Thyroid beta-agonist dosing regimen for the treatment of X-ALD

Abstract

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

Description

Background Art

[0001] Cross - reference to related applications This application claims the benefit of priority of U.S. Provisional Application No. 63 / 352,350, filed on June 15, 2022, the entire content of which is incorporated herein by reference.

[0002] Adrenoleukodystrophy (also known as X - linked adrenoleukodystrophy, X - ALD) is a disorder of peroxisomal fatty acid beta - oxidation, in which very - long - chain fatty acids accumulate in tissues throughout the body. The tissues most severely affected are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells of the testes. Since X - ALD is an X - linked disorder, it mainly affects males, although about 50% of heterozygous females show some symptoms later in life. The most severe form of X - ALD is known as cerebral ALD, which is characterized by a rapidly progressive inflammatory demyelination process in the brain tissue. This form is commonly seen in infancy and typically appears in children under 12 years of age. Patients with cerebral ALD usually experience a rapid progression to a vegetative state within 3 to 5 years. A more common form of X - ALD is known as adrenomyeloneuropathy (AMN). This type of disease generally develops in later life, typically between the ages of 25 and 45. AMN affects the spinal cord and motor neurons, but there is no inflammatory component or involvement of the brain. AMN patients initially present with difficulty walking and then progress to a progressive movement disorder with leg paralysis.

[0003] ALD is caused by mutations in the ATP - binding cassette transporter d1 (ABCD1) gene located on the X chromosome. The function of ABCD1 is to transport very - long - chain fatty acids (VLCFAs) into peroxisomes for degradation. In X - ALD, the defective ABCD1 causes the accumulation of VLCFAs. In X - ALD patients, the concentration of unbranched saturated very - long - chain fatty acids, especially cerotic acid (26:0), becomes very high. Since there is no cure or approved treatment for X - ALD, treatment options are limited.

[0004] Therefore, improved methods and dosing regimens are needed for the treatment of X-ALD.

Summary of the Invention

[0005] In certain embodiments, the present disclosure provides 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)

Chemical Formula

[0006] In a further embodiment, the present disclosure provides 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)

Chemical Formula

[0007] In yet another embodiment, the present disclosure provides 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)

Chemical Formula

[0008] In yet another aspect, the present disclosure provides a method of treating X-linked adrenoleukodystrophy, which comprises administering a therapeutically effective dosing regimen of compound (1) [Chemical formula] (1) or a pharmaceutically acceptable salt thereof to a subject in need of treatment, the dosing regimen being sufficient for the area under the mean plasma concentration-time curve (AUC 0~24 ) of the compound in the subject to reach from about 800 to about 7000 h*ng / mL over 24 hours.

[0009] In certain aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy, which comprises administering a therapeutically effective dosing regimen of compound (1) [Chemical formula] (1) or a pharmaceutically acceptable salt thereof to a subject in need of treatment, the dosing regimen being sufficient for the average time to reach the maximum plasma concentration (T 最大 ) of the compound to be from about 2.0 to about 7.0 hours.

[0010] In a further aspect, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need of treatment, the method comprising administering a therapeutically effective dosing regimen of compound (1) [Chemical formula] (1) or a pharmaceutically acceptable salt thereof to the subject, the dosing regimen being sufficient for the average half-life (T 1 / 2 ) of the compound in the subject to reach from about 10 hours to about 20 hours.

[0011] In yet another aspect, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need of treatment, the method comprising administering a therapeutically effective dosing regimen of compound (1) [Chemical formula] (1) and includes conducting a therapeutically effective dosing regimen for the compound or a pharmaceutically acceptable salt thereof, the dosing regimen being sufficient for the average oral clearance (CL / F) of the compound in the subject to reach from about 15 L / hour to about 30 L / hour. BRIEF DESCRIPTION OF THE DRAWINGS

[0012]

Figure 1

[0013] The disclosed method In certain embodiments, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective dosing regimen of compound (1)

Chemical formula

[0014] In certain embodiments, any method of the present disclosure may include a dosing regimen that includes administering to the subject once daily a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg. In some such embodiments, the dose is about 20 mg. In other such embodiments, the dose is about 40 mg. In still other such embodiments, the dose is about 60 mg. In yet other such embodiments, the dose is about 80 mg.

[0015] In other embodiments, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective dosing regimen of compound (1)

Chemical formula

[0016] In some embodiments, any method of the present disclosure can include a dosing regimen that is sufficient to reduce the concentration of one or more saturated very long chain fatty acids (VLCFAs) in the plasma of a 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, the dosing regimen is sufficient to reduce the behenic acid concentration in the plasma of the subject from baseline. In further embodiments, the reduction in the behenic acid concentration in the plasma is from about 1% to about 60% from baseline. In certain embodiments, the reduction in the behenic acid concentration in the plasma is from about 4% to about 24% from baseline. In some embodiments, the reduction in the behenic acid concentration in the plasma is at least about 4% from baseline. In other embodiments, the reduction in the behenic acid concentration in the plasma is at least about 12% from baseline. In still further embodiments, the reduction in the behenic acid concentration in the plasma is at least about 14% from baseline. In still further embodiments, the reduction in the behenic acid concentration in the plasma is at least about 24% from baseline. In other embodiments, the reduction in the behenic acid concentration in the plasma is about 4% from baseline. In still further embodiments, the reduction in the behenic acid concentration in the plasma is about 12% from baseline. In still further embodiments, the reduction in the behenic acid concentration in the plasma is about 14% from baseline. In other embodiments, the reduction in the behenic acid concentration in the plasma is about 24% from baseline. In certain embodiments, the reduction in the behenic acid concentration in the plasma is about 30% from baseline. In other embodiments, the reduction in the behenic acid concentration in the plasma is about 40% from baseline. In still further embodiments, the reduction in the behenic acid concentration in the plasma is about 50% from baseline. In still further embodiments, the reduction in the behenic acid concentration in the plasma is about 60% from baseline.

[0017] In certain such embodiments, the decrease in behenic acid concentration in plasma is from about 1 μmol / L to about 40 μmol / L from baseline. In some such embodiments, the decrease in behenic acid concentration in plasma is from about 4 μmol / L to about 16 μmol / L from baseline. In some embodiments, the decrease in behenic acid concentration in plasma is at least about 4 μmol / L from baseline. In other embodiments, the decrease in behenic acid concentration in plasma is at least about 10 μmol / L from baseline. In yet other embodiments, the decrease in behenic acid concentration in plasma is at least about 11 μmol / L from baseline. In yet other embodiments, the decrease in behenic acid concentration in plasma is at least about 16 μmol / L from baseline. In other embodiments, the decrease in behenic acid concentration in plasma is about 4 μmol / L from baseline. In yet other embodiments, the decrease in behenic acid concentration in plasma is about 10 μmol / L from baseline. In other embodiments, the decrease in behenic acid concentration in plasma is about 11 μmol / L from baseline. In yet other embodiments, the decrease in behenic acid concentration in plasma is about 16 μmol / L from baseline. In certain embodiments, the decrease in behenic acid concentration in plasma from baseline is about 20 μmol / L. In other embodiments, the decrease in behenic acid concentration in plasma from baseline is about 25 μmol / L. In yet other embodiments, the decrease in behenic acid concentration in plasma from baseline is about 40 μmol / L.

[0018] In certain embodiments, the dosing regimen is sufficient to reduce the plasma hexacosanoic acid concentration in the subject from baseline. In some such embodiments, the reduction in plasma hexacosanoic acid concentration is from about 1% to about 30% from baseline. In further embodiments, the reduction in plasma hexacosanoic acid concentration is from about 10% to about 23% from baseline. In certain such embodiments, the reduction in plasma hexacosanoic acid concentration is at least about 10% from baseline. In other such embodiments, the reduction in plasma hexacosanoic acid concentration is at least about 15% from baseline. In yet further such embodiments, the reduction in plasma hexacosanoic acid concentration is at least about 23% from baseline. In yet further such embodiments, the reduction in plasma hexacosanoic acid concentration is about 10% from baseline. In certain embodiments, the reduction in plasma hexacosanoic acid concentration is about 15% from baseline. In other embodiments, the reduction in plasma hexacosanoic acid concentration is about 23% from baseline. In certain embodiments, the reduction in plasma hexacosanoic acid concentration from baseline is about 30%. In certain embodiments, the reduction in plasma hexacosanoic acid concentration from baseline is about 40%. In certain embodiments, the reduction in plasma hexacosanoic acid concentration from baseline is about 50%.

[0019] In certain embodiments, the decrease in plasma hexacosanoic acid concentration is from about 0.01 μmol / L to about 1 μmol / L from baseline. In some such embodiments, the decrease in plasma hexacosanoic acid concentration is from about 0.05 μmol / L to about 0.1 μmol / L from baseline. In further embodiments, the decrease in plasma hexacosanoic acid concentration is at least about 0.05 μmol / L from baseline. In other embodiments, the decrease in plasma hexacosanoic acid concentration is at least about 0.06 μmol / L from baseline. In yet further embodiments, the decrease in plasma hexacosanoic acid concentration is at least about 0.1 μmol / L from baseline. In yet further embodiments, the decrease in plasma hexacosanoic acid concentration is about 0.05 μmol / L from baseline. In other embodiments, the decrease in plasma hexacosanoic acid concentration is about 0.06 μmol / L from baseline. In yet further embodiments, the decrease in plasma hexacosanoic acid concentration is about 0.1 μmol / L from baseline. In certain embodiments, the decrease in plasma hexacosanoic acid concentration from baseline is about 0.2 μmol / L. In other embodiments, the decrease in plasma hexacosanoic acid concentration from baseline is about 0.5 μmol / L. In yet further embodiments, the decrease in plasma hexacosanoic acid concentration from baseline is about 1 μmol / L.

[0020] In certain embodiments, the dosing regimen is sufficient to reduce the plasma tetracosanoic acid concentration in the subject from baseline. In some such embodiments, the reduction in plasma tetracosanoic acid concentration is from about 1% to about 50% from baseline. In further embodiments, the reduction in plasma tetracosanoic acid concentration is from about 3% to about 24% from baseline. In certain such embodiments, the reduction in plasma tetracosanoic acid concentration is at least about 3% from baseline. In other such embodiments, the reduction in plasma tetracosanoic acid concentration is at least about 14% from baseline. In still other such embodiments, the reduction in plasma tetracosanoic acid concentration is at least about 24% from baseline. In still other such embodiments, the reduction in plasma tetracosanoic acid concentration is about 3% from baseline. In other such embodiments, the reduction in plasma tetracosanoic acid concentration is about 14% from baseline. In still other such embodiments, the reduction in plasma tetracosanoic acid concentration is about 24% from baseline. In certain embodiments, the reduction in plasma tetracosanoic acid concentration from baseline is about 40%. In other embodiments, the reduction in plasma tetracosanoic acid concentration from baseline is about 50%.

[0021] In certain embodiments, the decrease in plasma tetracosanoic acid concentration is from about 1 μmol / L to about 40 μmol / L from baseline. In some such embodiments, the decrease in plasma tetracosanoic acid concentration is from about 3 μmol / L to about 14 μmol / L from baseline. In further embodiments, the decrease in plasma tetracosanoic acid concentration is at least about 3 μmol / L from baseline. In other embodiments, the decrease in plasma tetracosanoic acid concentration is at least about 10 μmol / L from baseline. In still further embodiments, the decrease in plasma tetracosanoic acid concentration is at least about 14 μmol / L from baseline. In still further embodiments, the decrease in plasma tetracosanoic acid concentration is about 3 μmol / L from baseline. In other embodiments, the decrease in plasma tetracosanoic acid concentration is about 10 μmol / L from baseline. In still further embodiments, the decrease in plasma tetracosanoic acid concentration is about 14 μmol / L from baseline. In certain embodiments, the decrease in plasma tetracosanoic acid concentration from baseline is about 30 μmol / L. In other embodiments, the decrease in plasma tetracosanoic acid concentration from baseline is about 40 μmol / L.

[0022] In certain embodiments, in the dosing regimen, the ratio of the plasma concentration of tetracosanoic acid to behenic acid does not substantially change from baseline. In some embodiments, in the dosing regimen, the ratio of the plasma concentration of tetracosanoic acid to behenic acid changes from baseline to about 0. In certain embodiments, in the dosing regimen, the ratio of the plasma concentration of tetracosanoic acid to behenic acid changes from baseline by about -0.1 to about 0.1. In other embodiments, in the dosing regimen, the ratio of the plasma concentration of tetracosanoic acid to behenic acid decreases from baseline. In still further embodiments, in the dosing regimen, the ratio of the plasma concentration of tetracosanoic acid to behenic acid increases from baseline.

[0023] In certain embodiments, in the dosing regimen, the ratio of the plasma concentration of hexacosanoic acid:behenic acid does not substantially change from baseline. In some embodiments, in the dosing regimen, the ratio of the plasma concentration of hexacosanoic acid:behenic acid changes from baseline to about 0. In certain embodiments, in the dosing regimen, the ratio of the plasma concentration of hexacosanoic acid:behenic acid changes from baseline by about -0.1 to about 0.1. In certain embodiments, in the dosing regimen, the ratio of the plasma concentration of hexacosanoic acid:behenic acid decreases from baseline. In other embodiments, in the dosing regimen, the ratio of the plasma concentration of hexacosanoic acid:behenic acid increases from baseline.

[0024] In certain embodiments, in the dosing regimen, the ratio of hexacosanoic acid:lysophosphatidylcholine in red blood cells does not substantially change from the baseline value. In other embodiments, the dosing regimen is sufficient to decrease the ratio of hexacosanoic acid:lysophosphatidylcholine in red blood cells from the baseline value. In still other embodiments, the dosing regimen is sufficient to increase the ratio of hexacosanoic acid:lysophosphatidylcholine in red blood cells from the baseline value.

[0025] In still other aspects, the present disclosure provides a method of treating X-linked adrenoleukodystrophy in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective dosing regimen of compound (1) [Chemical formula] (1) or a pharmaceutically acceptable salt thereof, the dosing regimen being sufficient for the maximum average plasma concentration (C 最大 ) of the compound in the subject to reach about 100 ng / mL to about 800 ng / mL.

[0026] In some embodiments, any method of the present disclosure may include a dosing regimen, the dosing regimen being sufficient for the maximum average plasma concentration (C 最大 ) of the compound in the subject to reach about 100 ng / mL to about 800 ng / mL. In further embodiments, C 最大is from about 104 ng / mL to about 653 ng / mL. In some such embodiments, C 最大 is at least about 104 ng / mL. In other such embodiments, C 最大 is at least about 274 ng / mL. In still other such embodiments, C 最大 is at least about 395 ng / mL. In still other such embodiments, C 最大 is at least about 603 ng / mL. In other such embodiments, C 最大 is about 104 ng / mL. In still other such embodiments, C 最大 is about 274 ng / mL. In still other such embodiments, C 最大 is about 395 ng / mL. In still other such embodiments, C 最大 is about 603 ng / mL.

[0027] In still other aspects, the present disclosure provides a method for treating X-linked adrenoleukodystrophy, which comprises administering a therapeutically effective dosing regimen of compound (1)

Chemical formula

[0028] In certain embodiments, any method of the present disclosure may include a dosing regimen that is sufficient for the area under the plasma concentration-time curve (AUC 0~24 ) of the compound in the subject to reach from about 800 to about 7000 h*ng / mL over 24 hours. In further embodiments, AUC 0~24 is from about 999 h*ng / mL to about 4550 h*ng / mL. In certain such embodiments, AUC 0~24 is at least about 999 h*ng / mL. In other such embodiments, AUC0~24 is at least about 2980 h*ng / mL. In yet other such embodiments, the AUC 0~24 is at least about 3320 h*ng / mL. In yet other such embodiments, the AUC 0~24 is at least about 4550 h*ng / mL. In other such embodiments, the AUC 0~24 is about 999 / mL. In yet other such embodiments, the AUC 0~24 is about 2980 h*ng / mL. In yet other such embodiments, the AUC 0~24 is about 3320 h*ng / mL. In other such embodiments, the AUC 0~24 is about 4550 / mL.

[0029] In certain embodiments, the present disclosure provides a method of treating X-linked adrenoleukodystrophy, which comprises administering to a subject in need of treatment a therapeutically effective dosing regimen of compound (1) [Chemical formula] (1) or a pharmaceutically acceptable salt thereof, the dosing regimen being sufficient for the average time to reach the maximum plasma concentration (T 最大 ) of the compound to be from about 2.0 to about 7.0 hours.

[0030] In certain embodiments, any method of the present disclosure may include a dosing regimen that is sufficient for the average time to reach the maximum plasma concentration (T 最大 ) of the compound to be from about 2.0 to about 7.0 hours. In some embodiments, T 最大 is from about 3.86 hours to about 5.19 hours. In certain such embodiments, T 最大 is at least about 3.86 hours. In other such embodiments, T 最大 is at least about 5.19 hours. In yet other such embodiments, T 最大 is at least about 4.36 hours. In yet other such embodiments, T 最大 is about 3.86 hours. In other such embodiments, T最大 is about 5.19 hours. In still other such embodiments, T 最大 is 4.36 hours.

[0031] In other aspects, the present disclosure provides a method for treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering a therapeutically effective dosing regimen of compound (1)

Chemical formula

[0032] In certain embodiments, any method of the present disclosure may include a dosing regimen, the dosing regimen being sufficient for the average half-life (T 1 / 2 ) of the compound in the subject to reach from about 10 hours to about 20 hours. In further embodiments, T 1 / 2 is from about 13.1 hours to about 15.3 hours. In some such embodiments, T 1 / 2 is at least about 13.1 hours. In other such embodiments, T 1 / 2 is at least about 14.9 hours. In still other such embodiments, T 1 / 2 is at least about 15.3 hours. In still further such embodiments, T 1 / 2 is at least about 14.3 hours. In other such embodiments, T 1 / 2 is about 13.1 hours. In still further such embodiments, T 1 / 2 is about 14.9 hours. In still further such embodiments, T 1 / 2 is about 15.3 hours. In other such embodiments, T 1 / 2 is about 14.3 hours.

[0033] In still other aspects, the present disclosure provides a method for treating X-linked adrenoleukodystrophy in a subject in need thereof, the method comprising administering a therapeutically effective dosing regimen of compound (1) [Chem.] (1) including conducting a therapeutically effective dosing regimen for the compound or a pharmaceutically acceptable salt thereof, the dosing regimen being sufficient for the average oral clearance (CL / F) of the compound in the subject to reach from about 15 L / hour to about 30 L / hour.

[0034] In certain such embodiments, any method of the present disclosure may include a dosing regimen that is sufficient for the CL / F of the compound in the subject to reach from about 15 L / hour to about 30 L / hour. In some embodiments, the CL / F is from about 16.4 L / hour to about 27.5 L / hour. In further embodiments, the CL / F is at least about 27.5 L / hour. In other embodiments, the CL / F is at least about 16.4 L / hour. In still further embodiments, the CL / F is at least about 22.6 L / hour. In still further embodiments, the CL / F is at least about 20.1 L / hour. In other embodiments, the CL / F is about 27.5 L / hour. In still further embodiments, the CL / F is about 16.4 L / hour. In still further embodiments, the CL / F is about 22.6 L / hour. In other embodiments, the CL / F is about 20.1 L / hour.

[0035] Pharmaceutical composition The compositions and methods of the present invention can 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 compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline, or oils such as glycols, glycerol, olive oil, or other solvents or vehicles such as injectable organic esters. In a preferred embodiment, when such a pharmaceutical composition is intended for administration to a human, particularly via an invasive route of administration (i.e., a route such as injection or implantation that avoids transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to delay the release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in a unit dosage form such as tablets, capsules (including sprinkle capsules, gelatin capsules), granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system, such as in a skin patch. The composition can also be present as a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0036] A pharmaceutically acceptable carrier may include, for example, a physiologically acceptable agent that acts to stabilize, increase the solubility, or enhance the absorption of a compound such as a compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid, glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) can be, for example, a liposome or other polymeric matrix that can incorporate the compound of the present invention. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, metabolizable carriers that are relatively easy to manufacture and administer.

[0037] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reaction, or other problems or complications, and that exhibit a reasonable benefit / risk ratio.

[0038] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers are: (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 used in pharmaceutical formulations.

[0039] The pharmaceutical composition (formulation) can be administered to a subject by any of a number of routes of administration, including, for example, oral (such as aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes applied to the tongue), absorption through the oral mucosa (such as sublingual), subcutaneous, transdermal (such as as a patch applied to the skin), and topical (such as as a cream, ointment or spray applied to the skin). The compound can further be formulated for inhalation. In certain embodiments, the compound can be readily dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor are described, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and the patents cited therein.

[0040] The formulations are conveniently provided in unit dosage form and can be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host to be treated and 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 that produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0041] The method of preparing these formulations or compositions involves combining an active compound, such as a compound of the invention, with a carrier and optionally one or more accessory ingredients. Generally, the formulations are prepared by uniformly and sufficiently mixing the compound of the invention with a liquid carrier, or a finely divided solid carrier, or both, and then shaping the product, if necessary.

[0042] The formulations of the present invention suitable for oral administration are in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilized agents, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or water-in-oil or oil-in-water liquid emulsions, or elixirs or syrups, or troches (using an inert base such as gelatin and glycerin, or sucrose and acacia) and / or mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The composition or compound can also be administered as a bolus, a lick or a paste.

[0043] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following. (1) Fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid, (2) Binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, (3) Humectants such as glycerol, (4) Disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, (5) Dissolution retardants such as paraffin, (6) Absorption promoters such as quaternary ammonium compounds, (7) Wetting agents such as cetyl alcohol and glycerol monostearate, (8) Absorbents such as kaolin and bentonite clay, (9) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, mixtures thereof, etc., (10) Complexing agents such as modified cyclodextrin and unmodified cyclodextrin, and (11) Colorants. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may further contain a buffering agent. Solid compositions of the same type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0044] Tablets can be prepared by compression or molding, optionally with one or more auxiliary components. Compressed tablets can be prepared using binders (such as gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent using a suitable machine.

[0045] Tablets, as well as other solid dosage forms of pharmaceutical compositions such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills, granules, etc., can, if necessary, be scored or prepared with coatings and shells such as enteric coatings and other coatings well known in pharmaceutical formulation technology. They can also be formulated to provide sustained or controlled release of the active ingredient(s) therein using hydroxypropylmethylcellulose, other polymeric matrices, liposomes and / or microspheres in various proportions to provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions can optionally contain opacifying agents and can optionally be compositions that release the active ingredient(s) only or preferentially in a specific part of the gastrointestinal tract in a delayed manner. Examples of implantable compositions that can be used include polymeric substances and waxes. The active ingredient can, where appropriate, be in microencapsulated form together with one or more of the above excipients.

[0046] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0047] In addition to the inert diluent, the oral composition may further contain auxiliary agents such as wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, coloring agents, fragrances, preservatives, and the like.

[0048] In addition to the active compound, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0049] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers or propellants.

[0050] Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0051] Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may further contain conventional propellants such as volatile unsubstituted hydrocarbons such as chlorofluorohydrocarbons, butane and propane.

[0052] Transdermal patches have the additional advantage of being able to provide controlled delivery of the compounds of the present invention into the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption promoters can also be used to increase the flow of the compound across the skin. The rate of flow can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0053] As used herein, the terms "parenteral administration" and "administered parenterally" mean a route of administration other than enteral administration and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions. Pharmaceutical compositions suitable for parenteral administration include combinations of one or more active compounds with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted immediately prior to use into sterile injectable solutions or dispersions, and may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0054] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0055] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, etc. Prevention of the action of microorganisms can be ensured by adding various antibacterial and antifungal agents such as parabens, chlorobutanol, phenolsorbic acid, etc. It may also be desirable to include in the composition isotonic agents such as sugars, sodium chloride, etc. Furthermore, sustained absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0056] In some cases, it may be desirable to delay the absorption of a drug by subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of the drug depends on the dissolution rate, which may depend on the crystal size and crystal form. Alternatively, to delay the absorption of a parenterally administered dosage form, the drug is dissolved or suspended in an oily medium.

[0057] Injectable depot dosage forms are prepared by forming a microencapsulation matrix of the target compound in a biodegradable polymer such as polylactic acid - polyglycolide. Depending on the ratio of the drug to the polymer and the properties of the specific polymer used, the release rate of the drug can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0058] When used in the methods of the present invention, the active compound can be administered by itself or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0059] The introduction method can also be provided by a rechargeable or biodegradable device. In recent years, various sustained - release polymer devices have been developed and tested in vivo for the controlled delivery of drugs including protein - based biopharmaceuticals. Using various biocompatible polymers (including hydrogels) that include both biodegradable and non - degradable polymers, implants can be formed to continuously release a compound at a specific target site.

[0060] The actual dosage level of the active ingredient in the pharmaceutical composition can 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 method of administration without causing toxicity to the patient.

[0061] The dosage level selected will vary depending on a variety of factors including the activity of the specific compound or combination of compounds used, or esters, salts or amides thereof, the route of administration, the time of administration, the rate of excretion of the specific compound(s) used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific compound(s) used, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, as well as similar factors well known in the medical arts.

[0062] 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, a physician or veterinarian can initiate administration of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" means a concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the weight, sex, age, and medical history of the subject. Other factors that can affect the effective amount include, but are not limited to, the severity of the patient's condition, the disease being treated, the stability of the compound, and the type of other therapeutic agents administered in conjunction with the compounds of the invention, if any. Larger total doses can be administered by dividing the dosage into multiple administrations. Methods for determining efficacy and dosage are known to those of skill in the art (see Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, which is incorporated herein by reference).

[0063] Generally, the appropriate daily amount of the active compound used in the compositions and methods of the present invention will be that amount of the compound that is the lowest amount effective to produce a therapeutic effect. Such effective amounts generally will vary depending on the factors described above.

[0064] If necessary, the effective daily amount of the active compound can optionally be administered in unit dosage form as one, two, three, four, five, six or more divided administrations, which are administered separately at appropriate intervals throughout the day. In certain embodiments of the invention, the active compound can be administered two to three times a day. In a preferred embodiment, the active compound is administered once a day.

[0065] The patients to be treated with this are any animals in need of treatment, including primates, especially humans, and other mammals such as horses, cattle, pigs, sheep, cats, dogs, poultry, and pets in general.

[0066] In certain embodiments, the compounds of the invention may be used alone or administered in combination with other types of therapeutic agents.

[0067] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. In certain embodiments, salts contemplated by the invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, salts contemplated by the invention include, but are not limited to, L-arginine, benzamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, salts contemplated by the invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, salts contemplated by the present invention include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, 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, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0068] Pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. The source of such solvates may be from the crystallization solvent, inherent to the preparation or crystallization solvent, or associated with such a solvent.

[0069] Wetting agents, emulsifying agents, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, and fragrances, preservatives, and antioxidants can also be present in the composition.

[0070] Examples of pharmaceutically acceptable inhibitors include (1) water-soluble antioxidants (such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite), (2) oil-soluble antioxidants (such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol), and (3) metal chelating agents (such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid).

[0071] Definitions Unless otherwise defined herein, the technical terms used in this application shall have the meanings generally understood by those skilled in the art. Generally, the nomenclature and techniques related to chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, as well as protein and nucleic acid chemistry described herein are well known and commonly used in the art.

[0072] The methods and techniques of the present disclosure, unless otherwise indicated, generally are performed according to conventional methods well known in the art and as described in various general and more specific references cited and described throughout this specification. See, for example, “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).

[0073] Chemical terms used herein, unless otherwise defined herein, are used according to conventional usage in the art as exemplified in “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0074] All of the above, and other publications, patents, published patent applications referred to in this application, are hereby expressly incorporated by reference into this specification. In case of conflict, this specification, including specific definitions, will control.

[0075] In this specification, the term "agent" is used to refer to a chemical compound (organic or inorganic compound, mixture of chemical compounds, etc.), a biopolymer (nucleic acid, antibody (including a part thereof, humanized antibody, chimeric antibody, human antibody, monoclonal antibody), protein or a part thereof, such as a peptide, lipid, carbohydrate), or an extract made from biological materials such as cells or tissues of bacteria, plants, fungi, animals (especially mammals). Agents include, for example, agents with known structures and agents with unknown structures.

[0076] "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, domestic animals (including cows, pigs, etc.), pet animals (e.g., dogs, cats, etc.), and rodents (e.g., mice, rats, etc.).

[0077] "Treating" a condition or a patient refers to taking measures to obtain a beneficial or desired result, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, reduction in the degree of illness, a stable state of the illness (i.e., a state that is not deteriorating), prevention of the spread of the illness, delay or deceleration of the progression of the illness, improvement or alleviation of the state of the illness, and remission (partial or complete), whether detectable or undetectable. "Treatment" can also mean extending survival compared to the survival expected if the treatment were not received.

[0078] The term "prevention" is recognized in the art and, when used in connection with conditions such as local recurrence (e.g., pain), diseases such as cancer, syndrome complexes such as heart failure, or other medical conditions, is well understood in the art and includes administration of a composition that reduces the frequency of symptoms of a medical condition in a subject, or delays the onset of the condition, as compared to a subject not receiving the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment as compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in the treated population as compared to the untreated control population by, for example, a statistically and / or clinically significant amount.

[0079] "Administering" or "administration" of a substance, compound, or agent to a subject can be effected using one of a variety of methods known to those of skill in the art. For example, a compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, intravitreally, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracranially, and transdermally (e.g., by absorption through a skin patch). A compound or agent can also be suitably introduced by a rechargeable or biodegradable polymeric device, or other devices such as patches or pumps, or by a formulation that provides for extended, slow, or controlled release of the compound or agent. Administration can be effected, for example, once, a plurality of times, and / or over one or more extended periods of time.

[0080] The appropriate method of administering a substance, compound, or agent to a subject also depends, for example, on the age and physical condition of the subject, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, toxicity). In some embodiments, a compound or agent is administered to a subject orally, e.g., by ingestion. In some embodiments, a compound or agent administered orally is a sustained release or slow release formulation, or is administered using a device for such sustained release or slow release.

[0081] As used herein, "co - administration" refers to any form of administration in which two or more different therapeutic agents are administered such that the second therapeutic agent is administered while the previously administered therapeutic agent is still exerting its effect in the body (e.g., the two agents exert their effects simultaneously in the patient, and a synergistic effect between the two agents may occur). For example, the different therapeutic compounds can be administered simultaneously or sequentially, in the same formulation or in separate formulations. Thus, an individual undergoing such treatment can benefit from the synergistic effects of the various therapeutic agents.

[0082] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is the amount of the drug or agent that, when administered to a subject, produces the intended therapeutic effect. A complete therapeutic effect is not necessarily obtained with a single administration and may be obtained only after a series of administrations. Thus, a therapeutically effective amount can be administered in one or multiple doses. The exact effective amount required for a subject varies depending on the subject's physique, health status, age, the nature and degree of the disease being treated such as cancer or MDS, etc. One of ordinary skill in the art can readily determine the effective amount in a particular situation by routine experimentation.

[0083] As used herein, the terms "optional" or "optionally" mean that the event or circumstance described thereafter may or may not occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted alkyl" refers to both the case where the alkyl is substituted and the case where the alkyl is not substituted.

[0084] As used herein, the term "modulate" includes the inhibition or suppression of a function or activity (such as cell proliferation), as well as the enhancement of a function or activity.

[0085] The expression "pharmaceutically acceptable" is recognized in the art. In certain embodiments, this term refers to compositions, excipients, adjuvants, polymers, other materials and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and having a reasonable benefit / risk ratio.

[0086] As used herein, the term "pharmaceutically acceptable salt" or "salt" is used to refer to acid addition salts or base addition salts that are suitable for or compatible with the treatment of a patient.

[0087] As used herein, the term "pharmaceutically acceptable base addition salt" means any non-toxic organic or inorganic base addition salt of any acid compound or intermediate represented by Formula I. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, cycloaliphatic, aromatic organic amines such as methylamine, trimethylamine, and picoline, or ammonia. The selection of suitable salts is known to those skilled in the art.

[0088] Some compounds may also exist as tautomers. Such forms are not explicitly shown in the formulas described herein but are intended to be included within the scope of the present disclosure.

[0089] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or medium such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material useful in formulating a medicament or therapeutic agent for pharmaceutical or therapeutic use.

Examples

[0090] The present invention is generally described herein, but will be more readily understood by reference to the following examples, which are included for the purpose of illustrating specific aspects and embodiments of the invention only and are not intended to limit the invention.

[0091] Example 1, Phase 1b Pharmacodynamics Study of Compound 1 in Adrenomyeloneuropathy 1. Test Overview 1.1 Overview Compound 1 is a novel selective thyroid receptor beta agonist that has been developed as a disease-modifying agent in the treatment of X-linked adrenoleukodystrophy (X-ALD) and adrenomyeloneuropathy (AMN).

[0092] The objective of this Phase 1b study is to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of Compound 1 in subjects diagnosed with adrenomyeloneuropathy (AMN). Furthermore, this is the first proof-of-concept study to evaluate whether treatment with Compound 1 reduces plasma VLCFA concentrations in AMN patients. Table 1 below shows the objectives and endpoints of this Phase 1b study.

Table 1

[0093] Overall Design: This study is a multiple parallel escalating dose study to evaluate the safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of Compound 1 in AMN patients. This study consists of three periods applied to each cohort. · Screening period (maximum 21 days), · Treatment period (28 days), and · Follow-up period (7 days).

[0094] A maximum of 48 subjects will participate in this trial. The first two dose cohorts will enroll a maximum of 24 subjects each and will be conducted in parallel. Depending on the results of the first two cohorts, the third highest dose cohort may be initiated. And depending on the results of the third cohort, the fourth highest dose cohort may be initiated.

[0095] In each cohort, a maximum of 12 subjects will be randomly assigned to receive Compound 1 or placebo in a 3:1 ratio, with a maximum of 9 subjects and a maximum of 3 subjects receiving placebo for each active dose in each cohort.

[0096] Cohorts 1 and 2 will be administered in parallel as shown below. · Compound 1 20 mg QD (Dose Cohort 1, administer Compound 1 to a maximum of 9 subjects and placebo to a maximum of 3 subjects), · Compound 1 40 mg QD (Dose Cohort 2, administer Compound 1 to a maximum of 9 subjects and placebo to a maximum of 3 subjects), Based on the results of Cohorts 1 and 2, the trial may include a third dose cohort and a fourth dose cohort.

[0097] The dose levels for Cohorts 3 and 4 are set at 60 mg QD and 80 mg QD respectively (incremental increases of 1.5 times and 2 times the 40 mg dose used in Cohort 2).

[0098] Number of Subjects (planned): A maximum of 48 AMN patients are planned to participate in this trial. In the first two parallel cohorts, a total of 24 subjects, with a maximum of 18 subjects receiving active treatment (a maximum of 9 subjects per dose) and a maximum of 6 subjects in the placebo group (a maximum of 3 subjects per dose), will participate. Depending on the safety results of the first two dose cohorts, a maximum of 12 subjects with AMN will be randomly assigned to the treatment group within the third cohort at a higher dose (60 mg), with a maximum of 9 subjects receiving active treatment and a maximum of 3 subjects receiving placebo. Depending on the results of the third cohort, the fourth highest dose cohort (80 mg) may be initiated.

[0099] In each cohort, up to 12 subjects are randomly assigned to receive Compound 1 or placebo at a ratio of 3:1, and in each cohort, up to 9 subjects and up to 3 subjects will receive placebo for each effective dose.

[0100] Intervention Group and Period The trial consists of the following three periods applied to each cohort. Screening period (up to 21 days), treatment period (28 days), follow-up period (7 days).

[0101] Subjects start in parallel from two dose cohorts and are randomly assigned to one of two treatments within four possible dose treatment cohorts in a dose escalation process. Subsequently, if necessary, it is increased to the third dose cohort (60 mg). If necessary, the fourth highest dose cohort (80 mg) is planned to be started.

[0102] The doses used in this trial were determined based on the preliminary results of six multiple-dose cohorts (up to 100 mg) and seven single-dose cohorts (up to 125 mg) in the previous Phase 1 trial, which resulted in a decrease in plasma lipid concentration and had no safety issues.

[0103] 3. Trial Design 3.1. Overall Design Subjects are administered Compound 1 multiple times in a cohort dose escalation process. A total of up to 48 subjects are enrolled in this trial and participate in one of four dose cohorts. In each cohort, up to 12 subjects are randomly assigned to receive Compound 1 or placebo at a ratio of 3:1, and in each cohort, up to 9 subjects and up to 3 subjects will receive placebo for each effective dose.

[0104] The first part of this trial includes the first two dose cohorts and placebo, which are administered in parallel (up to N = 24). The first two doses used in these cohorts are 20 mg once a day and 40 mg once a day for 28 days.

[0105] Based on the analysis of the data of each cohort, the sample size may increase up to 12 people in a specific cohort.

[0106] The dose escalation from the parallel cohorts to the following single-dose cohorts is only permitted after all subjects in the two parallel cohorts have completed their cohorts safely. The dose escalation to Cohort 4 is only permitted after all subjects in Cohort 3 have completed their cohort safely.

[0107] This Phase 1b, multi-site, double-blind, multiple-dose escalation study is conducted at multiple sites in the United States. This study includes three effective periods for each cohort. · Screening period (up to 21 days), · Treatment period (28 days), and · Follow-up period (7 days).

[0108] 3.4. Dose Modification If administration becomes impossible due to adverse events, or if further dose escalation is shown to be unnecessary based on the PK / PD (dose-related decrease in VLCFA) data of the first two dose cohorts, the increase to the following dose levels is stopped.

[0109] 4. Study Drug The investigational drug is defined as any investigational medicinal product(s) or placebo intended to be administered to the subjects according to the study protocol.

[0110] 4.1. Administration of the Investigational Drug

Table 2

[0111] Incorporation by Reference All publications and patents mentioned in this specification are hereby incorporated by reference in their entirety as if each individual publication and patent were specifically and individually indicated to be incorporated by reference. In case of any conflict, this application shall prevail, including the definitions in this specification.

[0112] equivalent While particular embodiments of the present invention have been described, the above specification is exemplary and not limiting. Upon consideration of this specification and the following claims, many variations of the present invention will become apparent to those skilled in the art. The full scope of the present invention should be determined by reference to the claims, along with the full scope of their equivalents, and the specification in light of such variations.

Claims

1. Compound (1) for use in the treatment of X-linked adrenoleukodystrophy 【Chemistry 1】 （１） or a composition comprising a pharmaceutically acceptable salt thereof, a) The composition is formulated for administration to a subject once daily in doses selected from 20 mg, 40 mg, 60 mg, and 80 mg. b) The use described above reduces the concentration of one or more saturated very long-chain fatty acids (VLCFAs) in the plasma of the subject approximately 28 days later. c) As a result of the use described above, the maximum mean plasma concentration (C maximum) of compound (1) in the subject reaches approximately 100 ng / mL to approximately 800 ng / mL. d) As a result of the use described above, the area under the mean plasma concentration-time curve (AUC 0-24) of compound (1) in the subject reaches approximately 800-7000 h * ng g / mL over 24 hours. e) With the use described above, the average time to reach the maximum plasma concentration (T maximum) of compound (1) in the subject reaches approximately 2.0 hours to approximately 7.0 hours. f) The use described above results in the average half-life (T 1 / 2) of compound (1) in the subject reaching approximately 10 hours to approximately 20 hours, and / or g) With the use described above, the average oral clearance (CL / F) of compound (1) in the subject reaches approximately 15 L / hour to approximately 30 L / hour. The aforementioned composition.

2. The composition for use according to claim 1, wherein the subject is suffering from adrenal spinal neuropathy.

3. The composition for use according to claim 1, wherein the one or more VLCFAs are selected from behenic acid, tetracosanoic acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid, and combinations thereof.

4. The composition for use according to claim 3, wherein the use reduces the plasma behenate concentration in the subject, and optionally, the reduction in plasma behenate concentration is about 1% to about 60% from baseline, or about 4% to about 24% from baseline, and optionally, the reduction in plasma behenate concentration from baseline is selected from about 4%, about 12%, about 14%, about 24%, about 30%, about 40%, about 50%, and about 60%.

5. The composition for use according to claim 4, wherein the decrease in plasma behenic acid concentration is about 1 μmol / L to about 40 μmol / L from baseline, or about 4 μmol / L to about 16 μmol / L, and optionally, the decrease in plasma behenic acid concentration from baseline is selected from about 4 μmol / L, about 10 μmol / L, about 11 μmol / L, about 16 μmol / L, about 20 μmol / L, about 25 μmol / L, and about 40 μmol / L from baseline.

6. The composition for use according to claim 3, wherein the use reduces the plasma hexacosanoic acid concentration in the subject from baseline, and optionally, the reduction in the plasma hexacosanoic acid concentration from baseline is about 1% to about 50%, or about 10% to about 23%, and optionally, the reduction in the plasma hexacosanoic acid concentration from baseline is selected from about 10%, about 15%, about 23%, about 30%, about 40%, and about 50%.

7. The composition for use according to claim 6, wherein the decrease in plasma hexacosanoic acid concentration from baseline is about 0.01 μmol / L to about 1 μmol / L, or about 0.05 μmol / L to about 0.1 μmol / L, and optionally, the decrease in plasma hexacosanoic acid concentration from baseline is selected from about 0.05 μmol / L, about 0.06 μmol / L, about 0.1 μmol / L, about 0.2 μmol / L, about 0.5 μmol / L, and about 1 μmol / L.

8. The composition for use according to claim 3, wherein the use reduces the plasma tetracosanoic acid concentration in the subject from baseline, and optionally, the reduction in plasma tetracosanoic acid concentration from baseline is about 1% to about 50%, or about 3% to about 24%, and optionally, the reduction in plasma tetracosanoic acid concentration is selected from about 3%, about 14%, about 24%, about 40%, and about 50%.

9. The composition for use according to claim 8, wherein the decrease in plasma tetracosanoic acid concentration from baseline is about 1 μmol / L to about 40 μmol / L, or about 3 μmol / L to about 14 μmol / L, and optionally, the decrease in plasma tetracosanoic acid concentration from baseline is selected from about 3 μmol / L, about 10 μmol / L, about 14 μmol / L, about 30 μmol / L, and about 40 μmol / L.

10. The composition for use according to any one of claims 1 to 9, wherein the ratio of tetracosanoic acid to behenic acid in plasma concentrations from baseline does not substantially change in the use described above.

11. The composition for use according to any one of claims 1 to 9, wherein the ratio of hexacosanoic acid to behenic acid in plasma concentrations from baseline does not substantially change in the use described above.

12. The composition for use according to any one of claims 1 to 9, wherein the ratio of hexacosanoic acid to lysophosphatidylcholine in red blood cells from baseline does not substantially change in the use described above.

13. Compound (1) in the manufacture of a pharmaceutical product for the treatment of X-linked adrenoleukodystrophy in a subject 【Chemistry 1】 （１） or the use of a pharmaceutically acceptable salt thereof, a) The compound is formulated for administration in a dosage regimen selected from 20 mg, 40 mg, 60 mg, and 80 mg once daily. b) The treatment reduces the concentration of one or more saturated very long-chain fatty acids (VLCFAs) in the plasma of the subjects approximately 28 days later. c) As a result of the treatment, the maximum mean plasma concentration (C maximum) of the compound in the subject reaches approximately 100 ng / mL to approximately 800 ng / mL. d) As a result of the treatment, the mean area under the 24-hour plasma concentration-time curve (AUC 0–24) of the compound in the subject reaches approximately 800–7000 h * ng / mL. e) As a result of the treatment, the average time to reach the maximum plasma concentration (T maximum) of the compound in the subject reaches approximately 2.0 hours to approximately 7.0 hours. f) The treatment results in the mean half-life (T 1 / 2) of the compound in the subject reaching approximately 10 hours to approximately 20 hours, and / or g) The treatment results in an average oral clearance (CL / F) of the compound in the subject reaching approximately 15 L / hour to approximately 30 L / hour. The aforementioned use.

14. The use according to claim 13, wherein the subject is suffering from adrenal spinal neuropathy.

15. The use according to claim 13, wherein the one or more VLCFAs are selected from behenic acid, tetracosanoic acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid and combinations thereof.

16. The use according to claim 15, wherein the treatment reduces the plasma behenate concentration in the subject, and optionally, the reduction in plasma behenate concentration is about 1% to about 60% from baseline, or about 4% to about 24% from baseline, and optionally, the reduction in plasma behenate concentration from baseline is selected from about 4%, about 12%, about 14%, about 24%, about 30%, about 40%, about 50%, and about 60%.

17. The use according to claim 16, wherein the decrease in plasma behenate concentration is about 1 μmol / L to about 40 μmol / L from baseline, or about 4 μmol / L to about 16 μmol / L, and optionally, the decrease in plasma behenate concentration from baseline is selected from about 4 μmol / L, about 10 μmol / L, about 11 μmol / L, about 16 μmol / L, about 20 μmol / L, about 25 μmol / L, and about 40 μmol / L from baseline.

18. The use according to claim 15, wherein the treatment reduces the plasma hexacosanoic acid concentration in the subject from baseline, the reduction of the plasma hexacosanoic acid concentration from baseline being about 1% to about 50%, or about 10% to about 23%, and the reduction of the plasma hexacosanoic acid concentration from baseline being selected from about 10%, about 15%, about 23%, about 30%, about 40%, and about 50%.

19. The use according to claim 18, wherein the decrease in plasma hexacosanoic acid concentration from baseline is about 0.01 μmol / L to about 1 μmol / L, or about 0.05 μmol / L to about 0.1 μmol / L, and optionally, the decrease in plasma hexacosanoic acid concentration from baseline is selected from about 0.05 μmol / L, about 0.06 μmol / L, about 0.1 μmol / L, about 0.2 μmol / L, about 0.5 μmol / L, and about 1 μmol / L.

20. The use according to claim 15, wherein the treatment reduces the plasma tetracosanoic acid concentration in the subject from baseline, and optionally, the reduction in plasma tetracosanoic acid concentration from baseline is about 1% to about 50%, or about 3% to about 24%, and optionally, the reduction in plasma tetracosanoic acid concentration is selected from about 3%, about 14%, about 24%, about 40%, and about 50%.

21. The use according to claim 20, wherein the decrease in plasma tetracosanoic acid concentration from baseline is about 1 μmol / L to about 40 μmol / L, or about 3 μmol / L to about 14 μmol / L, and optionally, the decrease in plasma tetracosanoic acid concentration from baseline is selected from about 3 μmol / L, about 10 μmol / L, about 14 μmol / L, about 30 μmol / L, and about 40 μmol / L.

22. The use according to any one of claims 13 to 21, wherein the treatment substantially changes the ratio of tetracosanoic acid to behenic acid plasma concentrations from baseline.

23. The use according to any one of claims 13 to 21, wherein the ratio of hexacosanoic acid to behenic acid plasma concentrations from baseline does not substantially change in the treatment.

24. The use according to any one of claims 13 to 21, wherein the treatment does not substantially change the ratio of hexacosanoic acid to lysophosphatidylcholine in red blood cells from baseline.

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