WO2023245055A1 - Schémas posologiques faisant appel à des bêta-agonistes thyroïdiens pour le traitement de l'x-ald - Google Patents

Schémas posologiques faisant appel à des bêta-agonistes thyroïdiens pour le traitement de l'x-ald Download PDF

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WO2023245055A1
WO2023245055A1 PCT/US2023/068428 US2023068428W WO2023245055A1 WO 2023245055 A1 WO2023245055 A1 WO 2023245055A1 US 2023068428 W US2023068428 W US 2023068428W WO 2023245055 A1 WO2023245055 A1 WO 2023245055A1
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pmol
baseline
decrease
acid
plasma levels
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PCT/US2023/068428
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English (en)
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Brian Lian
Geoff BARKER
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Viking Therapeutics, Inc.
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Publication of WO2023245055A1 publication Critical patent/WO2023245055A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon

Definitions

  • Adrenoleukodystrophy also known as X-linked adrenoleukodystrophy, X-ALD
  • X-ALD X-linked adrenoleukodystrophy
  • X-ALD X-linked adrenoleukodystrophy
  • cerebral ALD X-linked adrenoleukodystrophy
  • AMN adrenomyeloneuropathy
  • 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.
  • 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):
  • the dosing regimen comprises administering a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg to the subject once daily.
  • 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):
  • 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):
  • 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):
  • T m ax average time to blood plasma concentration maximum
  • 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):
  • 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):
  • the dosing regimen comprises administering a dose selected from 20 mg, 40 mg, 60 mg, and 80 mg to the subject once daily.
  • 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.
  • the dose is about 20 mg.
  • the dose is about 40 mg.
  • the dose is about 60 mg.
  • the dose is about 80 mg.
  • 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):
  • 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.
  • the one or more VLCFAs are selected from behenic acid, tetracosanoic acid, hexacosanoic acid octacosanoic acid, triacontanoic acid, and combinations thereof.
  • dosing regimen is sufficient to decrease plasma levels of behenic acid in the subject from baseline.
  • 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.
  • 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.
  • 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.
  • the dosing regimen is sufficient to decrease plasma levels of hexacosanoic acid in the subject from baseline.
  • the decrease in plasma levels of hexacosanoic acid is from about 1 % to about 30% from baseline.
  • the decrease in plasma levels of hexacosanoic acid is from about 10% to about 23% from baseline.
  • the decrease in plasma levels of hexacosanoic acid is at least about 10% from baseline.
  • the decrease in plasma levels of hexacosanoic acid is at least about 15% from baseline.
  • the decrease in plasma levels of hexacosanoic acid is at least about 23% from baseline.
  • 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%.
  • 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.
  • 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.
  • the dosing regimen is sufficient to decrease plasma levels of tetracosanoic acid in the subject from baseline.
  • the decrease in plasma levels of tetracosanoic acid is from about 1% to about 50% from baseline.
  • the decrease in plasma levels of tetracosanoic acid is from about 3% to about 24% from baseline.
  • the decrease in plasma levels of tetracosanoic acid is at least about 3% from baseline.
  • the decrease in plasma levels of tetracosanoic acid is at least about 14% from baseline.
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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):
  • 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.
  • Cmax maximum average blood plasma concentration
  • 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.
  • the Cmax is from about 104 ng/mL to about 653 ng/mL.
  • the Cmax is at least about 104 ng/mL.
  • the Cmax is at least about 274 ng/mL.
  • the Cmax is at least about 395 ng/mL.
  • the Cmax is at least about 603 ng/mL.
  • 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.
  • 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):
  • 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.
  • 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.
  • the AUC0-24 is from about 999 h*ng/mL to about 4550 h*ng/mL.
  • the AUC0-24 is at least about 999 h*ng/mL.
  • the AUC0-24 is at least about 2980 h*ng/mL.
  • the AUC0-24 is at least about 3320 h*ng/mL.
  • 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.
  • 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.
  • Tmax blood plasma concentration maximum
  • 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 (T m ax) of the compound from about 2.0 to about 7.0 hours.
  • T m ax is from about 3.86 h to about 5.19 h.
  • the Tmax is at least about 3.86 h.
  • the T m ax is at least about 5.19 h.
  • the T m ax is at least about 4.36 h.
  • wherein the T m ax is about 3.86 h.
  • the T m ax is about 5.19 h.
  • the T m ax is about 4.36 h.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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):
  • 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.
  • CL/F is from about 16.4 L/h to about 27.5 L/h.
  • CL/F is at least about 27.5 L/h.
  • CL/F is at least about 16.4 L/h.
  • CL/F is least about 22.6 L/h.
  • CL/F is at least about 20.1 L/h.
  • CL/F is about 27.5 L/h.
  • CL/F is about 16.4 L/h.
  • CL/F is about 22.6 L/h.
  • CL/F is about 20.1 L/h.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • phrases "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.
  • 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.
  • 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;
  • a pharmaceutical composition 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.
  • a compound may be simply dissolved or suspended in sterile water.
  • 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.
  • an active compound such as a compound of the invention
  • 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.
  • 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.
  • 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,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • 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.
  • 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.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions 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.
  • compositions 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.
  • 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.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • 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.
  • 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.
  • 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.
  • 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.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • 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.
  • 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.
  • 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.
  • aqueous and nonaqueous carriers examples 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.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • 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.
  • 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.
  • the absorption of the drug 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • 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.
  • 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 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.
  • 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.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • 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.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts.
  • 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.
  • 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
  • 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.
  • wetting agents 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.
  • antioxidants examples 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.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • 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.
  • 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).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • 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.
  • 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.
  • 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.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
  • 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.
  • 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.
  • “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.
  • pharmaceutically acceptable basic addition salt 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.
  • pharmaceutically acceptable carrier 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.
  • 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).
  • X-ALD X-linked Adrenoleukodystrophy
  • APN Adrenomyeloneuropathy Form
  • phase lb 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.
  • 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:
  • 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.
  • Cohort 1 and 2 will be dosed in parallel as listed below:
  • the study may include third and fourth dose cohorts.
  • 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).
  • Up to forty-eight subjects with AMN are planned to be included in this study.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • the first 2 doses used in these cohorts will be 20 mg QD and 40 mg QD for 28 days.
  • sample size may be increased by up to 12 subjects in a particular cohort.
  • 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.
  • 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:
  • Study Drug is defined as any investigational drug(s), or placebo, intended to be administered a study subject according to the study protocol.

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Abstract

La présente invention concerne des schémas posologiques et des méthodes pour le traitement de l'adrénoleucodystrophie liée à l'X (X-ALD) faisant appel à des bêta-agonistes des récepteurs thyroïdiens.
PCT/US2023/068428 2022-06-15 2023-06-14 Schémas posologiques faisant appel à des bêta-agonistes thyroïdiens pour le traitement de l'x-ald WO2023245055A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017185083A1 (fr) * 2016-04-22 2017-10-26 Viking Therapeutics Utilisation de bêta-agonistes des hormones thyroïdiennes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017185083A1 (fr) * 2016-04-22 2017-10-26 Viking Therapeutics Utilisation de bêta-agonistes des hormones thyroïdiennes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "A Study to Assess the Pharmacodynamics of VK0214 in Male Subjects With AMN ", CLINICAL TRIALS NCT04973657 (V5), 6 April 2022 (2022-04-06), XP093118498, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT04973657?cond=Adrenoleukodystrophy%20%5C(ALD%20and%20AMN%5C)&rank=3&tab=history&a=5> [retrieved on 20240111] *
ANONYMOUS: "Guideline for Industry Dose-Response Information to Support Drug Registration. ICH-E4 ", FDA.GOV, 1 November 1994 (1994-11-01), XP093118504, Retrieved from the Internet <URL:https://www.fda.gov/media/71279/download> [retrieved on 20240111] *
DESIRÈE PADILHA MARCHETTI; BRUNA DONIDA; CARLOS EDUARDO JACQUES; MARION DEON; TATIANE CRISTINA HAUSCHILD; PATRICIA KOEHLER‐SANTOS;: "Inflammatory profile in X‐linked adrenoleukodystrophy patients: Understanding disease progression", JOURNAL OF CELLULAR BIOCHEMISTRY, JOHN WILEY & SONS, INC. JOHN WILEY & SONS, INC., HOBOKEN, USA, vol. 119, no. 1, 23 August 2017 (2017-08-23), Hoboken, USA, pages 1223 - 1233, XP071661703, ISSN: 0730-2312, DOI: 10.1002/jcb.26295 *
SCHMIDT R: "DOSE-FINDING STUDIES IN CLINICAL DRUG DEVELOPMENT"; EUR J CLIN PHARMACOL: "vol. 34", NO. 1, DOI: 10.1007/BF01061410 (1988/12/31), pages 15 - 19 *

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