Thyroid beta-agonist dosing regimens for the treatment of x-ald

Abstract

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

Description

[0001] TH Y ROID BETA-AGONIST DOSING REGIMENS FOR THE TREATMENT OF X-ALD

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to US Provisional Application No. 63 / 352,350, filed on June 15, 2022, the contents of which are hereby incorporated by reference in their entirety.

[0004] BACKGROUND

[0005] Adrenoleukodystrophy (also known as X-linked adrenoleukodystrophy, X-ALD) is a disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the body. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes. As an X-linked disorder, X-ALD primarily manifest in males; however, approximately 50% of heterozygote females show some symptoms later in life. The most severe form of X-ALD is known as cerebral ALD, and is characterized by a rapidly progressive inflammatory demyelination process in brain tissue. This form is more common in early childhood, typically presenting in children under the age of 12. Patients with cerebral ALD typically experience rapid degeneration to a vegetative state within 3 to 5 years. The more common form of X-ALD is known as adrenomyeloneuropathy (AMN). This form of the disease manifests later in life, typically between the ages of 25 and 45. AMN affects the spinal cord and motor neurons, but has no inflammatory component or brain involvement. AMN patients first present with trouble walking leading to progressive motor impairment with leg paralysis.

[0006] ALD is caused by mutations in the gene for the ATP-Binding Cassette transporter dl (ABCD1) located on the X chromosome. ABCD1 functions to transport very long chain fatty acids (VLCFA) into peroxisome for degradation. In X-ALD, defective ABCD1 leads to the accumulation of VLCFA. Individuals with X-ALD show 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 therapy. Thus, there is a need for improved methods and dosing regimens for treating X-ALD.

[0007] SUMMARY OF THE INVENTION

[0008] In certain aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of compound (1):

[0009] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen comprises administering a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg to the subject once daily.

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

[0011] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to decrease blood plasma levels of saturated very long- chain fatty acids (VLCFAs) in the subject after about 28 days.

[0012] In yet further aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of a compound (1):

[0013]

[0014] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL in the subject.

[0015] In still further aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy, comprising administering to a subject in need thereof a therapeutically effective dose regimen of a compound (1):

[0016] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUC0-24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL.

[0017] In certain aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy, comprising administering to a subject in need thereof a therapeutically effective dose regimen of a compound (1):

[0018] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 to about 7.0 hours.

[0019] In further aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of a compound (1):

[0020] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average half-life (T 1 / 2) of the compound from about 10 h to about 20 h in the subject.

[0021] In yet further aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of a compound (1):

[0022] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h in the subject.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a scheme showing the setup of the Phase lb study of Compound 1 detailed in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0025] Methods of the disclosure

[0026] In certain aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of compound (1):

[0027] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen comprises administering a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg to the subject once daily.

[0028] In certain embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the dosing regimen comprises administering a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg to the subject once daily. In some such embodiments, the dose is about 20 mg. In other such embodiments, the dose is about 40 mg. In yet other such embodiments, the dose is about 60 mg. In still other such embodiments, the dose is about 80 mg.

[0029] In other aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of a compound (1):

[0030] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to decrease blood plasma levels of saturated very long- chain fatty acids (VLCFAs) in the subject after about 28 days. In some embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the dosing regimen is sufficient to decrease blood plasma levels of one or more saturated very long-chain fatty acids (VLCFAs) in the subject. In certain such embodiments, the one or more VLCFAs are selected from behenic acid, tetracosanoic acid, hexacosanoic acid octacosanoic acid, triacontanoic acid, and combinations thereof. In further embodiments, dosing regimen is sufficient to decrease plasma levels of behenic acid in the subject from baseline. In further embodiments, the decrease in plasma levels of behenic acid is from about 1% to about 60% from baseline. In certain such embodiments, the decrease in plasma levels of behenic acid is from about 4% to about 24% from baseline. In some embodiments, the decrease in plasma levels of behenic acid is at least about 4% from baseline. In other embodiments, the decrease in plasma levels of behenic acid is at least about 12% from baseline. In yet other embodiments, the decrease in plasma levels of behenic acid is at least about 14% from baseline. In still other embodiments, the decrease in plasma levels of behenic acid is at least about 24% from baseline. In other embodiments, the decrease in plasma levels of behenic acid is about 4% from baseline. In yet other embodiments, the decrease in plasma levels of behenic acid is about 12% from baseline. In still other embodiments, the decrease in plasma levels of behenic acid is about 14% from baseline. In other embodiments, the decrease in plasma levels of behenic acid is about 24% from baseline. In certain embodiments, the decrease in plasma levels of behenic acid is about 30% from baseline. In other embodiments, the decrease in plasma levels of behenic acid is about 40% from baseline. In yet other embodiments, the decrease in plasma levels of behenic acid is about 50% from baseline. In still other embodiments, the decrease in plasma levels of behenic acid is about 60% from baseline.

[0031] In certain embodiments, the decrease in plasma levels of behenic acid is from about 1 pmol / L to about 40 pmol / L from baseline. In some such embodiments, the decrease in plasma levels of behenic acid is from about 4 pmol / L to about 16 pmol / L from baseline. In some embodiments, the decrease in plasma levels of behenic acid is at least about 4 pmol / L from baseline. In other embodiments, the decrease in plasma levels of behenic acid is at least about 10 pmol / L from baseline. In yet other embodiments, the decrease in plasma levels of behenic acid is at least about 11 pmol / L from baseline. In still other embodiments, the decrease in plasma levels of behenic acid is at least about 16 mol / L from baseline. In other embodiments, the decrease in plasma levels of behenic acid is about 4 pmol / L from baseline. In yet other embodiments, the decrease in plasma levels of behenic acid is about 10 pmol / L from baseline. In other embodiments, the decrease in plasma levels of behenic acid is about 11 pmol / L from baseline. In yet other embodiments, the decrease in plasma levels of behenic acid is about 16 pmol / L from baseline. In certain embodiments, the decrease in plasma levels of behenic acid from baseline is about 20 pmol / L. In other embodiments, the decrease in plasma levels of behenic acid from baseline is about 25 pmol / L. In yet other embodiments, the decrease in plasma levels of behenic acid from baseline is about 40 pmol / L.

[0032] In certain embodiments, the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid in the subject from baseline. In some such embodiments, the decrease in plasma levels of hexacosanoic acid is from about 1 % to about 30% from baseline. In further embodiments, the decrease in plasma levels of hexacosanoic acid is from about 10% to about 23% from baseline. In certain such embodiments, the decrease in plasma levels of hexacosanoic acid is at least about 10% from baseline. In other such embodiments, the decrease in plasma levels of hexacosanoic acid is at least about 15% from baseline. In yet other such embodiments, the decrease in plasma levels of hexacosanoic acid is at least about 23% from baseline. In still other such embodiments, the decrease in plasma levels of hexacosanoic acid is about 10% from baseline. In certain embodiments, the decrease in plasma levels of hexacosanoic acid is about 15% from baseline. In other embodiments, the decrease in plasma levels of hexacosanoic acid is about 23% from baseline. In certain embodiments, the decrease in plasma levels of hexacosanoic acid from baseline is about 30%. In certain embodiments, the decrease in plasma levels of hexacosanoic acid from baseline is about 40%. In certain embodiments, the decrease in plasma levels of hexacosanoic acid from baseline is about 50%.

[0033] In certain embodiments, the decrease in plasma levels of hexacosanoic acid is from about 0.01 pmol / L to about 1 pmol / L from baseline. In some such embodiments, the decrease in plasma levels of hexacosanoic acid is from about 0.05 pmol / L to about 0.1 pmol / L from baseline. In further embodiments the decrease in plasma levels of hexacosanoic acid is at least about 0.05 pmol / L from baseline. In other embodiments, the decrease in plasma levels of hexacosanoic acid is at least about 0.06 pmol / L from baseline. In yet other embodiments, the decrease in plasma levels of hexacosanoic acid is at least about 0.1 pmol / L from baseline. In still other embodiments, the decrease in plasma levels of hexacosanoic acid is about 0.05 pmol / L from baseline. In other embodiments, the decrease in plasma levels of hexacosanoic acid is about 0.06 pmol / L from baseline. In yet other embodiments, the decrease in plasma levels of hexacosanoic acid is about 0.1 pmol / L from baseline. In certain embodiments, the decrease in plasma levels of hexacosanoic acid from baseline is about 0.2 pmol / L. In other embodiments, the decrease in plasma levels of hexacosanoic acid from baseline is about 0.5 pmol / L. In yet other embodiments, the decrease in plasma levels of hexacosanoic acid from baseline is about 1 pmol / L.

[0034] In certain embodiments, the dosing regimen is sufficient to decrease plasma levels of tetracosanoic acid in the subject from baseline. In some such embodiments, the decrease in plasma levels of tetracosanoic acid is from about 1% to about 50% from baseline. In further embodiments, the decrease in plasma levels of tetracosanoic acid is from about 3% to about 24% from baseline. In certain such embodiments, the decrease in plasma levels of tetracosanoic acid is at least about 3% from baseline. In other such embodiments, the decrease in plasma levels of tetracosanoic acid is at least about 14% from baseline. In yet other such embodiments, the decrease in plasma levels of tetracosanoic acid is at least about 24% from baseline. In still other such embodiments, the decrease in plasma levels of tetracosanoic acid is about 3% from baseline. In other such embodiments, the decrease in plasma levels of tetracosanoic acid is about 14% from baseline. In yet other such embodiments, the decrease in plasma levels of tetracosanoic acid is about 24% from baseline. In certain embodiments, the decrease in plasma levels of tetracosanoic acid from baseline is about 40%. In other embodiments, the decrease in plasma levels of tetracosanoic acid from baseline is about 50%.

[0035] In certain embodiments, the decrease in plasma levels of tetracosanoic acid is from about 1 pmol / L to about 40 pmol / L from baseline. In some such embodiments, the decrease in plasma levels of tetracosanoic acid is from about 3 pmol / L to about 14 pmol / L from baseline. In further embodiments, the decrease in plasma levels of tetracosanoic acid is at least about 3 pmol / L from baseline. In other embodiments, the decrease in plasma levels of tetracosanoic acid is at least about 10 pmol / L from baseline. In yet other embodiments, the decrease in plasma levels of tetracosanoic acid is at least about 14 mol / L from baseline. In still other embodiments, the decrease in plasma levels of tetracosanoic acid is about 3 pmol / L from baseline. In other embodiments, the decrease in plasma levels of tetracosanoic acid is about 10 pmol / L from baseline. In yet other embodiments, the decrease in plasma levels of tetracosanoic acid is about 14 pmol / L from baseline. In certain embodiments, the decrease in plasma levels of tetracosanoic acid from baseline is about 30 pmol / L. In other embodiments, the decrease in plasma levels of tetracosanoic acid from baseline is about 40 pmol / L.

[0036] In certain embodiments, the dosing regimen results in effectively no change to the plasma level ratio of tetracosanoic:behenic acids from baseline. In some embodiments, the dosing regimen results in a change of about 0 to the plasma level ratio of tetracosanoic :behenic acids from baseline. In certain embodiments, the dosing regimen results in a change of from about -0.1 to about 0.1 in the plasma level ratio of tetracosanoic :behenic acids from baseline. In other embodiments, the dosing regimen results in a decrease in the plasma level ratio of tetracosanoic:behenic acids from baseline. In yet other embodiments, the dosing regimen results in an increase in the plasma level ratio of tetracosanoic :behenic acids from baseline.

[0037] In certain embodiments, the dosing regimen results in effectively no change to the plasma level ratio of hexacosanoic:behenic acids from baseline. In some embodiments, the dosing regimen results in a change of about 0 to the plasma level ratio of hexacosanoic:behenic acids from baseline. In certain embodiments, the dosing regimen results in a change of from about -0.1 to about 0.1 in the plasma level ratio of hexacosanoic:behenic acids from baseline. In certain embodiments, the dosing regimen results in a decrease in the plasma level ratio of hexacosanoic:behenic acids from baseline. In other embodiments, the dosing regimen results in an increase in the plasma level ratio of hexacosanoic:behenic acids from baseline.

[0038] In certain embodiments, the dosing regimen results in effectively no change to the ratio of hexacosanoic aciddysophosphatidylcholines in red blood cells from baseline levels. In other embodiments, the dosing regimen is sufficient to decrease the ratio of hexacosanoic aciddysophosphatidylcholines in red blood cells from baseline levels. In yet other embodiments, the dosing regimen is sufficient to increase the ratio of hexacosanoic aciddysophosphatidylcholines in red blood cells from baseline levels. In yet other aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of a compound (1):

[0039] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL in the subject.

[0040] In some embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL in the subject. In further embodiments, the Cmax is from about 104 ng / mL to about 653 ng / mL. In some such embodiments, the Cmax is at least about 104 ng / mL. In other such embodiments, the Cmax is at least about 274 ng / mL. In yet other such embodiments, the Cmax is at least about 395 ng / mL. In still other such embodiments, the Cmax is at least about 603 ng / mL. In other such embodiments, the Cmax is about 104 ng / mL. In yet other such embodiments, the Cmax is about 274 ng / mL. In yet other such embodiments, the Cmax is about 395 ng / mL. In still other such embodiments, the Cmax is about 603 ng / mL.

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

[0042] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUC0-24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL.

[0043] In certain embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUC0-24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL. In further embodiments, the AUC0-24 is from about 999 h*ng / mL to about 4550 h*ng / mL. In certain such embodiments, the AUC0-24 is at least about 999 h*ng / mL. In other such embodiments, the AUC0-24 is at least about 2980 h*ng / mL. In yet other such embodiments, the AUC0-24 is at least about 3320 h*ng / mL. In still other such embodiments, the AUCo-24 is at least about 4550 h*ng / mL. In other such embodiments, the AUC0-24 is about 999 h*ng / mL. In yet other such embodiments, the AUCo-24 is about 2980 h*ng / mL. In still other such embodiments, the AUCo-24 is about 3320 h*ng / mL. In other such embodiments, the AUCo-24 is about 4550 h*ng / mL.

[0044] In certain aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy, comprising administering to a subject in need thereof a therapeutically effective dose regimen of a compound (1): or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 to about 7.0 hours.

[0045] In certain embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 to about 7.0 hours. In some embodiments, the Tmax is from about 3.86 h to about 5.19 h. In certain such embodiments, the Tmax is at least about 3.86 h. In other such embodiments, the Tmax is at least about 5.19 h. In yet other such embodiments, the Tmax is at least about 4.36 h. In still other such embodiments, wherein the Tmax is about 3.86 h. In other such embodiments, the Tmax is about 5.19 h. In still other such embodiments, the Tmax is about 4.36 h.

[0046] In other aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of a compound (1): or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average half-life (T 1 / 2) of the compound from about 10 h to about 20 h in the subject.

[0047] In certain embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the dosing regimen is sufficient to achieve an average half-life (T 1 / 2) of the compound from about 10 h to about 20 h in the subject. In further embodiments, the T1 / 2 is from about 13.1 h to about 15.3 h. In some such embodiments, the T1 / 2 is at least about 13.1 h. In other such embodiments, the T1 / 2 is at least about 14.9 h. In yet other such embodiments, the T1 / 2 is at least about 15.3 h. In still other such embodiments, the T1 / 2 is at least about 14.3 h. In other such embodiments, wherein the T1 / 2 is about 13.1 h. In yet other such embodiments, the T1 / 2 is about 14.9 h. In still other such embodiments, the T1 / 2 is about 15.3 h. In other such embodiments, the T1 / 2 is about 14.3 h.

[0048] In yet other aspects, the present disclosure provides methods of treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dosing regimen of a compound (1):

[0049]

[0050] (1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h in the subject.

[0051] In certain such embodiments, any of the methods of the present disclosure may comprise a dosing regimen, wherein the dosing regimen is sufficient to achieve a CL / F of the compound from about 15 L / h to about 30 L / h in the subject. In some embodiments, CL / F is from about 16.4 L / h to about 27.5 L / h. In further embodiments, CL / F is at least about 27.5 L / h. In other embodiments, CL / F is at least about 16.4 L / h. In yet other embodiments, CL / F is least about 22.6 L / h. In still other embodiments, CL / F is at least about 20.1 L / h. In other embodiments, CL / F is about 27.5 L / h. In yet other embodiments, CL / F is about 16.4 L / h. In still other embodiments, CL / F is about 22.6 L / h. In other embodiments, CL / F is about 20.1 L / h.

[0052] Pharmaceutical Compositions

[0053] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the 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 preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0054] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0055] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0056] The phrase "pharmaceutically acceptable carrier" as used herein 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 which can serve 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (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 and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0057] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, 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, as well as in patents cited therein.

[0058] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular 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 that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory 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.

[0059] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a 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 pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0060] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), 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 or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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 sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0061] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0062] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion 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 micro-encapsulated form, if appropriate, with one or more of the abovedescribed excipients.

[0063] Liquid dosage forms useful 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 forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0064] 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.

[0065] 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, and mixtures thereof.

[0066] Dosage forms for the 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 with any preservatives, buffers, or propellants that may be required.

[0067] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0068] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0069] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0070] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0071] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0072] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0073] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0074] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide -polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release 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 tissue.

[0075] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0076] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0077] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0078] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) 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.

[0079] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0080] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0081] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0082] The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.

[0083] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.

[0084] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxyl- naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic 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, 1-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, proprionic acid, 1-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid acid salts.

[0085] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0086] 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.

[0087] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0088] Definitions

[0089] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, 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, are those well known and commonly used in the art.

[0090] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0091] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0092] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0093] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known.

[0094] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0095] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0096] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0097] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0098] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0099] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0100] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0101] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0102] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0103] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0104] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

[0105] The term “pharmaceutically acceptable basic addition salt” as used herein means any nontoxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

[0106] Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure.

[0107] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

[0108] EXAMPLES

[0109] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. E ample 1 : Phase lb Pharmacodynamic Study of Compound 1 in Adrenomyeloneuropathy

[0110] 1. Protocol Summary

[0111] 1.1 Synopsis

[0112] Compound 1 is a novel, selective thyroid receptor- P agonist being developed as a disease modifying agent in the treatment of X-linked Adrenoleukodystrophy (X-ALD) and the Adrenomyeloneuropathy Form (AMN).

[0113] The purpose of this study, a phase lb, is to evaluate safety, tolerability, pharmacodynamics and pharmacokinetics of Compound 1 in subjects diagnosed with Adrenomyeloneuropathy (AMN). In addition, this will be the first proof of concept study to evaluate whether Compound 1 treatment results in lowering plasma levels of VLCFAs in subjects with AMN. Table 1 below gives objectives and endpoints of this phase lb study.

[0114] Table 1

[0115]

[0116] Overall Design:

[0117] This study will be a multiple parallel and ascending dose study to evaluate safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of Compound 1, in subjects with AMN. The study will be comprised of 3 periods, effective to each cohort:

[0118] • Screening Period (up to 21 days),

[0119] • Treatment Period (28 days), and

[0120] • Follow-Up Period (7 days).

[0121] A total of up to 48 subjects will be enrolled into the study. Up to 24 subjects will be enrolled in the first two dose cohorts, which will be done in parallel. A potential third higher dose cohort will be started depending on the results of the first two cohorts. And a potential fourth higher dose cohort will be started depending on the results of the third cohort. For each cohort, up to 12 subjects will be randomized to receive Compound 1 or placebo in a 3: 1 ratio so that there will be a total of up to 9 subjects for each of the active doses and up to 3 subjects dosed with placebo in each cohort.

[0122] Cohort 1 and 2 will be dosed in parallel as listed below:

[0123] • Compound 1 20 mg QD (Dose cohort 1 ; up to 9 Subjects on Compound 1 and up to 3 on Placebo),

[0124] • Compound 1 40 mg QD (Dose cohort 2; up to 9 Subjects on Compound 1 and up to 3 on Placebo),

[0125] Based upon outcomes in Cohorts 1 and 2, the study may include third and fourth dose cohorts.

[0126] The dose levels for Cohorts 3 and 4 have been established as 60 mg QD and 80 mg QD (1.5- and 2-fold incremental increases of the 40 mg dose used in Cohort 2, respectively).

[0127] Number of subjects (Planned):

[0128] Up to forty-eight subjects with AMN are planned to be included in this study. In the first 2 parallel cohorts there will be a total of up to 24 subjects with up to 18 subjects on active treatment (up to 9 on each dose) and up to 6 in the placebo group (up to 3 on each dose). Depending on safety results from the first two dose cohorts, up to twelve other subjects with AMN will be randomized to a treatment group within the third cohort (60 mg) on a higher dose where up to 9 subjects will be on active treatment and up to 3 subjects will be on placebo. A potential fourth higher dose cohort (80 mg) will be started depending on the results of the third cohort.

[0129] For each cohort, up to 12 subjects will be randomized to receive Compound 1 or placebo in a 3: 1 ratio so that there will be a total of up to 9 subjects for each of the active doses and up to 3 subjects dosed with placebo in each cohort.

[0130] Intervention Groups and Duration

[0131] The study will be comprised of 3 periods, effective to each cohort, being as follows: Screening Period (up to 21 days), Treatment Period (28 days), and Follow-Up Period (7 days).

[0132] Subjects will be randomized to one of two treatments within four possible dose treatment cohorts in a dose escalation process, 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 started as appropriate.

[0133] The doses used in this study have been determined based on the doses that led to lowering of lipid plasma levels and without safety issues, based on preliminary results from 6 multiple dose cohorts (up to 100 mg) and 7 single dose cohorts (up to 125 mg) from the previous phase 1 study. 3. Study Design

[0134] 3.1. Overall Design

[0135] Subjects will be administered multiple doses of Compound 1 in a cohort dose escalation process. A total of up to 48 subjects will be enrolled in the study, 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 there will be a total of up to 9 subjects for each of the active doses and up to 3 subjects dosed with placebo in each cohort.

[0136] The first part of this study will include the first 2 dose cohorts and placebo, which will be dosed in parallel (up to N=24). The first 2 doses used in these cohorts will be 20 mg QD and 40 mg QD for 28 days.

[0137] Based on analyses of data from each cohort, sample size may be increased by up to 12 subjects in a particular cohort.

[0138] Dose escalation from the parallel cohorts to the next single dose cohort will be permitted only after all subjects in the 2 parallel cohorts have safely completed those cohorts. Dose escalation to cohort 4 will be permitted only after all subjects in cohort 3 have safely completed the cohort.

[0139] This Phase lb, multi-center, double -blind, multiple ascending dose study will be conducted at multiple sites in the United States. The study includes 3 periods, effective to each cohort:

[0140] • Screening Period (up to 21 days),

[0141] • Treatment Period (28 days), and

[0142] • Follow-Up Period (7 days).

[0143] 3.4. Dose Modification

[0144] Escalation to the next dose level will stop when either adverse events preclude dosing or

[0145] PK / PD (dose related VLCFA reduction) data from the first two dose cohorts indicate no further dose escalation is warranted. Study Drug

[0146] Study Drug is defined as any investigational drug(s), or placebo, intended to be administered a study subject according to the study protocol.

[0147] 4.1. Study Drug Administered

[0148] Table 3 INCORPORATION BY REFERENCE

[0149] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0150] EQUIVALENTS

[0151] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMSWe claim:

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

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 of any one of claims 1-5, wherein the subject has Adrenomyeloneuropathy.

7. The method of any one of claims 1-6, wherein the dosing regimen is sufficient to decrease blood plasma levels of one or more saturated very long-chain fatty acids (VLCFAs) in the subject.

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

9. The method of claim 8, wherein the dosing regimen is sufficient to decrease plasma levels of behenic acid in the subject; optionally wherein the decrease in plasma levels of behenic acid is from about 1 % to about 60% from baseline or from about 4% to about 24% from baseline; optionally wherein the decrease in plasma levels of behenic acid from 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 decrease in plasma levels of behenic acid is from about 1 pmol / L to about 40 pmol / L or from about 4 pmol / L to about 16 pmol / L from baseline; optionally wherein the decrease in plasma levels of behenic acid from baseline is selected from about 4 pmol / L, about 10 pmol / L, about 11 pmol / L, about 16 pmol / L, about 20 pmol / L and about 25 pmol / L, and about 40 pmol / L from baseline.

11. The method of claim 8, wherein the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid in the subject from baseline; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is from about 1 % to about 50% or from about 10% to about 23%; optionally wherein the decrease in plasma levels of hexacosanoic acid from 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 decrease in plasma levels of hexacosanoic acid from baseline is from about 0.01 pmol / L to about 1 pmol / L or from about 0.05 pmol / L to about 0.1 pmol / L; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is selected from about 0.05 pmol / L, about 0.06 pmol / L, about 0.1 pmol / L, about 0.2 pmol / L, about 0.5 pmol / L, and about 1 pmol / L.

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

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

15. The method of any one of claims 1-14, wherein the dosing regimen results in effectively no change to the plasma level ratio of tetracosanoic :behenic acids from baseline.

16. The method of any one of claims 1-14, wherein the dosing regimen results in effectively no change to the plasma level ratio of hexacosanoic:behenic acids from baseline.

17. The method of any one of claims 1-16, wherein the dosing regimen results in effectively no change to the ratio of hexacosanoic acid:lysophosphatidylcholines in red blood cells from baseline levels.

18. The method of any one of claims 1-17, wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL or from about 104 ng / mL to about 653 ng / mL in the subject; optionally wherein the Cmax is 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 1-18, wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUCo-h*ng / mL to about 4550 h*ng / mL; optionally wherein the AUC0-24 is 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 1-19, wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 h to about 7.0 h or from 3.86 h to about 5.19 h; optionally wherein the Tmax is selected from about 3.86 h, about 5.19 h, and about 4.36 h.

21. The method of any one of claims 1-20, wherein the dosing regimen is sufficient to achieve an average half-life (T1 / 2) of the compound from about 10 h to about 20 h or from about 13.1 to about 15.3 h in the subject; optionally wherein the T1 / 2 is 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 1-21, wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h or from about 16.4 L / h to about 27.5 L / h in the subject; 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 a therapeutically effective dosing regimen of a compound (1):or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to decrease blood plasma levels of one or more saturated very long-chain fatty acids (VLCFAs) in the subject after about 28 days.

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

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

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

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

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

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

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

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

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

33. The method of claim 26, wherein the decrease in plasma levels of behenic acid is about12% from baseline.

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

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

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

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

38. The method of claim 36, wherein the decrease in plasma levels of behenic acid is at least about 4 pmol / L from baseline.

39. The method of claim 36, wherein the decrease in plasma levels of behenic acid is at least about 10 pmol / L from baseline.

40. The method of claim 36, wherein the decrease in plasma levels of behenic acid is at least about 11 pmol / L from baseline.

41. The method of claim 36, wherein the decrease in plasma levels of behenic acid is at least about 16 pmol / L from baseline.

42. The method of claim 36, wherein the decrease in plasma levels of behenic acid is about 4 pmol / L from baseline.

43. The method of claim 36, wherein the decrease in plasma levels of behenic acid is about 10 pmol / L from baseline.

44. The method of claim 36, wherein the decrease in plasma levels of behenic acid is about 11 pmol / L from baseline.

45. The method of claim 36, wherein the decrease in plasma levels of behenic acid is about 16 pmol / L from baseline.

46. The method of claim 24, wherein the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid from baseline.

47. The method of claim 46, wherein the decrease in plasma levels of hexacosanoic acid is from about 1 % to about 50% from baseline.

48. The method of claim 47, wherein the decrease in plasma levels of hexacosanoic acid is from about 10% to about 23% from baseline.

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

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

51. The method of claim 47, wherein the decrease in plasma levels of hexacosanoic acid is at least about 23% from baseline.

52. The method of claim 47, wherein the decrease in plasma levels of hexacosanoic acid is about 10% from baseline.

53. The method of claim 47, wherein the decrease in plasma levels of hexacosanoic acid is about 15% from baseline.

54. The method of claim 47, wherein the decrease in plasma levels of hexacosanoic acid is about 23% from baseline.

55. The method of claim 46, wherein the decrease in plasma levels of hexacosanoic acid is from about 0.01 pmol / L to about 1 pmol / L from baseline.

56. The method of claim 55, wherein the decrease in plasma levels of hexacosanoic acid is from about 0.05 pmol / L to about 0.1 pmol / L from baseline.

57. The method of claim 55, wherein the decrease in plasma levels of hexacosanoic acid is at least about 0.05 pmol / L from baseline.

58. The method of claim 55, wherein the decrease in plasma levels of hexacosanoic acid is at least about 0.06 pmol / L from baseline.

59. The method of claim 55, wherein the decrease in plasma levels of hexacosanoic acid is at least about 0.1 pmol / L from baseline.

60. The method of claim 55, wherein the decrease in plasma levels of hexacosanoic acid is about 0.05 pmol / L from baseline.

61. The method of claim 55, wherein the decrease in plasma levels of hexacosanoic acid is about 0.06 pmol / L from baseline.

62. The method of claim 55, wherein the decrease in plasma levels of hexacosanoic acid is about 0.1 pmol / L from baseline.

63. The method of claim 24, wherein the dosing regimen is sufficient to decrease plasma levels of tetracosanoic acid from baseline.

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

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

66. The method of claim 64, wherein the decrease in plasma levels of tetracosanoic acid is at least about 3% from baseline.

67. The method of claim 64, wherein the decrease in plasma levels of tetracosanoic acid is at least about 14% from baseline.

68. The method of claim 64, wherein the decrease in plasma levels of tetracosanoic acid is at least about 24% from baseline.

69. The method of claim 64, wherein the decrease in plasma levels of tetracosanoic acid is about 3% from baseline.

70. The method of claim 64, wherein the decrease in plasma levels of tetracosanoic acid is about 14% from baseline.

71. The method of claim 64, wherein the decrease in plasma levels of tetracosanoic acid is about 24% from baseline.

72. The method of claim 63, wherein the decrease in plasma levels of tetracosanoic acid is from about 1 pmol / L to about 40 pmol / L from baseline.

73. The method of claim 72, wherein the decrease in plasma levels of tetracosanoic acid is from about 3 pmol / L to about 14 pmol / L from baseline.

74. The method of claim 72, wherein the decrease in plasma levels of tetracosanoic acid is at least about 3 pmol / L from baseline.

75. The method of claim 72, wherein the decrease in plasma levels of tetracosanoic acid is at least about 10 pmol / L from baseline.

76. The method of claim 72, wherein the decrease in plasma levels of tetracosanoic acid is at least about 14 pmol / L from baseline.

77. The method of claim 72, wherein the decrease in plasma levels of tetracosanoic acid is about 3 pmol / L from baseline.

78. The method of claim 72, wherein the decrease in plasma levels of tetracosanoic acid is about 10 pmol / L from baseline.

79. The method of claim 72, wherein the decrease in plasma levels of tetracosanoic acid is about 14 pmol / L from baseline.

80. The method of any one of claims 23-79, wherein the dosing regimen results in effectively no change to the plasma level ratio of tetracosanoic :behenic acids from baseline.

81. The method of any one of claims 23-79, wherein the dosing regimen results in effectively no change to the plasma level ratio of hexacosanoic:behenic acids from baseline.

82. The method of any one of claims 23-79, wherein the dosing regimen results in effectively no change to the ratio of hexacosanoic acid:lysophosphatidylcholines in red blood cells from baseline levels.

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

84. The method of any one of claims 23-83, wherein the subject has Adrenomyeloneuropathy.

85. The method of any one of claims 23-84, wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL or from about 104 ng / mL to about 653 ng / mL in the subject; optionally wherein the Cmax is 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 23-85, wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUCo- 24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL or from 999 h*ng / mL to about 4550 h*ng / mL; optionally wherein the AUC0-24 is 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 23-86, wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 h to about 7.0 h or from 3.86 h to about 5.19 h; optionally wherein the Tmax is selected from about 3.86 h, about 5.19 h, and about 4.36 h.

88. The method of any one of claims 23-87, wherein the dosing regimen is sufficient to achieve an average half-life (T1 / 2) of the compound from about 10 h to about 20 h or from about 13.1 to about 15.3 h in the subject; optionally wherein the T1 / 2 is 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 23-88, wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h or from about 16.4 L / h to about 27.5 L / h in the subject; 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 a therapeutically effective dosing regimen of a compound (1):(1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL in the subject.

91. The method of claim 90, wherein the Cmax is from about 104 ng / mL to about 653 ng / mL.

92. The method of claim 90, wherein the Cmax is at least about 104 ng / mL.

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

94. The method of claim 90, wherein the Cmax is at least about 395 ng / mL.

95. The method of claim 90, wherein the Cmax is at least about 603 ng / mL.

96. The method of claim 90, wherein the Cmax is about 104 ng / mL.

97. The method of claim 90, wherein the Cmax is about 274 ng / mL.

98. The method of claim 90, wherein the Cmax is about 395 ng / mL.

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

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

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

102. The method of claim 101, wherein the dosing regimen is sufficient to decrease plasma levels of behenic acid in the subject; optionally wherein the decrease in plasma levels of behenic acid is from about 1 % to about 60% from baseline or from about 4% to about 24% from baseline; optionally wherein the decrease in plasma levels of behenic acid from 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 decrease in plasma levels of behenic acid is from about 1 pmol / L to about 40 pmol / L or from about 4 pmol / L to about 16 pmol / L from baseline; optionally wherein the decrease in plasma levels of behenic acid from baseline is selected from about 4 pmol / L, about 10 pmol / L, about 11 pmol / L, about 16 pmol / L, about 20 pmol / L and about 25 pmol / L, and about 40 pmol / L from baseline.

104. The method of claim 101, wherein the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid in the subject from baseline; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is from about 1 % to about 50% or from about 10% to about 23%; optionally wherein the decrease in plasma levels of hexacosanoic acid from 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 decrease in plasma levels of hexacosanoic acid from baseline is from about 0.01 pmol / L to about 1 pmol / L or from about 0.05 pmol / L to about0.1 mol / L; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is selected from about 0.05 pmol / L, about 0.06 pmol / L, about 0.1 pmol / L, about 0.2 pmol / L, about 0.5 pmol / L, and about 1 pmol / L.

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

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

108. The method of any one of claims 90-107, wherein the dosing regimen results in effectively no change to the plasma level ratio of tetracosanoic :behenic acids from baseline.

109. The method of any one of claims 90-107, wherein the dosing regimen results in effectively no change to the plasma level ratio of hexacosanoic :behenic acids from baseline.

110. The method of any one of claims 90-109, wherein the dosing regimen results in effectively no change to the ratio of hexacosanoic aciddysophosphatidylcholines in red blood cells from baseline levels.

111. The method of any one of claims 90-110, wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUCo- 24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL or from 999h*ng / mL to about 4550 h*ng / mL; optionally wherein the AUC0-24 is 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 90-111, wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 h to about 7.0 h or from 3.86 h to about 5.19 h; optionally wherein the Tmax is selected from about 3.86 h, about 5.19 h, and about 4.36 h.

113. The method of any one of claims 90-112, wherein the dosing regimen is sufficient to achieve an average half-life (T1 / 2) of the compound from about 10 h to about 20 h or from about 13.1 to about 15.3 h in the subject; optionally wherein the T1 / 2 is 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 90-113, wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h or from about 16.4 L / h to about 27.5 L / h in the subject; 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 of treating X-linked adrenoleukodystrophy, comprising administering to a subject in need thereof a therapeutically effective dose regimen of a compound (1):(1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUC0-24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL.

116. The method of claim 115, wherein the AUCo-24 is from about 999 h*ng / mL to about 4550 h*ng / mL.

117. The method of claim 115, wherein the AUCo-24 is at least about 999 h*ng / mL.

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

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

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

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

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

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

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

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

126. The method of any one of claims 115-125, wherein the subject has Adrenomyeloneuropathy.

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

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

129. The method of claim 128, wherein the dosing regimen is sufficient to decrease plasma levels of behenic acid in the subject; optionally wherein the decrease in plasma levels of behenic acid is from about 1 % to about 60% from baseline or from about 4% to about 24% from baseline; optionally wherein the decrease in plasma levels of behenic acid from 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 decrease in plasma levels of behenic acid is from about 1 pmol / L to about 40 pmol / L or from about 4 pmol / L to about 16 pmol / L from baseline; optionally wherein the decrease in plasma levels of behenic acid from baseline is selected from about 4 pmol / L, about 10 pmol / L, about 11 pmol / L, about 16 pmol / L, about 20 pmol / L and about 25 pmol / L, and about 40 pmol / L from baseline.

131. The method of claim 128, wherein the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid in the subject from baseline; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is from about 1 % to about 50% or from about 10% to about 23%; optionally wherein the decrease in plasma levels of hexacosanoic acid from 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 decrease in plasma levels of hexacosanoic acid from baseline is from about 0.01 pmol / L to about 1 pmol / L or from about 0.05 pmol / L to about 0.1 pmol / L; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is selected from about 0.05 pmol / L, about 0.06 pmol / L, about 0.1 pmol / L, about 0.2 pmol / L, about 0.5 pmol / L, and about 1 pmol / L.

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

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

135. The method of any one of claims 115-134, wherein the dosing regimen results in effectively no change to the plasma level ratio of tetracosanoic :behenic acids from baseline.

136. The method of any one of claims 115-134, wherein the dosing regimen results in effectively no change to the plasma level ratio of hexacosanoic:behenic acids from baseline.

137. The method of any one of claims 115-136, wherein the dosing regimen results in effectively no change to the ratio of hexacosanoic aciddysophosphatidylcholines in red blood cells from baseline levels.

138. The method of any one of claims 115-137, wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL or from about 104 ng / mL to about 653 ng / mL in the subject; optionally wherein the Cmax is 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 115-138, wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from-SO-about 2.0 h to about 7.0 h or from 3.86 h to about 5.19 h; optionally wherein the Tmax is selected from about 3.86 h, about 5.19 h, and about 4.36 h.

140. The method of any one of claims 115-139, wherein the dosing regimen is sufficient to achieve an average half-life (T1 / 2) of the compound from about 10 h to about 20 h or from about 13.1 to about 15.3 h in the subject; optionally wherein the T1 / 2 is 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 115-140, wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h or from about 16.4 L / h to about 27.5 L / h in the subject; 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 of treating X-linked adrenoleukodystrophy, comprising administering to a subject in need thereof a therapeutically effective dose regimen of a compound (1):or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 to about 7.0 hours.

143. The method of claim 142, wherein the Tmax is from about 3.86 h to about 5.19 h.

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

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

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

147. The method of claim 142, wherein the Tmax is about 3.86 h.

148. The method of claim 142, wherein the Tmax is about 5.19 h.

149. The method of claim 142, wherein the Tmax is about 4.36 h.

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

151. The method of any one of claims 142-150, wherein the subject has Adrenomyeloneuropathy.

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

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

154. The method of claim 153, wherein the dosing regimen is sufficient to decrease plasma levels of behenic acid in the subject; optionally wherein the decrease in plasma levels of behenic acid is from about 1 % to about 60% from baseline or from about 4% to about 24% from baseline; optionally wherein the decrease in plasma levels of behenic acid from 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 decrease in plasma levels of behenic acid is from about 1 pmol / L to about 40 pmol / L or from about 4 pmol / L to about 16 pmol / L from baseline; optionally wherein the decrease in plasma levels of behenic acid from baseline is selected from about 4 pmol / L, about 10 pmol / L, about 11 pmol / L, about 16 pmol / L, about 20 pmol / L and about 25 pmol / L, and about 40 pmol / L from baseline.

156. The method of claim 153, wherein the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid in the subject from baseline; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is from about 1 % to about 50% or from about 10% to about 23%; optionally wherein the decrease in plasma levels of hexacosanoic acid from 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 decrease in plasma levels of hexacosanoic acid from baseline is from about 0.01 pmol / L to about 1 pmol / L or from about 0.05 pmol / L to about 0.1 pmol / L; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is selected from about 0.05 pmol / L, about 0.06 pmol / L, about 0.1 pmol / L, about 0.2 pmol / L, about 0.5 pmol / L, and about 1 pmol / L.

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

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

160. The method of any one of claims 142-159, Wherein the dosing regimen results in effectively no change to the plasma level ratio of tetracosanoic :behenic acids from baseline.

161. The method of any one of claims 142-159, wherein the dosing regimen results in effectively no change to the plasma level ratio of hexacosanoic :behenic acids from baseline.

162. The method of any one of claims 142-161, wherein the dosing regimen results in effectively no change to the ratio of hexacosanoic aciddysophosphatidylcholines in red blood cells from baseline levels.

163. The method of any one of claims 142-162, wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL or from about 104 ng / mL to about 653 ng / mL in the subject; optionally wherein the Cmax is 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 142-163, wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUCo- 24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL or from 999 h*ng / mL to about 4550 h*ng / mL; optionally wherein the AUC0-24 is 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 142-164, wherein the dosing regimen is sufficient to achieve an average half-life (T1 / 2) of the compound from about 10 h to about 20 h or from about 13.1 to about 15.3 h in the subject; optionally wherein the T1 / 2 is 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 142-165, wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h or from about 16.4 L / h to about 27.5 L / h in the subject; 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 a therapeutically effective dosing regimen of a compound (1):(1); or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average half-life (T 1 / 2) of the compound from about 10 h to about 20 h in the subject.

168. The method of claim 167, wherein the T1 / 2 is from about 13.1 h to about 15.3 h.

169. The method of claim 167, wherein the T1 / 2 is at least about 13.1 h.

170. The method of claim 167, wherein the T1 / 2 is at least about 14.9 h.

171. The method of claim 167, wherein the T1 / 2 is at least about 15.3 h.

172. The method of claim 167, wherein the T1 / 2 is at least about 14.3 h.

173. The method of claim 167, wherein the T1 / 2 is about 13.1 h.

174. The method of claim 167, wherein the T1 / 2 is about 14.9 h.

175. The method of claim 167, wherein the T1 / 2 is about 15.3 h.

176. The method of claim 167, wherein the T1 / 2 is about 14.3 h.

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

178. The method of any one of claims 167-177, wherein the subject has Adrenomyeloneuropathy.

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

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

181. The method of claim 180, wherein the dosing regimen is sufficient to decrease plasma levels of behenic acid in the subject; optionally wherein the decrease in plasma levels of behenic acid is from about 1 % to about 60% from baseline or from about 4% to about 24% from baseline; optionally wherein the decrease in plasma levels of behenic acid from 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 decrease in plasma levels of behenic acid is from about 1 pmol / L to about 40 pmol / L or from about 4 pmol / L to about 16 pmol / L from baseline; optionally wherein the decrease in plasma levels of behenic acid from baseline is selected from about 4 pmol / L, about 10 pmol / L, about 11 pmol / L, about 16 pmol / L, about 20 pmol / L and about 25 pmol / L, and about 40 pmol / L from baseline.

183. The method of claim 180, wherein the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid in the subject from baseline; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is from about 1 % to about 50% or from about 10% to about 23%; optionally wherein the decrease in plasma levels of hexacosanoic acid from 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 decrease in plasma levels of hexacosanoic acid from baseline is from about 0.01 pmol / L to about 1 pmol / L or from about 0.05 pmol / L to about 0.1 pmol / L; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is selected from about 0.05 pmol / L, about 0.06 pmol / L, about 0.1 pmol / L, about 0.2 pmol / L, about 0.5 pmol / L, and about 1 pmol / L.

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

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

187. The method of any one of claims 167-186, wherein the dosing regimen results in effectively no change to the plasma level ratio of tetracosanoic :behenic acids from baseline.

188. The method of any one of claims 167-186, wherein the dosing regimen results in effectively no change to the plasma level ratio of hexacosanoic :behenic acids from baseline.

189. The method of any one of claims 167-188, wherein the dosing regimen results in effectively no change to the ratio of hexacosanoic aciddysophosphatidylcholines in red blood cells from baseline levels.

190. The method of any one of claims 167-189, wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL or from about 104 ng / mL to about 653 ng / mL in the subject;optionally wherein the Cmax is 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 167-190, wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUCo- 24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL or from 999 h*ng / mL to about 4550 h*ng / mL; optionally wherein the AUC0-24 is 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 167-191, wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 h to about 7.0 h or from 3.86 h to about 5.19 h; optionally wherein the Tmax is selected from about 3.86 h, about 5.19 h, and about 4.36 h.

193. The method of any one of claims 167-192, wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h or from about 16.4 L / h to about 27.5 L / h in the subject; 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 a therapeutically effective dosing regimen of a compound (1):or a pharmaceutically acceptable salt thereof; wherein the dosing regimen is sufficient to achieve an average oral clearance (CL / F) of the compound from about 15 L / h to about 30 L / h in the subject.

195. The method of claim 194, wherein CL / F is from 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 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 194-203, wherein the dosing regimen comprises administering a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg to the subject once daily.

205. The method of any one of claims 194-204, wherein the subject has Adrenomyeloneuropathy.

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

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

208. The method of claim 207, wherein the dosing regimen is sufficient to decrease plasma levels of behenic acid in the subject; optionally wherein the decrease in plasma levels of behenic acid is from about 1 % to about 60% from baseline or from about 4% to about 24% from baseline; optionally wherein the decrease in plasma levels of behenic acid from 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 decrease in plasma levels of behenic acid is from about 1 pmol / L to about 40 pmol / L or from about 4 pmol / L to about 16 pmol / L from baseline; optionally wherein the decrease in plasma levels of behenic acid from baseline is selected from about 4 pmol / L, about 10 pmol / L, about 11 pmol / L, about 16 pmol / L, about 20 pmol / L and about 25 pmol / L, and about 40 pmol / L from baseline.

210. The method of claim 207, wherein the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid in the subject from baseline; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is from about 1 % to about 50% or from about 10% to about 23%; optionally wherein the decrease in plasma levels of hexacosanoic acid from 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 decrease in plasma levels of hexacosanoic acid from baseline is from about 0.01 pmol / L to about 1 pmol / L or from about 0.05 pmol / L to about 0.1 pmol / L; optionally wherein the decrease in plasma levels of hexacosanoic acid from baseline is selected from about 0.05 pmol / L, about 0.06 pmol / L, about 0.1 pmol / L, about 0.2 pmol / L, about 0.5 pmol / L, and about 1 pmol / L.

212. The method of claim 207, wherein the dosing regimen is sufficient to decrease plasma levels of tetracosanoic acid in the subject from baseline; optionally wherein the decrease in plasma levels of tetracosanoic acid from baseline is from about 1% to about 50% or from about3% to about 24%; optionally wherein the decrease in plasma levels of tetracosanoic acid is selected from about 3%, about 14%, about 24%, about 40% and about 50%.

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

214. The method of any one of claims 194-213, Wherein the dosing regimen results in effectively no change to the plasma level ratio of tetracosanoic :behenic acids from baseline.

215. The method of any one of claims 194-213, wherein the dosing regimen results in effectively no change to the plasma level ratio of hexacosanoic:behenic acids from baseline.

216. The method of any one of claims 194-215, wherein the dosing regimen results in effectively no change to the ratio of hexacosanoic aciddysophosphatidylcholines in red blood cells from baseline levels.

217. The method of any one of claims 194-216, wherein the dosing regimen is sufficient to achieve a maximum average blood plasma concentration (Cmax) of the compound from about 100 ng / mL to about 800 ng / mL or from about 104 ng / mL to about 653 ng / mL in the subject; optionally wherein the Cmax is 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 194-217, wherein the dosing regimen is sufficient to achieve an average blood plasma area under the concentration time curve over 24 hours (AUCo- 24) of the compound in the of the subject from about 800 to about 7000 h*ng / mL or from 999 h*ng / mL to about 4550 h*ng / mL; optionally wherein the AUC0-24 is 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 194-243, wherein the dosing regimen is sufficient to achieve an average time to blood plasma concentration maximum (Tmax) of the compound from about 2.0 h to about 7.0 h or from 3.86 h to about 5.19 h; optionally wherein the Tmax is selected from about 3.86 h, about 5.19 h, and about 4.36 h.

220. The method of any one of claims 194-244, wherein the dosing regimen is sufficient to achieve an average half-life (T1 / 2) of the compound from about 10 h to about 20 h or from about 13.1 to about 15.3 h in the subject; optionally wherein the T1 / 2 is selected from about 13.1 h, about 14.9 h, about 15.3 h, and about 14.3 h.

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