Thyroid beta agonist dosing regimen for treatment of X-ALD

Abstract

The present disclosure relates to dosing regimens and methods for the treatment of X-linked adrenoleukodystrophy (X-ALD) using thyroid receptor beta agonists.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 352,350, filed on June 15, 2022, the contents of which are hereby incorporated by reference in their entirety. Background Art

[0003] Adrenoleukodystrophy (also called X-linked adrenoleukodystrophy, X-ALD) is a disease of peroxisomal fatty acid beta oxidation that results in the accumulation of very long-chain fatty acids in tissues throughout the body. The tissues most severely affected are myelin in the central nervous system, the adrenal cortex, and Leydig cells in the testes. As an X-linked disease, X-ALD is seen primarily in males; however, approximately 50% of heterozygous females will exhibit some symptoms later in life. The most severe form of X-ALD is called cerebral ALD and is characterized by a rapidly progressive inflammatory demyelinating process in brain tissue. This form is more common in early childhood, typically presenting in children under 12 years of age. Patients with cerebral ALD typically experience rapid regression to a vegetative state within 3 to 5 years. A more common form of X-ALD is called adrenomyeloneuropathy (AMN). This form of the disease presents later in life, usually between the ages of 25 and 45. AMN affects the spinal cord and motor neurons but has no inflammatory component or brain involvement. Patients with AMN first experience difficulty walking, which leads to progressive movement disorders with paralysis of the legs.

[0004] ALD is caused by mutations in the gene for ATP-binding cassette transporter d1 (ABCD1) located on the X chromosome. The function of ABCD1 is to transport very long-chain fatty acids (VLCFA) to the peroxisomes for degradation. In X-ALD, defective ABCD1 leads to the accumulation of VLCFA. Individuals with X-ALD exhibit very high levels of unbranched, saturated, very long-chain fatty acids, particularly cerotic acid (26:0). Treatment options for X-ALD are limited as there is no cure and no approved therapies.

[0005] Therefore, improved methods and dosing regimens are needed to treat X-ALD. Summary of the invention

[0006] In certain aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0007]

[0008] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0009] Wherein the dosing regimen comprises administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg and 80 mg.

[0010] In a further aspect, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0011]

[0012] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0013] wherein the dosing regimen is sufficient to reduce plasma levels of saturated very long chain fatty acids (VLCFA) in the subject after about 28 days.

[0014] In yet a further aspect, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0015]

[0016] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0017] wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C) of the compound in the subject of about 100 ng / mL to about 800 ng / mL max ).

[0018] In still a further aspect, the present disclosure provides a method of treating X-linked adrenoleukodystrophy, the method comprising administering to a subject in need thereof compound (1):

[0019]

[0020] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0021] wherein the dosing regimen is sufficient to achieve a mean plasma concentration-time area under the curve (AUC) of the compound within 24 hours of about 800 h*ng / mL to about 7000 h*ng / mL in the subject. 0-24 ).

[0022] In certain aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy, the method comprising administering to a subject in need thereof compound (1):

[0023]

[0024] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0025] wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (T) of the compound of about 2.0 to about 7.0 hours max ).

[0026] In a further aspect, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0027]

[0028] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0029] The dosing regimen is sufficient to achieve a mean half-life (T) of the compound in the subject of about 10 h to about 20 h. 1 / 2 ).

[0030] In yet a further aspect, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0031]

[0032] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0033] wherein the dosing regimen is sufficient to achieve a mean oral clearance (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is a schematic diagram showing the setup of the Phase 1b study of Compound 1 described in detail in Example 1. DETAILED DESCRIPTION

[0035] Methods of the present disclosure

[0036] In certain aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0037]

[0038] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0039] wherein the dosing regimen comprises administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg and 80 mg.

[0040] In certain embodiments, any method of the present disclosure may include a dosing regimen, wherein the dosing regimen includes administering to a subject once daily a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg. In some such embodiments, the dose is about 20 mg. In other such embodiments, the dose is about 40 mg. In still other such embodiments, the dose is about 60 mg. In still other such embodiments, the dose is about 80 mg.

[0041] In other aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0042]

[0043] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0044] wherein the dosing regimen is sufficient to reduce plasma levels of saturated very long chain fatty acids (VLCFA) in the subject after about 28 days.

[0045] In some embodiments, any method of the present disclosure may include a dosing regimen, wherein the dosing regimen is sufficient to reduce the plasma level of one or more saturated very long chain fatty acids (VLCFA) in a subject. In certain such embodiments, one or more VLCFA are selected from behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanic acid and combinations thereof. In a further embodiment, the dosing regimen is sufficient to reduce the plasma level of behenic acid in a subject relative to a baseline. In a further embodiment, the reduction in the plasma level of behenic acid is about 1% to about 60% relative to a baseline. In certain such embodiments, the reduction in the plasma level of behenic acid is about 4% to about 24% relative to a baseline. In some embodiments, the reduction in the plasma level of behenic acid is at least about 4% relative to a baseline. In other embodiments, the reduction in the plasma level of behenic acid is at least about 12% relative to a baseline. In yet other embodiments, the reduction in the plasma level of behenic acid is at least about 14% relative to a baseline. In still other embodiments, the reduction in the plasma level of behenic acid is at least about 24% relative to a baseline. In other embodiments, the reduction in plasma levels of behenic acid is about 4% relative to baseline. In yet other embodiments, the reduction in plasma levels of behenic acid is about 12% relative to baseline. In still other embodiments, the reduction in plasma levels of behenic acid is about 14% relative to baseline. In other embodiments, the reduction in plasma levels of behenic acid is about 24% relative to baseline. In certain embodiments, the reduction in plasma levels of behenic acid is about 30% relative to baseline. In other embodiments, the reduction in plasma levels of behenic acid is about 40% relative to baseline. In yet other embodiments, the reduction in plasma levels of behenic acid is about 50% relative to baseline. In still other embodiments, the reduction in plasma levels of behenic acid is about 60% relative to baseline.

[0046] In certain embodiments, the reduction in plasma levels of behenic acid is from about 1 μmol / L to about 40 μmol / L relative to a baseline. In some such embodiments, the reduction in plasma levels of behenic acid is from about 4 μmol / L to about 16 μmol / L relative to a baseline. In some embodiments, the reduction in plasma levels of behenic acid is at least about 4 μmol / L relative to a baseline. In other embodiments, the reduction in plasma levels of behenic acid is at least about 10 μmol / L relative to a baseline. In still other embodiments, the reduction in plasma levels of behenic acid is at least about 11 μmol / L relative to a baseline. In still other embodiments, the reduction in plasma levels of behenic acid is at least about 16 μmol / L relative to a baseline. In other embodiments, the reduction in plasma levels of behenic acid is about 4 μmol / L relative to a baseline. In still other embodiments, the reduction in plasma levels of behenic acid is about 10 μmol / L relative to a baseline. In other embodiments, the reduction in plasma levels of behenic acid is about 11 μmol / L relative to a baseline. In yet other embodiments, the reduction in plasma levels of behenic acid is about 16 μmol / L relative to baseline. In certain embodiments, the reduction in plasma levels of behenic acid relative to baseline is about 20 μmol / L. In other embodiments, the reduction in plasma levels of behenic acid relative to baseline is about 25 μmol / L. In yet other embodiments, the reduction in plasma levels of behenic acid relative to baseline is about 40 μmol / L.

[0047] In certain embodiments, the dosing regimen is sufficient to reduce the plasma level of hexacosanoid in the subject relative to baseline. In some such embodiments, the reduction in the plasma level of hexacosanoid is from about 1% to about 30% relative to baseline. In further embodiments, the reduction in the plasma level of hexacosanoid is from about 10% to about 23% relative to baseline. In certain such embodiments, the reduction in the plasma level of hexacosanoid is at least about 10% relative to baseline. In other such embodiments, the reduction in the plasma level of hexacosanoid is at least about 15% relative to baseline. In still other such embodiments, the reduction in the plasma level of hexacosanoid is at least about 23% relative to baseline. In still other such embodiments, the reduction in the plasma level of hexacosanoid is about 10% relative to baseline. In certain embodiments, the reduction in the plasma level of hexacosanoid is about 15% relative to baseline. In other embodiments, the reduction in the plasma level of hexacosanoid is about 23% relative to baseline. In certain embodiments, the reduction in the plasma level of hexacosanoid is about 30% relative to baseline. In certain embodiments, the reduction in the plasma level of hexacosanoid is about 40% relative to baseline. In certain embodiments, the reduction in plasma levels of hexacosanoid is about 50% relative to baseline.

[0048] In certain embodiments, the reduction in plasma levels of hexacosanoids is from about 0.01 μmol / L to about 1 μmol / L relative to a baseline. In some such embodiments, the reduction in plasma levels of hexacosanoids is from about 0.05 μmol / L to about 0.1 μmol / L relative to a baseline. In further embodiments, the reduction in plasma levels of hexacosanoids is at least about 0.05 μmol / L relative to a baseline. In other embodiments, the reduction in plasma levels of hexacosanoids is at least about 0.06 μmol / L relative to a baseline. In still other embodiments, the reduction in plasma levels of hexacosanoids is at least about 0.1 μmol / L relative to a baseline. In still other embodiments, the reduction in plasma levels of hexacosanoids is about 0.05 μmol / L relative to a baseline. In other embodiments, the reduction in plasma levels of hexacosanoids is about 0.06 μmol / L relative to a baseline. In still other embodiments, the reduction in plasma levels of hexacosanoids is about 0.1 μmol / L relative to a baseline. In certain embodiments, the reduction in plasma levels of hexacosanoids is about 0.2 μmol / L relative to a baseline. In other embodiments, the reduction in plasma levels of hexacosanoid relative to baseline is about 0.5 μmol / L. In still other embodiments, the reduction in plasma levels of hexacosanoid relative to baseline is about 1 μmol / L.

[0049] In certain embodiments, the dosing regimen is sufficient to reduce the plasma level of lignoceric acid in the subject relative to baseline. In some such embodiments, the reduction in the plasma level of lignoceric acid is from about 1% to about 50% relative to baseline. In further embodiments, the reduction in the plasma level of lignoceric acid is from about 3% to about 24% relative to baseline. In certain such embodiments, the reduction in the plasma level of lignoceric acid is at least about 3% relative to baseline. In other such embodiments, the reduction in the plasma level of lignoceric acid is at least about 14% relative to baseline. In still other such embodiments, the reduction in the plasma level of lignoceric acid is at least about 24% relative to baseline. In still other such embodiments, the reduction in the plasma level of lignoceric acid is about 3% relative to baseline. In other such embodiments, the reduction in the plasma level of lignoceric acid is about 14% relative to baseline. In still other such embodiments, the reduction in the plasma level of lignoceric acid is about 24% relative to baseline. In certain embodiments, the reduction in the plasma level of lignoceric acid relative to baseline is about 40%. In other embodiments, the reduction in the plasma level of lignoceric acid relative to baseline is about 50%.

[0050] In certain embodiments, the reduction in plasma levels of lignoceric acid is from about 1 μmol / L to about 40 μmol / L relative to baseline. In some such embodiments, the reduction in plasma levels of lignoceric acid is from about 3 μmol / L to about 14 μmol / L relative to baseline. In further embodiments, the reduction in plasma levels of lignoceric acid is at least about 3 μmol / L relative to baseline. In other embodiments, the reduction in plasma levels of lignoceric acid is at least about 10 μmol / L relative to baseline. In still other embodiments, the reduction in plasma levels of lignoceric acid is at least about 14 μmol / L relative to baseline. In still other embodiments, the reduction in plasma levels of lignoceric acid is about 3 μmol / L relative to baseline. In other embodiments, the reduction in plasma levels of lignoceric acid is about 10 μmol / L relative to baseline. In still other embodiments, the reduction in plasma levels of lignoceric acid is about 14 μmol / L relative to baseline. In certain embodiments, the reduction in plasma levels of lignoceric acid is about 30 μmol / L relative to baseline. In other embodiments, the decrease in plasma levels of lignoceric acid relative to baseline is about 40 μmol / L.

[0051] In certain embodiments, the dosing regimen results in substantially no change in the ratio of plasma levels of lignoceric acid: behenic acid relative to baseline. In some embodiments, the dosing regimen results in a change in the ratio of plasma levels of lignoceric acid: behenic acid relative to baseline of about 0. In certain embodiments, the dosing regimen results in a change in the ratio of plasma levels of lignoceric acid: behenic acid relative to baseline of about -0.1 to about 0.1. In other embodiments, the dosing regimen results in a decrease in the ratio of plasma levels of lignoceric acid: behenic acid relative to baseline. In yet other embodiments, the dosing regimen results in an increase in the ratio of plasma levels of lignoceric acid: behenic acid relative to baseline.

[0052] In certain embodiments, the dosing regimen results in substantially no change in the ratio of plasma levels of leucanoic acid: behenic acid relative to baseline. In some embodiments, the dosing regimen results in a change in the ratio of plasma levels of leucanoic acid: behenic acid relative to baseline of about 0. In certain embodiments, the dosing regimen results in a change in the ratio of plasma levels of leucanoic acid: behenic acid relative to baseline of about -0.1 to about 0.1. In certain embodiments, the dosing regimen results in a decrease in the ratio of plasma levels of leucanoic acid: behenic acid relative to baseline. In other embodiments, the dosing regimen results in an increase in the ratio of plasma levels of leucanoic acid: behenic acid relative to baseline.

[0053] In certain embodiments, the dosing regimen results in substantially no change in the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to baseline levels. In other embodiments, the dosing regimen is sufficient to reduce the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to baseline levels. In yet other embodiments, the dosing regimen is sufficient to increase the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to baseline levels.

[0054] In yet other aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0055]

[0056] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0057] wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C) of the compound in the subject of about 100 ng / mL to about 800 ng / mL max ).

[0058] In some embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C ) of about 100 ng / mL to about 800 ng / mL of the compound in the subject. max In a further embodiment, C max In some such embodiments, C max In other such embodiments, C max In yet other such embodiments, C max In still other such embodiments, C max In other such embodiments, C max In yet other such embodiments, C max In yet other such embodiments, C max In still other such embodiments, C max It is about 603ng / mL.

[0059] In still other aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy, the method comprising administering to a subject in need thereof compound (1):

[0060]

[0061] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0062] wherein the dosing regimen is sufficient to achieve a mean plasma concentration-time area under the curve (AUC) of the compound within 24 hours of about 800 h*ng / mL to about 7000 h*ng / mL in the subject. 0-24 ).

[0063] In certain embodiments, any of the methods of the present disclosure may include a dosing regimen, wherein the dosing regimen is sufficient to achieve a mean plasma concentration-time area under the curve (AUC) of about 800 h*ng / mL to about 7000 h*ng / mL of the compound over a 24-hour period in the subject. 0-24 ). In a further embodiment, AUC 0-24 In certain such embodiments, AUC 0-24 is at least about 999 h*ng / mL. In other such embodiments, AUC 0-24 is at least about 2980 h*ng / mL. In yet other such embodiments, AUC 0-24 is at least about 3320 h*ng / mL. In still other such embodiments, AUC 0-24 is at least about 4550 h*ng / mL. In other such embodiments, AUC 0-24 In yet other such embodiments, AUC 0-24 is about 2980 h*ng / mL. In still other such embodiments, AUC 0-24 is about 3320 h*ng / mL. In other such embodiments, AUC 0-24 It is about 4550h*ng / mL.

[0064] In certain aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy, the method comprising administering to a subject in need thereof compound (1):

[0065]

[0066] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0067] wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (T) of the compound of about 2.0 to about 7.0 hours max ).

[0068] In certain embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (Tmax) of about 2.0 to about 7.0 hours for the compound. max). In some embodiments, T max In certain such embodiments, T max is at least about 3.86 h. In other such embodiments, T max is at least about 5.19 h. In yet other such embodiments, T max is at least about 4.36 h. In still other such embodiments, wherein T max In other such embodiments, T max In still other such embodiments, T max It is about 4.36h.

[0069] In other aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0070]

[0071] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0072] The dosing regimen is sufficient to achieve a mean half-life (T) of the compound in the subject of about 10 h to about 20 h. 1 / 2 ).

[0073] In certain embodiments, any of the methods of the present disclosure may include a dosing regimen, wherein the dosing regimen is sufficient to achieve a mean half-life (T ) of the compound in a subject of about 10 h to about 20 h. 1 / 2 ). In a further embodiment, T 1 / 2 In some such embodiments, T 1 / 2 is at least about 13.1 h. In other such embodiments, T 1 / 2 is at least about 14.9 h. In yet other such embodiments, T 1 / 2 In still other such embodiments, T 1 / 2 is at least about 14.3 h. In other such embodiments, wherein T 1 / 2 In yet other such embodiments, T 1 / 2 In still other such embodiments, T 1 / 2 In other such embodiments, T 1 / 2 It is about 14.3h.

[0074] In yet other aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1):

[0075]

[0076] or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof;

[0077] wherein the dosing regimen is sufficient to achieve a mean oral clearance (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h.

[0078] In certain such embodiments, any method of the present disclosure may include a dosing regimen, wherein the dosing regimen is sufficient to achieve a CL / F of about 15 L / h to about 30 L / h of the compound in the subject. In some embodiments, the CL / F is about 16.4 L / h to about 27.5 L / h. In further embodiments, the CL / F is at least about 27.5 L / h. In other embodiments, the CL / F is at least about 16.4 L / h. In yet other embodiments, the CL / F is at least about 22.6 L / h. In still other embodiments, the CL / F is at least about 20.1 L / h. In other embodiments, the CL / F is about 27.5 L / h. In yet other embodiments, the CL / F is about 16.4 L / h. In still other embodiments, the CL / F is about 22.6 L / h. In other embodiments, the CL / F is about 20.1 L / h.

[0079] Pharmaceutical composition

[0080] The compositions and methods of the present invention can be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human or non-human mammal. When administered to an animal such as a human, the composition or compound is preferably administered as a pharmaceutical composition, which includes, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly for invasive administration routes (i.e., routes of transport or diffusion that bypass epithelial barriers such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to achieve delayed release of the agent or selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophiles for reconstruction, powders, solutions, syrups, suppositories, injections, etc. The composition may also be presented in a transdermal delivery system, for example, a skin patch. The composition may also be presented in a solution suitable for topical administration, such as a lotion, cream or ointment.

[0081] Pharmaceutically acceptable carriers can contain physiologically acceptable agents, which are used for example to stabilize, increase solubility or increase the absorption of compounds such as compounds of the present invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextran, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The selection of pharmaceutically acceptable carriers (including physiologically acceptable agents) depends on, for example, the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, which can have a compound of the present invention incorporated therein. Liposomes, for example, liposomes including phospholipids or other lipids are relatively simple non-toxic, physiologically acceptable and metabolizable carriers for preparation and administration.

[0082] The phrase "pharmaceutically acceptable" is used 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 problems or complications commensurate with a reasonable benefit / risk ratio.

[0083] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, etc. and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0084] The pharmaceutical composition (preparation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral administration (e.g., as a drench in an aqueous or non-aqueous solution or suspension, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes suitable for the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (e.g., in the form of a patch suitable for the skin); and topical administration (e.g., in the form of a cream, ointment, or spray suitable for the skin). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions useful therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896 and patents cited therein.

[0085] The formulation can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical industry. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated, the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, out of 100%, this amount will be in the range of about 1% to about 99%, preferably about 5% to about 70%, and most preferably about 10% to about 30% of the active ingredient.

[0086] The method of preparing these formulations or compositions comprises the step of bringing into association an active compound such as a compound of the present invention with a carrier and optionally one or more auxiliary ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product.

[0087] Formulations of the present invention suitable for oral administration may be in the form of capsules (including dusting capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophiles, powders, granules; or as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; or as a pastille (using an inert base, such as gelatin and glycerin or sucrose and acacia); and / or as a mouthwash, etc., each containing a predetermined amount of the compound of the present invention as the active ingredient. The composition or compound may also be administered as a bolus, electuary or paste.

[0088] To prepare solid dosage forms for oral administration (capsules (including dispersible capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers / extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) Humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite clays; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including dusting capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also include a buffer. Solid compositions of a similar type may also use excipients such as lactose or milk sugar and high molecular weight polyethylene glycols as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules.

[0089] Tablets can be prepared by optionally compressing or molding with one or more auxiliary components. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium carboxymethyl starch or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. Molded tablets can be manufactured by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine.

[0090] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including dusting capsules and gelatin capsules), pills and granules, can optionally be coated or prepared with coatings and shells, such as enteric coatings and other coatings well-known in the field of drug formulation. The dosage form can also be formulated to use, for example, different proportions of hydroxypropyl methylcellulose to provide a sustained or controlled release of the active ingredient therein to provide a desired release curve, other polymer matrices, liposomes and / or microspheres. The dosage form can be, for example, filtered through a bacteria retention filter before use or sterilized by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium. These compositions can also optionally contain an emulsifier and the composition of the composition can be such that it releases one or more active ingredients only or preferably in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in a microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0091] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, cyclodextrins and derivatives thereof, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0092] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0093] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, mixtures thereof, and the like.

[0094] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0095] In addition to the active compounds, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0096] Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0097] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0098] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral administration and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0099] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0100] These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Can ensure to prevent the action of microorganisms by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It is also possible to expect that isotonic agents, such as sugar, sodium chloride, etc. are included in these compositions. In addition, the extended absorption of injectable drug forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0101] In some cases, in order to prolong the effect of the drug, it is necessary to slow down the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.

[0102] Injectable depot forms are prepared by forming a microencapsulation matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the properties of the specific polymer employed, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0103] For use in the methods of the present invention, the active compound may be administered per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) active ingredient and a pharmaceutically acceptable carrier.

[0104] The introduction method can also be provided by a rechargeable or biodegradable device. In recent years, various slow-release polymer devices have been developed and tested in vivo for controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable polymers and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0105] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the patient.

[0106] The selected dosage level will depend upon a variety of factors, including the activity of the specific composition or combination of compounds employed, or the esters, salts or amides thereof; the route of administration; the time of administration; the rate of absorption of the specific compound employed; the duration of the treatment; other drugs, compounds and / or materials used in combination with the specific compound employed; the age, sex, weight, condition, general health and prior medical history of the patient being treated; and like factors well known in the medical arts.

[0107] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the pharmaceutical composition or compound at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" means the concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the subject's weight, sex, age and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient's condition, the condition being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al., (1996) Harrison's Principles of Internal Medicine 13th Edition, 1814-1882, incorporated herein by reference).

[0108] In general, an appropriate daily dose of the active compound used in the compositions and methods of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.

[0109] If desired, the effective daily dose of the active compound can be administered as one, two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments of the invention, the active compound can be administered twice or three times a day. In a preferred embodiment, the active compound will be administered once a day.

[0110] Patients receiving such treatment are any animal in need, including primates, particularly humans; other mammals such as horses, cattle, pigs, sheep, cats and dogs; poultry; and pets in general.

[0111] In certain embodiments, the compounds of the invention may be used alone or in combination with another type of therapeutic agent.

[0112] The disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, the salts considered by the present invention include but are not limited to alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, the salts considered by the present invention include but are not limited to L-arginine, phenylethylamine, benzathine, betaine, calcium hydroxide, choline, danol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine and zinc salts. In certain embodiments, the salts considered by the present invention include but are not limited to Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, the salts contemplated by the present invention include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid / decanoic acid, caproic acid / hexanoic acid, caprylic acid / octanoic acid acid), carbonic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptanoic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0113] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the crystallization solvent (either inherent in the solvent of preparation or crystallization, or foreign to such solvent).

[0114] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0115] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0116] definition

[0117] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. In general, the nomenclature used in connection with the chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein and their techniques are those well known and commonly used in the art.

[0118] Unless otherwise indicated, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout the present specification. See, e.g., "Principles of Neural Science", McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th Edition", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th Edition", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th Edition", Sinauer Associates, Inc., Sunderland, MA (2000).

[0119] Unless otherwise defined herein, chemical terms used herein are used according to conventional usage in the art, as exemplified in: "The McGraw-Hill Dictionary of Chemical Terms", Parker S., ed., McGraw-Hill, San Francisco, CA (1985).

[0120] All of the above and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In the event of a conflict, the present specification, including its specific definitions, will control.

[0121] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of chemical compounds), a biomacromolecule (e.g., a nucleic acid, an antibody, including portions thereof, and humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portions thereof, such as peptides, lipids, carbohydrates), or an extract made from a biological material (e.g., a bacterial, plant, fungal or animal (particularly mammalian) cell or tissue). For example, an agent includes an agent of known structure and an agent of unknown structure.

[0122] "Patient", "subject" and "individual" are used interchangeably and refer to human or non-human animals. These terms include mammals, such as humans, primates, livestock (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.) and rodents (e.g., mice and rats).

[0123] "Treating" a condition or patient means taking steps to obtain a beneficial or desired result, including a clinical result. Beneficial or desired clinical results may include, but are not limited to, relieving or ameliorating one or more symptoms or conditions, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, and remission (partial or complete), whether detectable or undetectable. "Treatment" may also refer to prolonging survival compared to expected survival if not receiving treatment.

[0124] The term "prevent" is art-recognized and fully understood in the art when applied to a condition such as local recurrence (e.g., pain), a disease (e.g., cancer), a syndrome (e.g., heart failure), or any other medical condition, and includes administering a composition that reduces the frequency of symptoms of, or delays the onset of, a medical condition in a subject relative to a subject not receiving the composition. Thus, preventing cancer includes, for example, reducing the number of detectable cancerous growths in a patient population receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population compared to an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0125] A substance, compound, or agent can be "administered" to a subject using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinal, intracerebrally, and transdermally (by absorption, such as through a skin catheter). The compound or agent can also be suitably introduced via a rechargeable or biodegradable polymer device or other device, such as a patch and pump, or a formulation that provides for extended, slow, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended time periods.

[0126] The appropriate method of administering a substance, compound, or medicament to a subject will also depend on, for example, the age and / or physical condition of the subject and the chemical and biological properties (e.g., solubility, digestibility, bioavailability, stability, and toxicity) of the compound or medicament. In some embodiments, the compound or medicament is administered orally, e.g., by ingestion to the subject. In some embodiments, the orally administered compound or medicament is in an extended release or sustained release formulation, or is administered using a device for such sustained release or extended release.

[0127] As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic agents such that a second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., both agents are effective in the patient's body at the same time, which may include a synergistic effect of the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or in separate formulations. Thus, an individual receiving such treatment may benefit from the combined effects of the different therapeutic agents.

[0128] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or pharmaceutical agent is an amount of the drug or pharmaceutical agent that will have the desired therapeutic effect when administered to a subject. The full therapeutic effect may not necessarily occur by administering one dose, and may occur only after a series of doses are administered. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, the precise effective amount required for a subject depends on the subject's size, health, and age, as well as the nature and extent of the condition being treated (e.g., cancer or MDS). A skilled artisan can readily determine the effective amount for a given situation by routine experimentation.

[0129] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs as well as instances where the event or circumstance does not occur. For example, "optionally substituted alkyl" refers to alkyl that can be substituted as well as unsubstituted alkyl.

[0130] As used herein, the term "modulate" encompasses inhibition or suppression of a function or activity (such as cell proliferation) as well as enhancement of a function or activity.

[0131] The term "pharmaceutically acceptable" is recognized in the art. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0132] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to acid addition salts or base addition salts that are suitable for use or compatible with patient treatment.

[0133] As used herein, the term "pharmaceutically acceptable base addition salt" means any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or any intermediate thereof. Illustrative inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide. Illustrative organic bases that form suitable salts include aliphatic, alicyclic or aromatic organic amines, such as methylamine, trimethylamine and picoline or ammonia. Those skilled in the art will appreciate the selection of suitable salts.

[0134] Some compounds may also exist in tautomeric forms. Although not explicitly indicated in the formulae described herein, these forms are intended to be encompassed within the scope of the present disclosure.

[0135] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material, which can be used to formulate a drug for medical or therapeutic use.

[0136] Examples

[0137] The invention now generally described will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting of the invention.

[0138] Example 1: Phase 1b pharmacodynamic study of compound 1 in adrenomyeloneuropathy

[0139] 1. Project Summary

[0140] 1.1 Overview

[0141] Compound 1 is a novel, selective thyroid receptor-β agonist that is being developed as a disease-modifying agent for the treatment of X-linked adrenoleukodystrophy (X-ALD) and adrenomyeloneuropathy (AMN).

[0142] The purpose of this Phase 1b study is to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of compound 1 in subjects diagnosed with adrenal myeloneuropathy (AMN). In addition, this will be the first proof-of-concept study to evaluate whether compound 1 treatment will lead to a reduction in plasma levels of VLCFA in subjects with AMN. Table 1 below gives the objectives and endpoints of this Phase 1b study.

[0143] Table 1

[0144]

[0145] Overall design:

[0146] This study will be a multiple concurrent and dose escalation study to evaluate the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of compound 1 in subjects with AMN. The study will consist of 3 phases with efficacy for each cohort:

[0147] Screening phase (up to 21 days),

[0148] The treatment phase (28 days), and

[0149] Follow-up phase (7 days).

[0150] The study will enroll up to 48 subjects in total. Up to 24 subjects will be enrolled in the first two dose cohorts, which will be run in parallel. Based on the results of the first two cohorts, a potential third higher dose cohort will be initiated. And based on the results of the third cohort, a potential fourth higher dose cohort will be initiated.

[0151] For each cohort, up to 12 subjects will be randomized to receive Compound 1 or placebo in a 3:1 ratio, such that a total of up to 9 subjects per cohort will receive each active dose and up to 3 subjects will take placebo.

[0152] Cohort 1 and Cohort 2 will be dosed concurrently as listed below:

[0153] Compound 1 20 mg QD (dose cohort 1; up to 9 subjects taking Compound 1 and up to 3 subjects taking placebo),

[0154] Compound 1 40 mg QD (Dose Cohort 2; up to 9 subjects taking Compound 1 and up to 3 subjects taking placebo),

[0155] Based on the results in Cohorts 1 and 2, the study may include third and fourth dose cohorts.

[0156] The dose levels for Cohorts 3 and 4 have been determined to be 60 mg QD and 80 mg QD (1.5-fold and 2-fold incremental increases, respectively, of the 40 mg dose used in Cohort 2).

[0157] Number of subjects (planned):

[0158] The study is planned to enroll up to 48 subjects with AMN. There will be up to 24 subjects total in the first 2 concurrent cohorts, with up to 18 subjects receiving active treatment (up to 9 at each dose) and up to 6 subjects in the placebo group (up to 3 at each dose). Based on the safety results from the first two dose cohorts, up to 12 additional subjects with AMN will be randomized to a higher dose treatment group within the third cohort (60 mg), of which up to 9 subjects will receive active treatment and up to 3 subjects will take placebo. Based on the results of the third cohort, a potential fourth higher dose cohort (80 mg) will be initiated.

[0159] For each cohort, up to 12 subjects will be randomized to receive Compound 1 or placebo in a 3:1 ratio, such that a total of up to 9 subjects per cohort will receive each active dose and up to 3 subjects will take placebo.

[0160] Intervention groups and duration

[0161] The study will consist of 3 phases, valid for each cohort, as follows: Screening Phase (up to 21 days), Treatment Phase (28 days), and Follow-up Phase (7 days).

[0162] During dose escalation, subjects will be randomized to one of two treatments out of four possible dose treatment cohorts, starting with 2 dose cohorts in parallel. This will be followed by escalation to a third dose cohort (60 mg) as appropriate. A potential fourth higher dose cohort (80 mg) will be initiated as appropriate.

[0163] The dose used in this study was determined based on the dose that resulted in a reduction in plasma lipid levels without safety concerns, based on preliminary results from 6 multiple-dose cohorts (up to 100 mg) and 7 single-dose cohorts (up to 125 mg) from a previous Phase 1 study.

[0164] 3. Study Design

[0165] 3.1. Overall design

[0166] Subjects will be administered multiple doses of Compound 1 during cohort dose escalation. A total of up to 48 subjects will be enrolled in the study, divided into one of four dose cohorts. For each cohort, up to 12 subjects will be randomized to receive Compound 1 or placebo in a 3:1 ratio, so that a total of up to 9 subjects in each cohort will receive each active dose and up to 3 subjects will take placebo.

[0167] The first part of this study will include the first 2 dose cohorts and placebo, which will be administered concurrently (maximum N=24). The first 2 doses used in these cohorts will be 20 mg QD and 40 mg QD for 28 days.

[0168] Based on the analysis of data from each cohort, the sample size in a particular cohort could be increased by up to 12 subjects.

[0169] Dose escalation from a concurrent cohort to the next single-dose cohort is permitted only after all subjects in 2 concurrent cohorts have safely completed those cohorts. Dose escalation to cohort 4 is permitted only after all subjects in cohort 3 have safely completed that cohort.

[0170] This Phase 1b, multicenter, double-blind, multiple ascending dose study will be conducted at multiple sites in the U.S. The study consists of 3 phases with efficacy for each cohort:

[0171] Screening phase (up to 21 days),

[0172] The treatment phase (28 days), and

[0173] Follow-up phase (7 days).

[0174] 3.4. Dosage adjustment

[0175] Escalation to the next dose level will be stopped when adverse events preclude dosing or when PK / PD (dose-related VLCFA reduction) data from the first two dose cohorts indicate that further dose escalation is not warranted.

[0176] 4. Study Drugs

[0177] Study drug was defined as any study drug or placebo to be administered to study subjects according to the study protocol.

[0178] 4.1. Study Drugs Administered

[0179] Table 3

[0180]

[0181] Incorporated by Reference

[0182] All publications and patents mentioned herein are hereby incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the event of conflict, the present application, including any definitions herein, will control.

[0183] Equivalent

[0184] Although specific embodiments of the present invention have been discussed, the above description is illustrative rather than restrictive. After reading this specification and the following claims, many variations of the present invention will become apparent to those skilled in the art. The full scope of the present invention should be determined by reference to the full scope of the claims and their equivalents and the specification and these variations.

Claims

1. A method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a compound (1): or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof; wherein the dosing regimen comprises administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg and 80 mg.

2. The method of claim 1, wherein the dose is about 20 mg.

3. The method of claim 1, wherein the dose is about 40 mg.

4. The method of claim 1, wherein the dose is about 60 mg.

5. The method of claim 1, wherein the dose is about 80 mg.

6. The method according to any one of claims 1 to 5, wherein the subject suffers from adrenomyeloneuropathy.

7. The method of any one of claims 1 to 6, wherein the dosing regimen is sufficient to reduce the plasma level of one or more saturated very long chain fatty acids (VLCFA) in the subject.

8. The method of claim 7, wherein the one or more VLCFAs are selected from behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and combinations thereof.

9. The method of claim 8, wherein the dosing regimen is sufficient to reduce plasma levels of behenic acid in the subject; optionally wherein the reduction in plasma levels of behenic acid is from about 1% to about 60% relative to baseline or from about 4% to about 24% relative to baseline; optionally wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4%, about 12%, about 14%, about 24%, about 30%, about 40%, about 50%, and about 60%.

10. The method of claim 9, wherein the reduction in plasma levels of behenic acid is from about 1 μmol / L to about 40 μmol / L or from about 4 μmol / L to about 16 μmol / L relative to baseline; optionally, wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4 μmol / L, about 10 μmol / L, about 11 μmol / L, about 16 μmol / L, about 20 μmol / L and about 25 μmol / L and about 40 μmol / L relative to baseline.

11. The method of claim 8, wherein the dosing regimen is sufficient to reduce plasma levels of hexacosanoid in the subject relative to baseline; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is from about 1% to about 50% or from about 10% to about 23%; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is selected from about 10%, about 15%, about 23%, about 30%, about 40% and about 50%.

12. The method of claim 11, wherein the reduction in plasma levels of cocoanoic acid relative to baseline is from about 0.01 μmol / L to about 1 μmol / L or from about 0.05 μmol / L to about 0.1 μmol / L; optionally wherein the reduction in plasma levels of cocoanoic acid relative to baseline is selected from about 0.05 μmol / L, about 0.06 μmol / L, about 0.1 μmol / L, about 0.2 μmol / L, about 0.5 μmol / L and about 1 μmol / L.

13. The method of claim 8, wherein the dosing regimen is sufficient to reduce plasma levels of lignoceric acid in the subject relative to baseline; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1% to about 50% or from about 3% to about 24%; optionally wherein the reduction in plasma levels of lignoceric acid is selected from about 3%, about 14%, about 24%, about 40%, and about 50%.

14. The method of claim 13, wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1 μmol / L to about 40 μmol / L or from about 3 μmol / L to about 14 μmol / L; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is selected from about 3 μmol / L, about 10 μmol / L, about 14 μmol / L, about 30 μmol / L and about 40 μmol / L.

15. The method of any one of claims 1 to 14, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of lignoceric acid:behenic acid relative to baseline.

16. The method of any one of claims 1 to 14, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of hexacosanoic acid:behenic acid relative to baseline.

17. The method of any one of claims 1 to 16, wherein the dosing regimen results in substantially no change in the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to baseline levels.

18. The method of any one of claims 1 to 17, wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C ) of the compound in the subject of about 100 ng / mL to about 800 ng / mL or about 104 ng / mL to about 653 ng / mL. max ); optionally wherein said C max Selected from about 104 ng / mL, about 274 ng / mL, about 395 ng / mL and about 603 ng / mL.

19. The method of any one of claims 1 to 18, wherein the dosing regimen is sufficient to achieve a mean plasma concentration-time area under the curve (AUC) of about 800 h*ng / mL to about 7000 h*ng / mL or 999 h*ng / mL to about 4550 h*ng / mL of the compound in the subject over 24 hours. 0-24 ); optionally wherein the AUC 0-24 Selected from about 999 h*ng / mL, about 2980 h*ng / mL, about 3320 h*ng / mL and about 4550 h*ng / mL.

20. The method of any one of claims 1 to 19, wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (Tmax) of the compound of about 2.0 h to about 7.0 h or 3.86 h to about 5.19 h. max ); optionally wherein said T max Selected from about 3.86h, about 5.19h and about 4.36h.

21. The method of any one of claims 1 to 20, wherein the dosing regimen is sufficient to achieve a mean half-life (T ) of the compound in the subject of about 10 h to about 20 h or about 13.1 to about 15.3 h. 1 / 2 ); optionally wherein said T 1 / 2 Selected from about 13.1 h, about 14.9 h, about 15.3 h and about 14.3 h.

22. The method of any one of claims 1 to 21, wherein the dosing regimen is sufficient to achieve a mean oral clearance (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h or about 16.4 L / h to about 27.5 L / h; optionally wherein CL / F is selected from about 27.5 L / h, about 16.4 L / h, about 22.6 L / h, and about 20.1 L / h.

23. A method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1): or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to reduce the plasma level of one or more saturated very long chain fatty acids (VLCFA) in the subject after about 28 days.

24. The method of claim 23, wherein the one or more VLCFAs are selected from behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and combinations thereof.

25. The method of claim 24, wherein the dosing regimen is sufficient to reduce plasma levels of behenic acid in the subject relative to baseline.

26. The method of claim 25, wherein the reduction in plasma levels of behenic acid is from about 1% to about 60%.

27. The method of claim 26, wherein the reduction in plasma levels of behenic acid is from about 4% to about 24% relative to baseline.

28. The method of claim 26, wherein the reduction in plasma levels of behenic acid is at least about 4% relative to baseline.

29. The method of claim 26, wherein the reduction in plasma levels of behenic acid is at least about 12% relative to baseline.

30. The method of claim 26, wherein the reduction in plasma levels of behenic acid is at least about 14% relative to baseline.

31. The method of claim 26, wherein the reduction in plasma levels of behenic acid is at least about 24% relative to baseline.

32. The method of claim 26, wherein the reduction in plasma levels of behenic acid is about 4% relative to baseline.

33. The method of claim 26, wherein the reduction in plasma levels of behenic acid is about 12% relative to baseline.

34. The method of claim 26, wherein the reduction in plasma levels of behenic acid is about 14% relative to baseline.

35. The method of claim 26, wherein the reduction in plasma levels of behenic acid is about 24% relative to baseline.

36. The method of claim 25, wherein the reduction in plasma levels of behenic acid is from about 1 μmol / L to about 40 μmol / L relative to baseline.

37. The method of claim 36, wherein the reduction in plasma levels of behenic acid is from about 4 μmol / L to about 16 μmol / L relative to baseline.

38. The method of claim 36, wherein the reduction in plasma levels of behenic acid is at least about 4 μmol / L relative to baseline.

39. The method of claim 36, wherein the reduction in plasma levels of behenic acid is at least about 10 μmol / L relative to baseline.

40. The method of claim 36, wherein the reduction in plasma levels of behenic acid is at least about 11 μmol / L relative to baseline.

41. The method of claim 36, wherein the reduction in plasma levels of behenic acid is at least about 16 μmol / L relative to baseline.

42. The method of claim 36, wherein the reduction in plasma levels of behenic acid is about 4 μmol / L relative to baseline.

43. The method of claim 36, wherein the reduction in plasma levels of behenic acid is about 10 μmol / L relative to baseline.

44. The method of claim 36, wherein the reduction in plasma levels of behenic acid is about 11 μmol / L relative to baseline.

45. The method of claim 36, wherein the reduction in plasma levels of behenic acid is about 16 μmol / L relative to baseline.

46. ​​The method of claim 24, wherein the dosing regimen is sufficient to reduce plasma levels of hexacosanoid relative to baseline.

47. The method of claim 46, wherein the reduction in plasma levels of hexacosanoid is from about 1% to about 50% relative to baseline.

48. The method of claim 47, wherein the reduction in plasma levels of hexacosanoid is from about 10% to about 23% relative to baseline.

49. The method of claim 47, wherein the reduction in plasma levels of hexacosanoic acid is at least about 10% relative to baseline.

50. The method of claim 47, wherein the reduction in plasma levels of hexacosanoic acid is at least about 15% relative to baseline.

51. The method of claim 47, wherein the reduction in plasma levels of hexacosanoid is at least about 23% relative to baseline.

52. The method of claim 47, wherein the reduction in plasma levels of hexacosanoid is about 10% relative to baseline.

53. The method of claim 47, wherein the reduction in plasma levels of hexacosanoid is about 15% relative to baseline.

54. The method of claim 47, wherein the reduction in plasma levels of hexacosanoid is about 23% relative to baseline.

55. The method of claim 46, wherein the reduction in plasma levels of hexacosanoid is from about 0.01 μmol / L to about 1 μmol / L relative to baseline.

56. The method of claim 55, wherein the reduction in plasma levels of hexacosanoid is from about 0.05 μmol / L to about 0.1 μmol / L relative to baseline.

57. The method of claim 55, wherein the reduction in plasma levels of hexacosanoid is at least about 0.05 μmol / L relative to baseline.

58. The method of claim 55, wherein the reduction in plasma levels of hexacosanoid is at least about 0.06 μmol / L relative to baseline.

59. The method of claim 55, wherein the reduction in plasma levels of hexacosanoid is at least about 0.1 μmol / L relative to baseline.

60. The method of claim 55, wherein the reduction in plasma levels of hexacosanoid is about 0.05 μmol / L relative to baseline.

61. The method of claim 55, wherein the reduction in plasma levels of hexacosanoid is about 0.06 μmol / L relative to baseline.

62. The method of claim 55, wherein the reduction in plasma levels of hexacosanoid is about 0.1 μmol / L relative to baseline.

63. The method of claim 24, wherein the dosing regimen is sufficient to reduce plasma levels of lignoceric acid relative to baseline.

64. The method of claim 63, wherein the reduction in plasma levels of lignoceric acid is from about 1% to about 50% relative to baseline.

65. The method of claim 64, wherein the reduction in plasma levels of lignoceric acid is from about 3% to about 24% relative to baseline.

66. The method of claim 64, wherein the reduction in plasma levels of lignoceric acid is at least about 3% relative to baseline.

67. The method of claim 64, wherein the reduction in plasma levels of lignoceric acid is at least about 14% relative to baseline.

68. The method of claim 64, wherein the reduction in plasma levels of lignoceric acid is at least about 24% relative to baseline.

69. The method of claim 64, wherein the reduction in plasma levels of lignoceric acid is about 3% relative to baseline.

70. The method of claim 64, wherein the reduction in plasma levels of lignoceric acid is about 14% relative to baseline.

71. The method of claim 64, wherein the reduction in plasma levels of lignoceric acid is about 24% relative to baseline.

72. The method of claim 63, wherein the reduction in plasma levels of lignoceric acid is from about 1 μmol / L to about 40 μmol / L relative to baseline.

73. The method of claim 72, wherein the reduction in plasma levels of lignoceric acid is from about 3 μmol / L to about 14 μmol / L relative to baseline.

74. The method of claim 72, wherein the reduction in plasma levels of lignoceric acid is at least about 3 μmol / L relative to baseline.

75. The method of claim 72, wherein the reduction in plasma levels of lignoceric acid is at least about 10 μmol / L relative to baseline.

76. The method of claim 72, wherein the reduction in plasma levels of lignoceric acid is at least about 14 μmol / L relative to baseline.

77. The method of claim 72, wherein the reduction in plasma levels of lignoceric acid is about 3 μmol / L relative to baseline.

78. The method of claim 72, wherein the reduction in plasma levels of lignoceric acid is about 10 μmol / L relative to baseline.

79. The method of claim 72, wherein the reduction in plasma levels of lignoceric acid is about 14 μmol / L relative to baseline.

80. The method of any one of claims 23 to 79, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of lignoceric acid:behenic acid relative to baseline.

81. The method of any one of claims 23 to 79, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of hexacosanoic acid:behenic acid relative to baseline.

82. The method of any one of claims 23 to 79, wherein the dosing regimen results in substantially no change in the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to a baseline level.

83. The method of any one of claims 23 to 82, wherein the dosing regimen comprises administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg.

84. The method of any one of claims 23 to 83, wherein the subject suffers from adrenomyeloneuropathy.

85. The method of any one of claims 23 to 84, wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C ) of about 100 ng / mL to about 800 ng / mL or about 104 ng / mL to about 653 ng / mL of the compound in the subject. max ); optionally wherein said C max Selected from about 104 ng / mL, about 274 ng / mL, about 395 ng / mL and about 603 ng / mL.

86. The method of any one of claims 23 to 85, wherein the dosing regimen is sufficient to achieve a mean plasma concentration time area under the curve (AUC) of about 800 h*ng / mL to about 7000 h*ng / mL or 999 h*ng / mL to about 4550 h*ng / mL of the compound in the subject over 24 hours. 0-24 ); optionally wherein the AUC 0-24 Selected from about 999 h*ng / mL, about 2980 h*ng / mL, about 3320 h*ng / mL and about 4550 h*ng / mL.

87. The method of any one of claims 23 to 86, wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (Tmax) of the compound of about 2.0 h to about 7.0 h or 3.86 h to about 5.19 h. max ); optionally wherein said T max Selected from about 3.86h, about 5.19h and about 4.36h.

88. The method of any one of claims 23 to 87, wherein the dosing regimen is sufficient to achieve a mean half-life (T ) of the compound in the subject of about 10 h to about 20 h or about 13.1 to about 15.3 h. 1 / 2 ); optionally wherein said T 1 / 2 Selected from about 13.1 h, about 14.9 h, about 15.3 h and about 14.3 h.

89. The method of any one of claims 23 to 88, wherein the dosing regimen is sufficient to achieve a mean oral clearance rate (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h or about 16.4 L / h to about 27.5 L / h; optionally wherein CL / F is selected from about 27.5 L / h, about 16.4 L / h, about 22.6 L / h, and about 20.1 L / h.

90. A method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1): or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C ) of about 100 ng / mL to about 800 ng / mL of the compound in the subject max ).

91. The method of claim 90, wherein said C max From about 104 ng / mL to about 653 ng / mL.

92. The method of claim 90, wherein said C max is at least about 104 ng / mL.

93. The method of claim 90, wherein the C max is at least about 274 ng / mL.

94. The method of claim 90, wherein said C max is at least about 395 ng / mL.

95. The method of claim 90, wherein said C max is at least about 603 ng / mL.

96. The method of claim 90, wherein said C max It is about 104ng / mL.

97. The method of claim 90, wherein said C max It is about 274ng / mL.

98. The method of claim 90, wherein said C max It is about 395ng / mL.

99. The method of claim 90, wherein the C max It is about 603ng / mL.

100. The method of any one of claims 90 to 99, wherein the dosing regimen is sufficient to reduce plasma levels of one or more saturated very long chain fatty acids (VLCFA) in the subject.

101. The method of claim 100, wherein the one or more VLCFAs are selected from behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and combinations thereof.

102. The method of claim 101, wherein the dosing regimen is sufficient to reduce plasma levels of behenic acid in the subject; optionally wherein the reduction in plasma levels of behenic acid is from about 1% to about 60% relative to baseline or from about 4% to about 24% relative to baseline; optionally wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4%, about 12%, about 14%, about 24%, about 30%, about 40%, about 50%, and about 60%.

103. The method of claim 102, wherein the reduction in plasma levels of behenic acid is from about 1 μmol / L to about 40 μmol / L or from about 4 μmol / L to about 16 μmol / L relative to baseline; optionally, wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4 μmol / L, about 10 μmol / L, about 11 μmol / L, about 16 μmol / L, about 20 μmol / L and about 25 μmol / L and about 40 μmol / L relative to baseline.

104. The method of claim 101, wherein the dosing regimen is sufficient to reduce plasma levels of hexacosanoid in the subject relative to baseline; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is from about 1% to about 50% or from about 10% to about 23%; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is selected from about 10%, about 15%, about 23%, about 30%, about 40%, and about 50%.

105. The method of claim 104, wherein the reduction in plasma levels of cocoanoic acid relative to baseline is from about 0.01 μmol / L to about 1 μmol / L or from about 0.05 μmol / L to about 0.1 μmol / L; optionally wherein the reduction in plasma levels of cocoanoic acid relative to baseline is selected from about 0.05 μmol / L, about 0.06 μmol / L, about 0.1 μmol / L, about 0.2 μmol / L, about 0.5 μmol / L and about 1 μmol / L.

106. The method of claim 101, wherein the dosing regimen is sufficient to reduce plasma levels of lignoceric acid in the subject relative to baseline; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1% to about 50% or from about 3% to about 24%; optionally wherein the reduction in plasma levels of lignoceric acid is selected from about 3%, about 14%, about 24%, about 40%, and about 50%.

107. The method of claim 106, wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1 μmol / L to about 40 μmol / L or from about 3 μmol / L to about 14 μmol / L; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is selected from about 3 μmol / L, about 10 μmol / L, about 14 μmol / L, about 30 μmol / L and about 40 μmol / L.

108. The method of any one of claims 90 to 107, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of lignoceric acid:behenic acid from baseline.

109. The method of any one of claims 90 to 107, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of hexacosanoic acid:behenic acid from baseline.

110. The method of any one of claims 90 to 109, wherein the dosing regimen results in substantially no change in the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to a baseline level.

111. The method of any one of claims 90 to 110, wherein the dosing regimen is sufficient to achieve a mean plasma concentration time curve area (AUC) of about 800 h*ng / mL to about 7000 h*ng / mL or 999 h*ng / mL to about 4550 h*ng / mL of the compound in the subject over 24 hours. 0-24 ); optionally wherein the AUC 0-24 Selected from about 999 h*ng / mL, about 2980 h*ng / mL, about 3320 h*ng / mL and about 4550 h*ng / mL.

112. The method of any one of claims 90 to 111, wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (Tmax) of the compound of about 2.0 h to about 7.0 h or 3.86 h to about 5.19 h. max ); optionally wherein said T max Selected from about 3.86h, about 5.19h and about 4.36h.

113. The method of any one of claims 90 to 112, wherein the dosing regimen is sufficient to achieve a mean half-life (T ) of the compound in the subject of about 10 h to about 20 h or about 13.1 to about 15.3 h. 1 / 2 ); optionally wherein said T 1 / 2 Selected from about 13.1 h, about 14.9 h, about 15.3 h and about 14.3 h.

114. The method of any one of claims 90 to 113, wherein the dosing regimen is sufficient to achieve a mean oral clearance rate (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h or about 16.4 L / h to about 27.5 L / h; optionally wherein CL / F is selected from about 27.5 L / h, about 16.4 L / h, about 22.6 L / h, and about 20.1 L / h.

115. A method for treating X-linked adrenoleukodystrophy, the method comprising administering to a subject in need thereof a compound (1): or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve a mean plasma concentration-time area under the curve (AUC) of about 800 h*ng / mL to about 7000 h*ng / mL of the compound within 24 hours in the subject. 0-24 ).

116. The method of claim 115, wherein the AUC 0-24 From about 999 h*ng / mL to about 4550 h*ng / mL.

117. The method of claim 115, wherein the AUC 0-24 At least about 999 h*ng / mL.

118. The method of claim 115, wherein the AUC 0-24 is at least about 2980 h*ng / mL.

119. The method of claim 115, wherein the AUC 0-24 is at least about 3320 h*ng / mL.

120. The method of claim 115, wherein the AUC 0-24 is at least about 4550 h*ng / mL.

121. The method of claim 115, wherein the AUC 0-24 It is about 999h*ng / mL.

122. The method of claim 115, wherein the AUC 0-24 It is about 2980h*ng / mL.

123. The method of claim 115, wherein the AUC 0-24 It is about 3320h*ng / mL.

124. The method of claim 115, wherein the AUC 0-24 It is about 4550h*ng / mL.

125. The method of any one of claims 115 to 124, wherein the dosing regimen comprises administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg.

126. The method of any one of claims 115 to 125, wherein the subject suffers from adrenomyeloneuropathy.

127. The method of any one of claims 115 to 126, wherein the dosing regimen is sufficient to reduce plasma levels of one or more saturated very long chain fatty acids (VLCFA) in the subject.

128. The method of claim 127, wherein the one or more VLCFAs are selected from behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and combinations thereof.

129. The method of claim 128, wherein the dosing regimen is sufficient to reduce plasma levels of behenic acid in the subject; optionally wherein the reduction in plasma levels of behenic acid is from about 1% to about 60% relative to baseline or from about 4% to about 24% relative to baseline; optionally wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4%, about 12%, about 14%, about 24%, about 30%, about 40%, about 50%, and about 60%.

130. The method of claim 129, wherein the reduction in plasma levels of behenic acid is from about 1 μmol / L to about 40 μmol / L or from about 4 μmol / L to about 16 μmol / L relative to baseline; optionally, wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4 μmol / L, about 10 μmol / L, about 11 μmol / L, about 16 μmol / L, about 20 μmol / L and about 25 μmol / L and about 40 μmol / L relative to baseline.

131. The method of claim 128, wherein the dosing regimen is sufficient to reduce plasma levels of hexacosanoid in the subject relative to baseline; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is from about 1% to about 50% or from about 10% to about 23%; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is selected from about 10%, about 15%, about 23%, about 30%, about 40%, and about 50%.

132. The method of claim 131, wherein the reduction in plasma levels of cocosanoic acid relative to baseline is from about 0.01 μmol / L to about 1 μmol / L or from about 0.05 μmol / L to about 0.1 μmol / L; optionally wherein the reduction in plasma levels of cocosanoic acid relative to baseline is selected from about 0.05 μmol / L, about 0.06 μmol / L, about 0.1 μmol / L, about 0.2 μmol / L, about 0.5 μmol / L and about 1 μmol / L.

133. The method of claim 128, wherein the dosing regimen is sufficient to reduce plasma levels of lignoceric acid in the subject relative to baseline; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1% to about 50% or from about 3% to about 24%; optionally wherein the reduction in plasma levels of lignoceric acid is selected from about 3%, about 14%, about 24%, about 40%, and about 50%.

134. The method of claim 133, wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1 μmol / L to about 40 μmol / L or from about 3 μmol / L to about 14 μmol / L; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is selected from about 3 μmol / L, about 10 μmol / L, about 14 μmol / L, about 30 μmol / L and about 40 μmol / L.

135. The method of any one of claims 115 to 134, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of lignoceric acid:behenic acid relative to baseline.

136. The method of any one of claims 115 to 134, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of hexacosanoic acid:behenic acid relative to baseline.

137. The method of any one of claims 115 to 136, wherein the dosing regimen results in substantially no change in the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to a baseline level.

138. The method of any one of claims 115 to 137, wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C ) of the compound in the subject of about 100 ng / mL to about 800 ng / mL or about 104 ng / mL to about 653 ng / mL. max ); optionally wherein said C max Selected from about 104 ng / mL, about 274 ng / mL, about 395 ng / mL and about 603 ng / mL.

139. The method of any one of claims 115 to 138, wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (Tmax) of the compound of about 2.0 h to about 7.0 h or 3.86 h to about 5.19 h. max ); optionally wherein said T max Selected from about 3.86h, about 5.19h and about 4.36h.

140. The method of any one of claims 115 to 139, wherein the dosing regimen is sufficient to achieve a mean half-life (T ) of the compound in the subject of about 10 h to about 20 h or about 13.1 to about 15.3 h. 1 / 2 ); optionally wherein said T 1 / 2 Selected from about 13.1 h, about 14.9 h, about 15.3 h and about 14.3 h.

141. The method of any one of claims 115 to 140, wherein the dosing regimen is sufficient to achieve a mean oral clearance rate (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h or about 16.4 L / h to about 27.5 L / h; optionally wherein CL / F is selected from about 27.5 L / h, about 16.4 L / h, about 22.6 L / h, and about 20.1 L / h.

142. A method for treating X-linked adrenoleukodystrophy, the method comprising administering to a subject in need thereof a compound (1): or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (T) of the compound of about 2.0 to about 7.0 hours max ).

143. The method of claim 142, wherein the T max From about 3.86h to about 5.19h.

144. The method of claim 142, wherein the T max is at least about 3.86 h.

145. The method of claim 142, wherein the T max is at least about 5.19 h.

146. The method of claim 142, wherein the T max is at least about 4.36 h.

147. The method of claim 142, wherein the T max It is about 3.86h.

148. The method of claim 142, wherein the T max It is about 5.19h.

149. The method of claim 142, wherein the T max It is about 4.36h.

150. The method of any one of claims 142 to 149, wherein the dosing regimen comprises administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg.

151. The method of any one of claims 142 to 150, wherein the subject suffers from adrenomyeloneuropathy.

152. The method of any one of claims 142 to 151, wherein the dosing regimen is sufficient to reduce plasma levels of one or more saturated very long chain fatty acids (VLCFA) in the subject.

153. The method of claim 152, wherein the one or more VLCFAs are selected from behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and combinations thereof.

154. The method of claim 153, wherein the dosing regimen is sufficient to reduce plasma levels of behenic acid in the subject; optionally wherein the reduction in plasma levels of behenic acid is from about 1% to about 60% relative to baseline or from about 4% to about 24% relative to baseline; optionally wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4%, about 12%, about 14%, about 24%, about 30%, about 40%, about 50%, and about 60%.

155. The method of claim 154, wherein the reduction in plasma levels of behenic acid is from about 1 μmol / L to about 40 μmol / L or from about 4 μmol / L to about 16 μmol / L relative to baseline; optionally, wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4 μmol / L, about 10 μmol / L, about 11 μmol / L, about 16 μmol / L, about 20 μmol / L and about 25 μmol / L and about 40 μmol / L relative to baseline.

156. The method of claim 153, wherein the dosing regimen is sufficient to reduce plasma levels of hexacosanoid in the subject relative to baseline; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is from about 1% to about 50% or from about 10% to about 23%; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is selected from about 10%, about 15%, about 23%, about 30%, about 40%, and about 50%.

157. The method of claim 156, wherein the reduction in plasma levels of cocoanoic acid relative to baseline is from about 0.01 μmol / L to about 1 μmol / L or from about 0.05 μmol / L to about 0.1 μmol / L; optionally wherein the reduction in plasma levels of cocoanoic acid relative to baseline is selected from about 0.05 μmol / L, about 0.06 μmol / L, about 0.1 μmol / L, about 0.2 μmol / L, about 0.5 μmol / L and about 1 μmol / L.

158. The method of claim 153, wherein the dosing regimen is sufficient to reduce plasma levels of lignoceric acid in the subject relative to baseline; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1% to about 50% or from about 3% to about 24%; optionally wherein the reduction in plasma levels of lignoceric acid is selected from about 3%, about 14%, about 24%, about 40%, and about 50%.

159. The method of claim 158, wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1 μmol / L to about 40 μmol / L or from about 3 μmol / L to about 14 μmol / L; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is selected from about 3 μmol / L, about 10 μmol / L, about 14 μmol / L, about 30 μmol / L and about 40 μmol / L.

160. The method of any one of claims 142 to 159, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of lignoceric acid:behenic acid relative to baseline.

161. The method of any one of claims 142 to 159, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of hexacosanoic acid:behenic acid relative to baseline.

162. The method of any one of claims 142 to 161, wherein the dosing regimen results in substantially no change in the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to a baseline level.

163. The method of any one of claims 142 to 162, wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C ) of the compound in the subject of about 100 ng / mL to about 800 ng / mL or about 104 ng / mL to about 653 ng / mL. max ); optionally wherein said C max Selected from about 104 ng / mL, about 274 ng / mL, about 395 ng / mL and about 603 ng / mL.

164. The method of any one of claims 142 to 163, wherein the dosing regimen is sufficient to achieve a mean plasma concentration time curve area (AUC) of about 800 h*ng / mL to about 7000 h*ng / mL or 999 h*ng / mL to about 4550 h*ng / mL of the compound in the subject over 24 hours. 0-24 ); optionally wherein the AUC 0-24 Selected from about 999 h*ng / mL, about 2980 h*ng / mL, about 3320 h*ng / mL and about 4550 h*ng / mL.

165. The method of any one of claims 142 to 164, wherein the dosing regimen is sufficient to achieve a mean half-life (T ) of the compound in the subject of about 10 h to about 20 h or about 13.1 to about 15.3 h. 1 / 2 ); optionally wherein said T 1 / 2 Selected from about 13.1 h, about 14.9 h, about 15.3 h and about 14.3 h.

166. The method of any one of claims 142 to 165, wherein the dosing regimen is sufficient to achieve a mean oral clearance rate (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h or about 16.4 L / h to about 27.5 L / h; optionally wherein CL / F is selected from about 27.5 L / h, about 16.4 L / h, about 22.6 L / h, and about 20.1 L / h.

167. A method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1): or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve a mean half-life (T) of the compound in the subject of about 10 h to about 20 h 1 / 2 ).

168. The method of claim 167, wherein the T 1 / 2 From about 13.1h to about 15.3h.

169. The method of claim 167, wherein the T 1 / 2 is at least about 13.1 h.

170. The method of claim 167, wherein the T 1 / 2 is at least about 14.9 h.

171. The method of claim 167, wherein the T 1 / 2 is at least about 15.3 h.

172. The method of claim 167, wherein the T 1 / 2 is at least about 14.3 h.

173. The method of claim 167, wherein the T 1 / 2 It is about 13.1h.

174. The method of claim 167, wherein the T 1 / 2 It is about 14.9h.

175. The method of claim 167, wherein the T 1 / 2 It is about 15.3h.

176. The method of claim 167, wherein the T 1 / 2 It is about 14.3h.

177. The method of any one of claims 167 to 176, wherein the dosing regimen comprises administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg.

178. The method of any one of claims 167 to 177, wherein the subject suffers from adrenomyeloneuropathy.

179. The method of any one of claims 167 to 178, wherein the dosing regimen is sufficient to reduce plasma levels of one or more saturated very long chain fatty acids (VLCFA) in the subject.

180. The method of claim 179, wherein the one or more VLCFAs are selected from behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and combinations thereof.

181. The method of claim 180, wherein the dosing regimen is sufficient to reduce plasma levels of behenic acid in the subject; optionally wherein the reduction in plasma levels of behenic acid is from about 1% to about 60% relative to baseline or from about 4% to about 24% relative to baseline; optionally wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4%, about 12%, about 14%, about 24%, about 30%, about 40%, about 50%, and about 60%.

182. The method of claim 181, wherein the reduction in plasma levels of behenic acid is from about 1 μmol / L to about 40 μmol / L or from about 4 μmol / L to about 16 μmol / L relative to baseline; optionally, wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4 μmol / L, about 10 μmol / L, about 11 μmol / L, about 16 μmol / L, about 20 μmol / L and about 25 μmol / L and about 40 μmol / L relative to baseline.

183. The method of claim 180, wherein the dosing regimen is sufficient to reduce plasma levels of hexacosanoid in the subject relative to baseline; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is from about 1% to about 50% or from about 10% to about 23%; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is selected from about 10%, about 15%, about 23%, about 30%, about 40% and about 50%.

184. The method of claim 183, wherein the reduction in plasma levels of cocoanoic acid relative to baseline is from about 0.01 μmol / L to about 1 μmol / L or from about 0.05 μmol / L to about 0.1 μmol / L; optionally wherein the reduction in plasma levels of cocoanoic acid relative to baseline is selected from about 0.05 μmol / L, about 0.06 μmol / L, about 0.1 μmol / L, about 0.2 μmol / L, about 0.5 μmol / L and about 1 μmol / L.

185. The method of claim 180, wherein the dosing regimen is sufficient to reduce plasma levels of lignoceric acid in the subject relative to baseline; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1% to about 50% or from about 3% to about 24%; optionally wherein the reduction in plasma levels of lignoceric acid is selected from about 3%, about 14%, about 24%, about 40%, and about 50%.

186. The method of claim 285, wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1 μmol / L to about 40 μmol / L or from about 3 μmol / L to about 14 μmol / L; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is selected from about 3 μmol / L, about 10 μmol / L, about 14 μmol / L, about 30 μmol / L and about 40 μmol / L.

187. The method of any one of claims 167 to 186, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of lignoceric acid:behenic acid relative to baseline.

188. The method of any one of claims 167 to 186, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of hexacosanoid:behenic acid relative to baseline.

189. The method of any one of claims 167 to 188, wherein the dosing regimen results in substantially no change in the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to a baseline level.

190. The method of any one of claims 167 to 189, wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C ) of the compound in the subject of about 100 ng / mL to about 800 ng / mL or about 104 ng / mL to about 653 ng / mL. max ); optionally wherein said C max Selected from about 104 ng / mL, about 274 ng / mL, about 395 ng / mL and about 603 ng / mL.

191. The method of any one of claims 167 to 190, wherein the dosing regimen is sufficient to achieve a mean plasma concentration time curve area (AUC) of about 800 h*ng / mL to about 7000 h*ng / mL or 999 h*ng / mL to about 4550 h*ng / mL of the compound in the subject over 24 hours. 0-24 ); optionally wherein the AUC 0-24 Selected from about 999 h*ng / mL, about 2980 h*ng / mL, about 3320 h*ng / mL and about 4550 h*ng / mL.

192. The method of any one of claims 167 to 191, wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (Tmax) of the compound of about 2.0 h to about 7.0 h or 3.86 h to about 5.19 h. max ); optionally wherein said T max Selected from about 3.86h, about 5.19h and about 4.36h.

193. The method of any one of claims 167 to 192, wherein the dosing regimen is sufficient to achieve a mean oral clearance rate (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h or about 16.4 L / h to about 27.5 L / h; optionally wherein CL / F is selected from about 27.5 L / h, about 16.4 L / h, about 22.6 L / h, and about 20.1 L / h.

194. A method of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject compound (1): or a therapeutically effective dosage regimen of a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve a mean oral clearance (CL / F) of the compound in the subject of about 15 L / h to about 30 L / h.

195. The method of claim 194, wherein CL / F is about 16.4 L / h to about 27.5 L / h.

196. The method of claim 194, wherein CL / F is at least about 27.5 L / h.

197. The method of claim 194, wherein CL / F is at least about 16.4 L / h.

198. The method of claim 194, wherein CL / F is at least about 22.6 L / h.

199. The method of claim 194, wherein CL / F is at least about 20.1 L / h.

200. The method of claim 194, wherein CL / F is about 27.5 L / h.

201. The method of claim 194, wherein CL / F is about 16.4 L / h.

202. The method of claim 194, wherein CL / F is about 22.6 L / h.

203. The method of claim 194, wherein CL / F is about 20.1 L / h.

204. The method of any one of claims 194 to 203, wherein the dosing regimen comprises administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg.

205. The method of any one of claims 194 to 204, wherein the subject suffers from adrenomyeloneuropathy.

206. The method of any one of claims 194 to 205, wherein the dosing regimen is sufficient to reduce plasma levels of one or more saturated very long chain fatty acids (VLCFA) in the subject.

207. The method of claim 206, wherein the one or more VLCFAs are selected from behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and combinations thereof.

208. The method of claim 207, wherein the dosing regimen is sufficient to reduce plasma levels of behenic acid in the subject; optionally wherein the reduction in plasma levels of behenic acid is from about 1% to about 60% relative to baseline or from about 4% to about 24% relative to baseline; optionally wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4%, about 12%, about 14%, about 24%, about 30%, about 40%, about 50%, and about 60%.

209. The method of claim 208, wherein the reduction in plasma levels of behenic acid is from about 1 μmol / L to about 40 μmol / L or from about 4 μmol / L to about 16 μmol / L relative to baseline; optionally, wherein the reduction in plasma levels of behenic acid relative to baseline is selected from about 4 μmol / L, about 10 μmol / L, about 11 μmol / L, about 16 μmol / L, about 20 μmol / L and about 25 μmol / L and about 40 μmol / L relative to baseline.

210. The method of claim 207, wherein the dosing regimen is sufficient to reduce plasma levels of hexacosanoid in the subject relative to baseline; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is from about 1% to about 50% or from about 10% to about 23%; optionally wherein the reduction in plasma levels of hexacosanoid relative to baseline is selected from about 10%, about 15%, about 23%, about 30%, about 40% and about 50%.

211. The method of claim 210, wherein the reduction in plasma levels of cocoanoic acid relative to baseline is from about 0.01 μmol / L to about 1 μmol / L or from about 0.05 μmol / L to about 0.1 μmol / L; optionally wherein the reduction in plasma levels of cocoanoic acid relative to baseline is selected from about 0.05 μmol / L, about 0.06 μmol / L, about 0.1 μmol / L, about 0.2 μmol / L, about 0.5 μmol / L and about 1 μmol / L.

212. The method of claim 207, wherein the dosing regimen is sufficient to reduce plasma levels of lignoceric acid in the subject relative to baseline; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1% to about 50% or from about 3% to about 24%; optionally wherein the reduction in plasma levels of lignoceric acid is selected from about 3%, about 14%, about 24%, about 40% and about 50%.

213. The method of claim 212, wherein the reduction in plasma levels of lignoceric acid relative to baseline is from about 1 μmol / L to about 40 μmol / L or from about 3 μmol / L to about 14 μmol / L; optionally wherein the reduction in plasma levels of lignoceric acid relative to baseline is selected from about 3 μmol / L, about 10 μmol / L, about 14 μmol / L, about 30 μmol / L and about 40 μmol / L.

214. The method of any one of claims 194 to 213, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of lignoceric acid:behenic acid relative to baseline.

215. The method of any one of claims 194 to 213, wherein the dosing regimen results in substantially no change in the ratio of plasma levels of hexacosanoic acid:behenic acid relative to baseline.

216. The method of any one of claims 194 to 215, wherein the dosing regimen results in substantially no change in the ratio of hexacosanoid:lysophosphatidylcholine in red blood cells relative to a baseline level.

217. The method of any one of claims 194 to 216, wherein the dosing regimen is sufficient to achieve a maximum mean plasma concentration (C ) of the compound in the subject of about 100 ng / mL to about 800 ng / mL or about 104 ng / mL to about 653 ng / mL. max ); optionally wherein said C max Selected from about 104 ng / mL, about 274 ng / mL, about 395 ng / mL and about 603 ng / mL.

218. The method of any one of claims 194 to 217, wherein the dosing regimen is sufficient to achieve a mean plasma concentration-time area under the curve (AUC) of about 800 h*ng / mL to about 7000 h*ng / mL or 999 h*ng / mL to about 4550 h*ng / mL of the compound in the subject over 24 hours. 0-24 ); optionally wherein the AUC 0-24 Selected from about 999 h*ng / mL, about 2980 h*ng / mL, about 3320 h*ng / mL and about 4550 h*ng / mL.

219. The method of any one of claims 194 to 243, wherein the dosing regimen is sufficient to achieve a mean time to maximum plasma concentration (Tmax) of the compound of about 2.0 h to about 7.0 h or 3.86 h to about 5.19 h. max ); optionally wherein said T max Selected from about 3.86h, about 5.19h and about 4.36h.

220. The method of any one of claims 194 to 244, wherein the dosing regimen is sufficient to achieve a mean half-life (T ) of the compound in the subject of about 10 h to about 20 h or about 13.1 to about 15.3 h. 1 / 2 ); optionally wherein said T 1 / 2 Selected from about 13.1 h, about 14.9 h, about 15.3 h and about 14.3 h.

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