventing a hemoglobin disorder in a subject in need thereof, the methods comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.

[0005] In some aspects, the present disclosure provides methods of treating and/or preventing a red blood cell disorder in a subject in need thereof, the methods comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.

[0006] In some aspects, the present disclosure provides methods of treating and/or preventing hemolytic anemia in a subject in need thereof, the methods comprising administering to the subject up to about 8g of a composition comprising EPA, a derivative of EPA, and/or a metabolite of EPA.

[0007] In some embodiments, the hematologic disorder is selected from the group consisting of anemia, blood cancer, and a coagulation defect. In some embodiments, the anemia is a nutritional anemia, a non-nutritional anemia, or a combination thereof. In some embodiments, the blood cancer is selected from the group consisting of lymphoma, leukemia, and myeloma. In some embodiments, the coagulation defect is selected from the group consisting of thrombophilia, hemophilia, Von Willebrand disease, and thrombocytopenia.

[0008] In some embodiments, the hemoglobin disorder and/or the red blood cell disorder is selected from the group consisting of inherited hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folate deficiency, B12 deficiency, and myelodysplastic syndrome. In some embodiments, the inherited hemolytic anemia is selected from the group consisting of sickle cell disease, sickle cell anemia, B-thalassemia, and hereditary spherocytosis. In some embodiments, the acquired hemolytic anemia is acquired from a disorder or condition selected from the group consisting of a condition secondary to a primary infection, a medication, a hematological malignancy, an autoimmune disease, hypersplenism, positioning of a mechanical heart valve, and a blood transfusion. In some embodiments, the sickle cell disease and sickle cell anemia are associated with sickle cell crisis, a vaso-occlusive crisis, and/or splenic sequestration.

[0009] In some aspects, the present disclosure provides methods of treating and/or preventing a thrombophilia disorder in a subject in need thereof, the methods comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.

[0010] In some aspects, the present disclosure provides methods of treating and/or preventing thrombophilia in a subject in need thereof, the methods comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.

[0011] In some aspects, the present disclosure provides methods of treating and/or preventing a venous thromboembolism in a subject in need thereof, the methods comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.

[0012] In some embodiments, the metabolite of EPA is not 15-hydroxyeicosapentaenoic acid (15-HE PE).

[0013] In some embodiments, the derivative of EPA is in esterified form, conjugate form, or salt form. In some embodiments, the derivative of EPA is EPA methyl ester, EPA ethyl ester, or both. In some embodiments, the derivative of EPA is EPA ethyl ester.

[0014] In some embodiments, the metabolite of EPA is at least one selected from the group consisting of 5-HEPE, 5(S)-HERE, 8-HEPE, 8(S)-HERE, 9-HEPE, 9(5)-HEPE, 11-HERE, 11(R)-HERE, 11(S)-HERE, 12-HERE, 12(R)-HERE, 12(S)-HERE, 18-HERE, 20-HERE, RvE1, RvE2, RvE3, and 18S-RvE1.

[0015] In some embodiments, EPA, the derivative of EPA, and/or the metabolite of EPA are present in an amount of greater than 50 wt% based on a total weight of the composition. In some embodiment, EPA is present in an amount of greater than 50 wt% based on a total weight of the composition.

[0016] In some embodiments, a total weight of the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition. In some embodiments, the EPA represent at least about 90% by weight, of all fatty acids in the composition.

[0017] In some embodiments, a composition useful in methods described herein comprises up to about 2 g of EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the composition comprises up to about 2 g of EPA.

[0018] In some embodiments, a composition useful in methods described herein comprises at least 2 g of EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the composition comprises at least 2 g of EPA.

[0019] In some embodiments of the methods described herein, the composition is administered in 1 to 8 capsules per day.

[0020] In some embodiments of the methods described herein, the composition is formulated to provide about 5 mg of EPA per kg of bodyweight (mg/kg), about 50 mg/kg, about 250 mg/kg, or about 500 mg/kg to the subject.

[0021] In some embodiments of the methods described herein, the EPA, the derivative of EPA, and/or the metabolite of EPA or the composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA is orally administered.

[0022] In various embodiments, the hematologic disorder is selected from the group consisting of inherited hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folate deficiency, B12 deficiency, and myelodysplastic syndrome.

DETAILED DESCRIPTION

[0023] While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any manner. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0024] The use of numerical values in the various quantitative values specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word "about." In this manner, slight variations from a stated value can be used to achieve substantially the same results as the stated value. Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited, as well as any ranges that can be formed by such values Also disclosed herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a recited numeric value into any other recited numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values presented herein; and, in all instances, such ratios, ranges, and ranges of ratios represent various embodiments of the present invention.

[0025] Unless otherwise defined, 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 disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety. In cases of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

Definitions [0026] As used herein, eicosapentaenoic acid (or EPA, 20:5n-3) refers to eicosa- 5,8,11,14,17-pentaenoic acid in its free acid form, which is an omega-3 fatty acid with a C20 chain.

[0027] As used herein, "derivative of EPA" refers to a chemically or biologically modified version of a chemical compound that is structurally similar to EPA and derivable from EPA. Non-limiting examples of derivative of EPA include esters of EPA, conjugates of EPA, and salts of EPA. In some embodiments, pharmaceutically acceptable esters or salts of EPA are used in the disclosure. In some embodiments, the EPA is in the form of a C1-4 alkyl ester such as methyl ester, ethyl ester, or a combination of methyl ester and ethyl ester. In yet another embodiment, the EPA is in a form of a glyceride (e.g., diglyceride or triglyceride). In another embodiment, the EPA is in the form of an ethyl ester (also referred to herein as ethyl EPA).

[0028] As used herein, "metabolite of EPA" refers to an intermediate or end product of a metabolic reaction (e.g., hydrolysis, oxidation) of EPA. Non-limiting examples of metabolite of EPA include EPA-based resolvins such as RvE1 (53,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA), RvE2 (5S,18R-dihydroxy- 6E,8Z, 1 1Z,1 4Z,1 6E-EPA), RvE3 (1 7R,18R/S-dihydroxy-5Z,8Z,1 1 Z,1 3E,1 5E-EPA), and 1 8S-RvE1 (58,12R,1 8S-trihydroxy-6Z.8E, 1 0E,1 4Z,16E-EPA).

[0029] As used herein, "treating" or "treatment" of a disease, disorder, or condition includes at least partially: (1) inhibiting the disease, disorder, or condition, i.e., arresting or reducing the development of the disease, disorder, or condition or its clinical symptoms; or (2) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, or condition or its clinical symptoms. The term "prevention" in relation to a given disease or disorder means: preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.

[0030] An "effective amount," as used herein, refers to the amount of an active composition that is required to confer a therapeutic effect on the subject. A "therapeutically effective amount," as used herein, refers to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease, disorder, or condition 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 alteration of a biological system. For example, in some embodiments, an "effective amount" for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. In some embodiments, an appropriate "effective amount" in any individual case is determined using techniques, such as a dose escalation study. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. In other embodiments, an "effective amount" of a compound disclosed herein, such as a compound of Formula (A) or Formula (I), is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. In other embodiments, it is understood that "an effect amount" or "a therapeutically effective amount" varies from subject to subject, due to variation in metabolism, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. The term "pharmaceutically acceptable" in the present context means that the substance in question does not produce unacceptable toxicity to the subject or interaction with other components of the composition.

[0031] Other features and advantages of the disclosure will be apparent from the

following detailed description.

[0032] Exemplary metabolites of EPA include, but are not limited to, 5-HERE ((±)- 5-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid), 5(S)-HEPE (55-hydroxy- 6E, 8Z,11Z,14Z,17Z-eicosapentaenoic acid), 8-HERE ((±)-8-hydroxy- 5Z, 9E,11Z,14Z,17Z-eicosapentaenoic acid), 8(S)-HEPE (8S-hydroxy- 57, 9E,117,147,17Z-eicosapentaenoic acid), 9-HERE ((±)-9-hydroxy- 5Z, 7E,11Z,14Z,17Z-eicosapentaenoic 5Z, 7E,11Z,14Z,17Z-eicosapentaenoic 5Z, 8Z, 12E,14Z,17Z-eicosapentaenoic 57, 87, 12E,147,17Z-eicosapentaenoic 5Z, 8Z, 12E,14Z,17Z-eicosapentaenoic 5Z, 8Z, 10E,14Z,17Z-eicosapentaenoic 57,87,10E,147,1 77-eicosapentaenoic 5Z, 8Z, 10E,14Z,17Z-eicosapentaenoic acid), acid), acid), acid), acid), acid), acid), acid), 9(S)-HEPE 11-HERE 11(R)-HERE 11(S)-HERE 12-HERE 12(R)-HERE 12(S)-HERE 18-HERE (9S-hydroxy- ((±)-11-hydroxy-(11R-hydroxy-(11S-hydroxy- ((±)-12-hydroxy-(12R-hydroxy-(12S-hydroxy- ((±)-18-hydroxy- 5Z,8Z,11Z,14Z,16E-eicosapentaenoic acid), 20-HEPE (20-hydroxy- 57,87,117,147,17Z-eicosapentaenoic acid), RvE1, RvE2, RvE3, and 18S-RvE1.

[0033] In some embodiments, the metabolite of EPA is at least one selected from the group consisting of 5-HERE, 5(S)-HERE, 8-HERE, 8(S)-HERE, 9-HERE, 9(5)-HEPE, 11-HERE, 11(R)-HERE, 11(S)-HERE, 12-HERE, 12(R)-HERE, 12(S)-HERE, 18-HERE, 20-HERE, RvE1, RvE2, RvE3, and 18S-RvE1.

[0034] In some embodiments, a total weight of the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100%, by weight, of all fatty acids present in a composition useful in methods of the disclosure.

[0035] In other embodiments, when present, the EPA represents at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100%, by weight, of all fatty acids present in a composition useful in methods of the disclosure.

[0036] In other embodiments, when present, the derivative of EPA represents at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100%, by weight, of all fatty acids present in a composition useful in methods of the disclosure.

[0037] In other embodiments, when present, the metabolite of EPA represents at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100%, by weight, of all fatty acids present in a composition useful in methods of the disclosure.

[0038] In one embodiment, a composition useful in methods described herein contains not more than about 10%, not more than about 9%, not more than about 8%, not more than about 7%, not more than about 6%, not more than about 5%, not more than about 4%, not more than about 3%, not more than about 2%, not more than about 1%, or not more than about 0.5%, by weight of other omega-3 fatty acids including alpha linolenic acid, stearidonic acid, docosahexaenoic acid (DHA) or derivatives thereof. In other embodiments there is substantially no, or no such other omega-3 fatty acids present.

Additional active agents [0039] In one embodiment, the pharmaceutical composition further comprises one or more additional active agent(s). In one embodiment, the pharmaceutical composition comprises an amount of the additional active agent that is less than the generally recognized therapeutically effective amount for that agent. In one embodiment, the pharmaceutical composition comprises an amount of the additional active agent that is equal to or greater than the generally recognized therapeutically effective amount for that agent. If an additional active agent is to be used, the EPA, the derivative of EPA, and/or the metabolite of EPA can be co-formulated as a single dosage unit or can be formulated as two to a plurality of dosage units for coordinated, combination or concomitant administration. If an additional active agent is to be used, the 15-HEPE can be co-formulated as a single dosage unit or can be formulated as two to a plurality of dosage units for coordinated, combination or concomitant administration.

[0040] In one embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA and one or more active agent(s) are present in a composition of the disclosure, or are co-administered in a weight ratio of 15-HEPE: additional agent of about 1:1000 to about 1000:1, about 1:500 to about 500:1, about 1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1, about 1:5 to about 5:1, about 1:4 to about 4:1 about 1:3 to about 3:1, about 1:2 to about 2:1 or about 1:1.

Dosage Forms [0041] A composition for use in accordance with the disclosure can be formulated as one or more dosage units. The terms "dose unit" and "dosage unit" herein refer to a portion of a composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered one to a plurality (e.g., 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as many times as needed to elicit a therapeutic response.

[0042] In some embodiments, compositions of the disclosure are in the form of orally deliverable dosage forms or units. Non-limiting examples of suitable dosage forms include tablets (e.g., suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, etc), caplets, capsules (e.g., a soft or a hard gelatin capsule or HPMC capsule), lozenges, sachets, cachets, troches, pellets, suspension, elixirs, syrups or any other solid dosage form reasonably adapted for oral administration. The terms "oral delivery" and "oral administration" herein include any form of delivery wherein the agent or composition is placed in the mouth of the subject under treatment, whether swallowed or not. This therefore includes buccal and sublingual administration, as well as esophageal administration.

[0043] In discussing the amount of the EPA, the derivative of EPA, and/or the metabolite of EPA in a composition of the disclosure, this may be split over several dosage forms. There is a limit as to the size for oral administration. For example, if a subject is to be administered about 1 to about 4 g EPA a day, this may be by up to 4 capsules, each providing about 1 g of EPA.

[0044] The compositions and formulations disclosed herein may be used in the treatment and/or prevention of hematologic disorders, hemoglobin disorders, and/or red blood cell disorders. Hematologic disorders refer to a class of conditions that affect the blood and blood-forming organs. While hemoglobin disorders and red blood cells disorders are similar to hematologic disorders, both hemoglobin disorders and red blood cell disorders define a narrower class of disorders. Specifically, hemoglobin disorders refer to defects in hemoglobin, the oxygen transport protein in red blood cells. And red blood cell disorders, refer to defects in the red blood cell itself. Non-limiting examples of risk factors of hematologic disorders, hemoglobin disorders, and red blood cell disorders include reduced red blood cell counts, increased red blood cell distribution widths, and increased reticulocyte counts. Non-limiting examples of hematologic disorders, hemoglobin disorders, and red blood cell disorders include anemia (nutritional anemias and non-nutritional anemias, inherited hemolytic anemia such as sickle cell disease, sickle cell anemia, p-thalassemia, and hereditary spherocytosis, acquired hemolytic anemia such as secondary to infection, medication, hematological malignancy, autoimmune disease, hypersplenism, mechanical heart valves, and blood transfusions, Fanconi anemia, iron deficiency anemia), blood cancer (lymphoma, leukemia, and myeloma), coagulation defects (thrombophilia, hemophilia, Von Willebrand disease, and thrombocytopenia), folate deficiency, B12 deficiency, and myelodysplastic syndrome. In some embodiments, sickle cell disease and sickle cell anemia are associated with sickle cell crisis, vaso-occlusive crisis, and/or splenic sequestration.

[0045] In some embodiments, the subject has a reduced red blood cell count of at least 10% below normal, at least 15% below normal, at least 20% below normal, at least 25% below normal, or at least 30% below normal.

[0046] In some embodiments, the subject has an increased red blood cell distribution width, where the red blood cells vary in size by about 15-20%, by about 20-25%, by about 25-30%, by about 30-35%, or by about 35-40%.

[0047] In another embodiment, the subject has an increased reticulocyte count of at least about 5% of the total amount of red blood cells, at least about 10% of the total amount of red blood cells, at least about 15% of the total amount of red blood cells, or at least about 20% of the total amount of red blood cells.

[0048] In some embodiments, the present disclosure provides a method of treating and/or preventing hematologic disease in a subject, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of the EPA, the derivative of EPA, and/or the metabolite of EPA,. In yet another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90%, by weight, all fatty acids in the composition.

[0049] In some embodiments, the present disclosure provides a method of treating and/or preventing hematologic disease in a subject, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In yet another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90%, by weight, all fatty acids in the composition.

[0050] In some embodiments, the present disclosure provides methods of treating and/or preventing a hematologic disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0051] In some embodiments, the present disclosure provides a method of treating and/or preventing hematologic disease in a subject, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the method further comprises determining that the subject has at least one risk factor for hematologic disease before the administering. In some embodiments, the method further comprises determining a baseline red blood cell count, a red blood cell distribution width, and/or a reticulocyte count of the subject before the administering. In one embodiment, the subject exhibits an increase in the red blood cell count, a decrease in the red blood cell distribution width, and/or a decrease in the reticulocyte count. In another embodiment, the method comprises administering to the subject up to about 8g of EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In yet another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90%, by weight, of all fatty acids in the composition.

[0052] In some embodiments, the present disclosure provides methods of treating and/or preventing a hematologic disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the method further comprises determining that the subject has at least one risk factor for hematologic disease before the administering. In some embodiments, the method further comprises determining a baseline red blood cell count, a red blood cell distribution width, and/or a reticulocyte count of the subject before the administering. In one embodiment, the subject exhibits an increase in the red blood cell count, a decrease in the red blood cell distribution width, and/or a decrease in the reticulocyte count. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0053] In some embodiments, the present disclosure provides methods of treating and/or preventing a hemoglobin disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0054] In some embodiments, the present disclosure provides methods of treating and/or preventing a hemoglobin disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the method further comprises determining that the subject has at least one risk factor for the hemoglobin disorder before the administering. In some embodiments, the method further comprises determining a baseline red blood cell count, a red blood cell distribution width, and/or a reticulocyte count of the subject before the administering. In one embodiment, the subject exhibits an increase in the red blood cell count, a decrease in the red blood cell distribution width, and/or a decrease in the reticulocyte count. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0055] In some embodiments, the present disclosure provides methods of treating and/or preventing a red blood cell disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0056] In some embodiments, the present disclosure provides methods of treating and/or preventing a red blood cell disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the method further comprises determining that the subject has at least one risk factor for the red blood cell disorder before the administering. In some embodiments, the method further comprises determining a baseline red blood cell count, a red blood cell distribution width, and/or a reticulocyte count of the subject before the administering. In one embodiment, the subject exhibits an increase in the red blood cell count, a decrease in the red blood cell distribution width, and/or a decrease in the reticulocyte count. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0057] In some embodiments, the present disclosure provides methods of treating and/or preventing a hematologic disorder, a hemoglobin disorder, and/or a red blood cell disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0058] In some embodiments, the present disclosure provides methods of treating and/or preventing a hematologic disorder, a hemoglobin disorder, and/or a red blood cell disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the method further comprises determining that the subject has at least one risk factor for a hematologic disorder, a hemoglobin disorder, and/or a red blood cell disorder before the administering. In some embodiments, at least one risk factor is reduced red blood cell counts, increased red blood cell distribution widths, and/or increased reticulocyte counts. In some embodiments, the subject exhibits one or more of an increase in red blood cell count, a decrease in red blood cell distribution width and/or a reduced reticulocyte count.

[0059] In some embodiments, the present disclosure provides methods of treating and/or preventing a hematologic disorder, a hemoglobin disorder, and/or a red blood cell disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition. In another embodiment, the hematologic disorder, the hemoglobin disorder, and/or the red blood cell disorder are selected from the group consisting of inherited hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folate deficiency, B12 deficiency, and myelodysplastic syndrome. In some embodiments, the method further comprises determining that the subject has at least one risk factor for inherited hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folate deficiency, B12 deficiency, and/or myelodysplastic syndrome before the administering. In some embodiments, the method further comprises determining a baseline red blood cell count, a red blood cell distribution width, and/or a reticulocyte count of the subject before the administering. In one embodiment, the subject exhibits an increase in the red blood cell count, a decrease in the red blood cell distribution width, and/or a decrease in the reticulocyte count.

[0060] In some embodiments, the present disclosure provides methods of treating and/or preventing hemolytic anemia in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0061] In some embodiments, the present disclosure provides methods of treating and/or preventing hemolytic anemia in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the method further comprises determining that the subject has at least one risk factor for hemolytic anemia before the administering. In some embodiments, at least one risk factor is reduced red blood cell counts, increased red blood cell distribution widths, and/or increased reticulocyte counts. In some embodiments, the subject exhibits one or more of an increase in red blood cell count, a decrease in red blood cell distribution width and/or a reduced reticulocyte count.

[0062] In some embodiments, the present disclosure provides methods of treating and/or preventing hemolytic anemia in a subject in need thereof, the method comprising administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition. In some embodiments, the hemolytic anemia is inherited hemolytic anemia or acquired hemolytic anemia. In another embodiment, the inherited hemolytic anemia is selected from the group consisting of sickle cell disease, sickle cell anemia, 8-thalassemia, and hereditary spherocytosis. In yet another embodiment, the acquired hemolytic anemia is selected from the group consisting of secondary to infection, medication, hematological malignancy, autoimmune disease, hypersplenism, mechanical head valves, and blood transfusions. In various embodiments, the sickle cell disease and sickle cell anemia are associated with sickle cell crisis, vaso-occlusive crisis, and/or splenic sequestration. In some embodiments, the subject exhibits an increase in red blood cell count, a decrease in red blood cell distribution width, and a decrease in reticulocyte count following administration.

[0063] In some embodiments, the present disclosure provides methods of treating and/or preventing hemolytic anemia in a subject in need thereof, the method comprising administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition. In some embodiments, the hemolytic anemia is inherited hemolytic anemia or acquired hemolytic anemia. In another embodiment, the inherited hemolytic anemia is selected from the group consisting of sickle cell disease, sickle cell anemia, 8-thalassemia, and hereditary spherocytosis. In some embodiments, the method further comprises determining that the subject has at least one risk factor for inherited hemolytic anemia or acquired hemolytic anemia before the administering. In yet another embodiment, the acquired hemolytic anemia is selected from the group consisting of secondary to infection, medication, hematological malignancy, autoimmune disease, hypersplenism, mechanical heart valves, and blood transfusions. In various embodiments, the sickle cell disease and sickle cell anemia are associated with sickle cell crisis, vaso-occlusive crisis, and/or splenic sequestration. In some embodiments, the method further comprises determining a baseline red blood cell count, a red blood cell distribution width, and/or a reticulocyte count of the subject before the administering. In one embodiment, the subject exhibits an increase in the red blood cell count, a decrease in the red blood cell distribution width, and/or a decrease in the reticulocyte count.

[0064] The compositions and formulations disclosed herein in any of their embodiments may further be used in the treatment and/or prevention of a thrombophilia disorder. Thrombophilia disorders refer to a class of conditions characterized by abnormal blood coagulation that increases the risk of thrombosis. Non-limiting examples of risk factors of thrombophilia disorders include decreased prothrombin times, decreased activated partial thromboplastin times, and increased fibrinogen concentration.

[0065] In some embodiments, the subject has a reduced prothrombin time of at least 10% below normal, at least 15% below normal, at least 20% below normal, at least 25% below normal, or at least 30% below normal.

[0066] In some embodiments, the subject has a reduced activated partial thromboplastin time of at least 10% below normal, at least 15% below normal, at least 20% below normal, at least 25% below normal, or at least 30% below normal.

[0067] In some embodiments, the subject has an increased fibrinogen concentration of at least 10% below normal, at least 15% below normal, at least 20% below normal, at least 25% below normal, or at least 30% below normal.

[0068] In some embodiments, the present disclosure provides methods of treating and/or preventing a thrombophilia disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0069] In some embodiments, the present disclosure provides methods of treating and/or preventing a thrombophilia disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the method further comprises determining that the subject has at least one risk factor for a thrombophilia disorder before the administering. In some embodiments, at least one risk factor is decreased prothrombin times, decreased activated partial thromboplastin times, and/or increased fibrinogen concentration. In some embodiments, the subject exhibits one or more of an increase in prothrombin time, an increase in activated partial thromboplastin time and/or a decrease in fibrinogen concentration after the administering.

[0070] In some embodiments, the present disclosure provides methods of treating and/or preventing a venous thromboembolism in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the method comprises administering to the subject up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In another embodiment, the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.

[0071] In some embodiments, the present disclosure provides methods of treating and/or preventing a venous thromboembolism in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments, the method further comprises determining that the subject has at least one risk factor for venous thromboembolism before the administering. In some embodiments, at least one risk factor is decreased prothrombin times, decreased activated partial thromboplastin times, and/or increased fibrinogen concentration. In some embodiments, the subject exhibits one or more of an increase in prothrombin time, an increase in activated partial thromboplastin time and/or a decrease in fibrinogen concentration.

[0072] In some embodiments, the present disclosure provides a method of treating, preventing, or reducing cell stress apoptosis, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA. In some embodiments the subject exhibits a reduction in markers associated with apoptosis such as proteins from the BcI-2 family, activated fragments of caspases and/or cleaved PARP-1.

[0073] [0074] Without further description, it is believed that one of ordinary skill in the art may, using the preceding description and the following illustrative examples, make and utilize the agents of the present disclosure and practice the claimed methods. The following working examples are provided to facilitate the practice of the present disclosure, and are not to be construed as limiting in any way the remainder of the disclosure.

Claims

CLAIMSWe claim: 1. A method of treating and/or preventing a hematologic disorder in a subject in need thereof, the method comprising administering to the subject eicosapentaenoic acid (EPA), a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.
2. A method of treating and/or preventing a hemoglobin disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.
3. A method of treating and/or preventing a red blood cell disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.
4. A method of treating and/or preventing hemolytic anemia in a subject in need thereof, the method comprising administering to the subject up to about 8g of a composition comprising EPA, a derivative of EPA, and/or a metabolite of EPA.
5. The method of claim 1, wherein the hematologic disorder is selected from the group consisting of anemia, blood cancer, and a coagulation defect.
6. The method of claim 5, wherein the anemia is a nutritional anemia, a non-nutritional anemia, or a combination thereof.
7. The method of claim 5, wherein the blood cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.
8. The method of claim 5, wherein the coagulation defect is selected from the group consisting of thrombophilia, hemophilia, Von Willebrand disease, and throm bocytopenia.
9. The method of any one of claims 2 to 8, wherein the hemoglobin disorder and/or the red blood cell disorder is selected from the group consisting of inherited hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folate deficiency, B12 deficiency, and myelodysplastic syndrome.
10. The method of claim 9, wherein the inherited hemolytic anemia is selected from the group consisting of sickle cell disease, sickle cell anemia, 8-thalassem ia, and hereditary spherocytosis.
11. The method of claim 9, wherein the acquired hemolytic anemia is acquired from a disorder or condition selected from the group consisting of a condition secondary to a primary infection, a medication, a hematological malignancy, an autoimmune disease, hypersplenism, positioning of a mechanical heart valve, and a blood transfusion.
12. The method of claim 10, wherein the sickle cell disease and sickle cell anemia are associated with sickle cell crisis, a vaso-occlusive crisis, and/or splenic sequestration.
13. A method of treating and/or preventing a thrombophilia disorder in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.
14. A method of treating and/or preventing thrombophilia in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.
15. A method of treating and/or preventing a venous thromboembolism in a subject in need thereof, the method comprising administering to the subject EPA, a derivative of EPA, and/or a metabolite of EPA, or up to about 8g of a composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA.
16. The method of any one of claims 1 to 15, wherein the metabolite of EPA is not 15-hydroxyeicosapentaenoic acid (15-HEPE).
17. The method of any one of claims 1 to 16, wherein the derivative of EPA is in esterified form, conjugate form, or salt form.
18. The method of any one of claims 1 to 17, wherein the derivative of EPA is EPA methyl ester, EPA ethyl ester, or both.
19. The method of any one of claims 1 to 18, wherein the derivative of EPA is EPA ethyl ester.
20. The method of any one of claims 1 to 19, wherein the metabolite of EPA is at least one selected from the group consisting of 5-HEPE, 5(S)-HERE, 8-HERE, 8(S)-HERE, 9-HERE, 9(S)-HERE, 11-HERE, 11(R)-HERE, 11(S)-HERE, 12-HERE, 12(R)-HERE, 12(S)-HERE, 18-HERE, 20-HERE, RvE1, RvE2, RvE3, and 18S-RvE1
21. The method of any one of claims 1 to 20, wherein EPA, the derivative of EPA, and/or the metabolite of EPA are present in an amount of greater than 50 wt% based on a total weight of the composition.
22. The method of any one of claims 1 to 21, wherein EPA is present in an amount of greater than 50 wt% based on a total weight of the composition.
23. The method of any one of claims 1 to 22, wherein a total weight of the EPA, the derivative of EPA, and/or the metabolite of EPA represents at least about 90% by weight, of all fatty acids in the composition.
24. The method of any one of claims 1 to 23, wherein the EPA represent at least about 90% by weight, of all fatty acids in the composition.
25. The method of any one of claims 1 to 24, wherein the composition comprises up to about 2 g of EPA, the derivative of EPA, and/or the metabolite of EPA.
26. The method of any one of claims 1 to 25, wherein the composition comprises up to about 2 g of EPA.
27. The method of any one of claims 1 to 26, wherein the composition comprises at least 2 g of EPA, the derivative of EPA, and/or the metabolite of EPA.
28. The method of any one of claims 1 to 27, wherein the composition comprises at least 2 g of EPA.
29. The method of any one of claims 1 to 28, wherein the composition is administered in 1 to 8 capsules per day.
30. The method of any one of claims 1 to 29, wherein the composition is formulated to provide about 5 mg of EPA per kg of bodyweight (mg/kg), about 50 mg/kg, about 250 mg/kg, or about 500 mg/kg to the subject.
31. The method of any one of claims 1 to 30, wherein the EPA, the derivative of EPA, and/or the metabolite of EPA or the composition comprising EPA, the derivative of EPA, and/or the metabolite of EPA is orally administered.