Topical compositions of GLP-1 agonists and use of GLP-1 agonists and compositions thereof in treating vitiligo

Abstract

The disclosed subject matter provides topical compositions comprising a GLP-1 agonist, kits comprising such compositions, and methods for treating or preventing vitiligo using a GLP- 1 agonist or compositions thereof.

Description

[0001] TOPICAL COMPOSITIONS OF GLP-1 AGONISTS AND

[0002] USE OF GLP-1 AGONISTS AND COMPOSITIONS THEREOF IN TREATING VITILIGO

[0003] 1. BACKGROUND

[0004] Vitiligo is a chronic autoimmune disorder in which the skin loses its natural color due to depigmentation. Normally, the immune system works throughout the body to fight infections, such as those caused by viruses and bacteria. In people with vitiligo, however, it is believed that the immune system attacks and destroys melanocytes - the cells that make the pigment responsible for skin color. This causes the skin to turn white in irregularly shaped patches, on any part of the skin surface. Vitiligo can change the color of a person’s hair and eyes, especially the iris and the retina. Over time, the white patches may grow in size and / or spread to other parts of the body. People with vitiligo are susceptible to sunburn, skin cancer, eye problems, and psychological distress.

[0005] Current treatments for vitiligo are directed to returning color to the white depigmented patches of skin. Medicines or topically applied medicated skin creams (such as corticosteroids or calcineurin inhibitors) may be able to return the color to the white patches of skin, presumably by suppressing the local autoimmune process causing the depigmentation. (Lee at al.. “Treatment Outcomes of Topical Calcineurin Inhibitor Therapy for Patients With Vitiligo.” JAMA Dermatol. 2019 Aug; 155(8): 929-938.) Topical ruxolitinib, a selective JAK1 / 2 inhibitor was also recently approved to treat non-semnetal vitiligo in children older than 12 years of age. Ruxolitinib regulates IFN- y mediated JAK-STAT signaling, which is thought to inhibit CD8+ T cells from destroying melanocytes or pigment producing cells in the skin. (Sheikh et al, “FDA approves Ruxolitinib (Opzelura) for Vitiligo Therapy: A breakthrough in the field of dermatology,” Ann Med Surg (Lond). 2022 Sep: 81: 104499.) Phototherapy in the fonn of narrow-band ultraviolet radiation B (nbUVB) is also used to help return the color of skin by locally inhibiting autoimmunity. Topical medications and phototherapy may be used together for best results.

[0006] Another method for treating vitiligo is depigmentation. In depigmentation, the color from dark areas of the skin is removed so that it matches the white patches. The depigmentation process can take more than a year to complete.

[0007] None of these vitiligo treatments are very effective long term.

[0008] Semaglutide is a glucagon-like peptide (GLP-1) receptor agonist and mimics the hormone GLP-1. See, e.g., U.S. Pat. Nos. 8,129,343; 8,536,122; 9,278,123; 9,764,003; 10,086,047; 10,335,462; and 10,888,605. GLP-1 works in the body in different ways. For example, at mealtime, GLP-1 is released into the gastrointestinal tract, prompting the body to produce more insulin, which, in turn, reduces the level of blood sugar. In higher amounts, GLP-1 interacts with parts of the brain that serve to reduce appetite and signal a feeling of fullness. Thus, by mimicking GLP-1, GLP-1 receptor agonists, like semaglutide, can be used to help the body make more insulin and reduce appetite . Currently, there are three FDA approved formulations of semaglutide: OZEMPIC®, WEGOVY® and RYBELSUS®, each developed by Novo Nordisk. (“Medications Containing Semaglutide Marketed for Type 2 Diabetes or Weight Loss” available on the World Wide Web at fda.gov / drugs / postmarket-drug-safety-information-patients-and- providers / medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss.)

[0009] W02006 / 097537 (“the ‘537 Publication”) discloses acylated GLP-1 analogs, which are said to be usefill for treating diseases, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia, and gastric ulcers. Example 4 of the ‘537 Publication describes the synthesis of semaglutide, which is also known as N-826-[2-(2-[2-(2-[2-(2-[4-( 17-Carboxyhepta-decanoylamino)- 4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)-acetyl][Aib8,Arg34]GLP-l-(7- 37)peptide.

[0010] Citation of any reference in Section 1 of this application is not to be construed as an admission that such reference is prior art to the present disclosure.

[0011] 2. SUMMARY OF THE DISCLOSURE

[0012] The present disclosure relates to the discovery1that GLP-1 agonists, such as semaglutide, can be highly? effective in treating vitiligo.

[0013] In one aspect, the present disclosure provides a topical composition comprising a GLP-1 agonist, such as semaglutide, or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

[0014] In a further aspect, the present disclosure provides a method for treating or preventing vitiligo, the method comprising administering an effective amount of a GLP-1 agonist, such as semaglutide, or a pharmacally acceptable salt thereof, or a composition comprising the GLP-1 agonist or a pharmacally acceptable salt thereof to a subject in need thereof.

[0015] In one aspect, the GLP- 1 agonist, such as semaglutide, or a pharmacally acceptable salt thereof can be administered orally. In another aspect, a composition comprising a GLP-1 agonist, such as semaglutide, or a pharmaceutically acceptable salt thereof can be administered via oral or topical administration.

[0016] 3. DETAILED DESCRIPTION

[0017] The invention includes the following:

[0018] 1. A topical composition comprising a GLP-1 agonist or a pharmaceutically salt thereof and at least one dermatologically acceptable excipient.

[0019] 2. A topical composition comprising semaglutide or a pharmaceutically salt thereof and at least one dermatologically acceptable excipient.

[0020] 3. The topical composition of the above 1 or 2, wherein the composition is formulated as a transdermal patch, a gel, a cream, an ointment, a lotion, or a foam.

[0021] 4. The topical composition of any of the above 1 to 3, wherein the at least one dermatologically acceptable excipient is mineral oil, paraffin, propylene carbonate, white petrolatum, white wax, or any combination thereof.

[0022] 5. The topical composition of any of the above 1 to 4, further comprising an additional therapeutic agent.

[0023] 6. Tire topical composition of the above 5, wherein the additional therapeutic agent is a corticosteroid, an immunomodulator, a calcineurin inhibitor, a JAK inhibitor, a retinoid, a vitamin or an analog thereof, a dietary supplement, or any combination thereof.

[0024] 7. Tire topical composition of the above 5, wherein the additional therapeutic agent is alclometasone, amcinonide, betamethasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide. fluticasone, halcinonide, halobetasol. hydrocortisone, mometasone, prednicarbate. triamcinolone, tacrolimus, pimecrolimus, ruxolitinib, tofacitinib, calcipotriene, beta carotene, alpha carotene, tretinoin, vitamin A, vitamin C, vitamin E, vitamin B12, vitamin D, folic acid, cartenoids (such as lycopene), or any combination thereof.

[0025] 8. A method of treating or preventing vitiligo comprising administering an effective amount of a GLP-1 agonist or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0026] 9. A method of treating or preventing vitiligo comprising administering an effective amount of semaglutide or a pharmaceutically acceptable salt thereof to a subject in need thereof. 10. The method of the above 8 or 9, wherein the GLP-1 agonist or semaglutide or a pharmaceutically acceptable salt thereof is administered orally.

[0027] 11. The method of any of the above 8 to 10. further comprising exposing the vitiligo-affected skin to phototherapy.

[0028] 12. A method of treating or preventing vitiligo comprising administering an effective amount of a composition comprising a GLP-1 agonist or a pharmaceutically salt thereof to a subject in need thereof.

[0029] 13. A method of treating or preventing vitiligo comprising administering an effective amount of a composition comprising semaglutide or a pharmaceutically salt thereof to a subject in need thereof.

[0030] 14. The method of the above 12 or 13, wherein the composition is administered orally.

[0031] 15. Tire method of the above 12 or 13, wherein the composition is administered topically.

[0032] 16. The method of any of the above 12 to 15, further comprising exposing the vitiligo-affected skin to phototherapy.

[0033] 17. A kit comprising the topical formulation of any of the above 1 to 7.

[0034] 18. Use of a GLP- 1 agonist for the manufacture of a medicament useful for treating vitiligo.

[0035] 19. Use of semaglutide for the manufacture of a medicament useful for treating vitiligo.

[0036] 20. Use of the topical composition of any of the above 1 to 7 for the manufacture of a medicament useful for treating vitiligo.

[0037] 21. A GLP- 1 agonist for use in the treatment of vitiligo .

[0038] 22. Semaglutide for use in the treatment of vitiligo.

[0039] 23. A topical composition of any one of the above 1 to 7 for use in the treatment of vitiligo.

[0040] 3.1 Definitions

[0041] Unless clearly indicated otherwise, the following terms as used herein have the meanings indicated below. Throughout this specification, the word '‘comprise” or variations such as ‘'comprises” or ‘'comprising” will be understood to imply the inclusion of a stated integer or groups of integers but not the exclusion of any other integer or group of integers. Each instance herein, any of the terms “comprising,” “consisting essentially of.” and “consisting of’ can be replaced with either of the two other terms.

[0042] The term “a” or “an” may mean more than one of an item.

[0043] The terms “and” and “or” may refer to either the conjunctive or disjunctive and mean “and / or”.

[0044] The term “about” means within plus or minus 10% of a stated value. For example, “about 100” would refer to any number between 90 and 110.

[0045] The term “topical composition” comprising a GLP-1 agonist or semaglutide refers to a formulation of a GLP-1 agonist or semaglutide and a medium known or accepted in the art for the delivery of a pharmaceutically active compound to skin, e.g., mammalian skin.

[0046] The term “GLP-1” refers to glucagon-like peptide- 1.

[0047] The term “GLP-1 agonist” refers to an agonist of the glucagon -like peptide- 1 receptor. GLP-1 agonists can be referred to as GLP-1 receptor agonists, incretin mimetics, GLP-1 analogs, and GLP-1 derivatives. Exemplary GLP-1 agonists include, but are not limited to, GLP-1, albiglutide, dulaglutide (LY2189265) , efpeglenatide, exenatide (Exendin-4), liraglutide (NN2211), lixisenatide, semaglutide, tirzepatide, ZP2929. NNC0113-0987, BPI-3016, and TT401. See, also, for example, additional GLP-1 agonists described in U.S. Patent Nos. 11.357.820; 10,370,426; 10,308,700: 10,259.823; 10.208,019; 9,920,106; 8,536,122; 8,501,698; 8,129,343; 8,114,833; 7,452,966; 7,141,547; and RE45313.

[0048] A “pharmacally acceptable salt” refers to a salt of any therapeutic agent disclosed herein, which salt can include any of a variety7of organic and inorganic counter ions known in the art and which salt is pharmaceutically acceptable.

[0049] “Dermatologically acceptable excipient” refers to any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, excipient, filler, binder, glidant, preservative, dye / coloring agent, surfactant, wetting agent, dispersing agent, suspending agent, buffering agent, solubilizer, viscosity enhancer, pH adjuster, stabilizing agents, antioxidant, radical scavenger, isotonic agent, solvent, thickening agent, lubricating agent, emulsifying agent, absorbent, penetration enhancer, humectant, binder, fragrance, emollient, chelating agent, and / or vehicle for delivery of a therapeutic agent to a subject, or added to a composition to improve administration and / or absorption of the therapeutic agent, or added to a composition to improve its handling or storage properties or to permit or facilitate formation of a composition into a dosage form for administration.

[0050] Dermatologically acceptable excipients are well known in the art and examples include gelatin; starch; pullulan; gum arabic; tragacanth gum; dextran; cellulose derivatives, such as methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose; polymers, such as carboxy vinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone; lecithin; collagen; alcohols, such as alkanols with one to twenty carbons, such as ethanol, propanol, propylene glycol, 1,3- butyleneglycol, phenol, oleyl alcohol, cetyl alcohol, octyldodecanol, cetostearyl alcohol, stearyl alcohol, benzyl alcohol, butylene glycol, diethylene glycol, glycofurol, glycerides, glycerin, glycerol, phenethyl alcohol, and phenoxyethanol; amino acids, such as L-a-amino acids and water-soluble proteins; oils, such as vegetable oil, almond oil, amyl butyrate, apricot kernel oil, avocado oil, camphor, castor oil, 1 -carvone, coconut oil, com oil, cotton seed oil, eugenol oil, menthol, anise oil, orange oil, olive oil, peanut oil, peppermint oil, rose oil, safflower oil, sesame oil, shark liver oil (squalene), soybean oil, sunflower oil, and walnut oil; vitamins and herbs, such as aloe, allantoin, black walnut extract, chamomile extract, panthenol, papain, tocopherol, and vitamin A palmitate; waxes, such as white wax, candelilla wax, camuba wax, ceresin wax, beeswax, lanolin wax, jojoba oil, paraffin, hydrophilic petrolatum, and petrolatum; animal fats or animal-derived ingredients, such as tallow, lanolin, collagen, lard, and butter; lanolin derivatives, such as lanolin alcohol, PEG 16 lanolin, and acetylated lanolin; oxazolines; oxazolindinones; proline esters; surfactants, including, cationic, anionic or nonionic, such as nonoxynols, polysorbates (e.g.. polysorbate 80), glycerol fatty acid esters, polyoxylene alcohols, polyoxylene fatty acid esters, sodium lauryl sulfate, and sorbitan monostearate, a saturated or unsaturated fatty acid ester, a polyoxythylene fatty ether, a polyoxylene fatty acid ester, diethylene glycol monoethyl ether, 1,3- dimethyl-2-imidazolidinone and / or dimethyl isosorbide, polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene glycol 1500 (PEG 1500), polyethylene glycol 1600 (PEG 1600), polyethylene glycol 4000 (PEG 4000). polyethylene glycol 6000 (PEG 6000), glycerol, Transcutol P (diethylene glycol monoethyl ether), propylene glycol, propylene carbonate 1,3 -dimethyl -2- imidazolidinone (DMI), sodium metabisulfite, butylated hydroxytoluene (BHT), benzyl alcohol, sodium benzoate, isopropyl myristate, diisopropyl adipate, crodamol OHS (ethylhexyl hydroxystearate), mineral oil, Bctadcx, polysorbate 20 (TWEEN 20), (polyoxyethylene (20) stearyl ether), silicones (e.g., dimethicone, cylcomethicone etc). Steareth-2 (Brij S2), Steareth-20 (Brij S20), glyceryl stearate, stearic acid, magnesium stearate, diethylene glycol monoethyl ether, l,3-dimethyl-2-imidazolidinone; ethylenediamine tetraacetic acid (EDTA); methylparaben and propylparaben. The term ‘'subject’’ refers to an animal, such as a mammal, including, but not limited to, a human. In particular embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0051] ‘'Effective amount” refers to an amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, that is sufficient to achieve the desired result but is generally insufficient to cause adverse side effects. As is understood in the art, an effective amount can be administered in one or more doses.

[0052] “Treatment”, “treating” and the like is an approach for obtaining a beneficial or desired result, including clinical results. For purposes of this disclosure, beneficial or desired results include but are not limited to inhibiting and / or suppressing the onset and / or development of a condition or reducing the severity of such condition, such as reducing the number and / or severity of symptoms associated with the condition, increasing the quality of life of those suffering from the condition, decreasing the dose of other medications required to treat the condition, enhancing the effect of another medication a patient is taking for the condition, and / or prolonging survival of patients having the condition.

[0053] “Prevent”, “preventing” and the like refers to reducing the probability of developing a condition in a patient who does not have, but is at risk of developing a condition. A patient “at risk” may or may not have a detectable condition, and may or may not have displayed a detectable condition prior to the treatment methods disclosed herein. “At risk” denotes that a patient has one or more so-called risk factors, which are measurable parameters that correlate with development of a condition and are known in the art. A patient having one or more of these risk factors has a higher probability of developing the condition than a patient without such risk factor(s).

[0054] When a range of values is provided, it is to be understood that the range includes each intervening integer value between the upper and lower limit of that range. For example, if a range of 1 to 10 is stated, it is understood to expressly include subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 1 to 6, from 1 to 7, from 1 to 8, from 1 to 9, from 2 to 4, from 2 to 6, from 2 to 8, etc., as well as individual values within the range, such as 1.1, 2, 2.6, 3, 3.9, 4, 4.2, 5, 5.7, 6. 6.5, 7, 7.4, 8, 8.8, 9, 9.1 and 10.

[0055] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods and examples are illustrative only, and are not intended to be limiting. All publications, patents and other documents mentioned herein are incorporated by reference in their entirety. 3.2 Topical Compositions

[0056] The present disclosure provides a topical formulation comprising a GLP-1 agonist or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

[0057] In various embodiments, the GLP-1 agonist can be GLP-1, albiglutide, dulaglutide (LY2189265) , efpeglenatide, exenatide (Exendin-4), liraglutide (NN2211), lixisenatide, semaglutide, tirzepatide, ZP2929, NNCO 113-0987, BPI-3016, and TT401. The GLP-1 agonist can also be one described in U.S. Patent Nos. 11,357,820; 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 8,536,122; 8,501,698; 8,129,343; 8.114,833; 7,452,966; 7,141,547; and RE45313.

[0058] In one embodiment, the present disclosure provides a topical formulation comprising semaglutide or a pharmaceutically acceptable salt thereof and at least one dermatologically acceptable excipient.

[0059] Examples of dermatologically acceptable excipients include those described above, such as a carrier, glidant, preservative, dye / colorant. surfactant, wetting agent, dispersing agent, suspending agent, buffering agent, solubilizer, viscosity enhancer, pH adjuster, stabilizing agent, antioxidant, radical scavenger, isotonic agent, solvent, lubricating agent, emulsifier, absorbent, absorption enhancer, penetration enhancer, humectant, binder, fragrance, emollient, lubricating agent, stiffening agent, and any combination thereof. It is understood that one dermatologically acceptable excipient can perform more than one function. For example, paraffin can serve as a lubricating agent as well as a humectant.

[0060] In various embodiments, the topical formulation comprises at least one dermatologically acceptable excipient. In one aspect, the topical formulation comprises at least two dermatologically acceptable excipients. In one aspect, the topical formulation comprises at least three dermatologically acceptable excipients. In one aspect, the topical formulation comprises at least four dermatologically acceptable excipients. In one aspect, the topical formulation comprises at least five dermatologically acceptable excipients. In one aspect, the topical formulation comprises at least six dermatologically acceptable excipients. In one aspect, the topical formulation comprises at least seven dermatologically acceptable excipients. In one aspect, the topical formulation comprises at least eight dermatologically acceptable excipients. In one aspect, the topical formulation comprises at least nine dermatologically acceptable excipients. In one aspect, the topical formulation comprises at least ten dermatologically acceptable excipients.

[0061] The amount of the GLP-1 agonist (e.g., semaglutide) present in the topical composition is an amount effective to treat or prevent vitiligo after the topical composition is applied to the affected area. In some embodiments, the GLP-1 agonist (e.g., semaglutide) is present in an amount of about 0.001% w / w to about 25% w / w, about 0.001% w / w to about 20% w / w, about 0.001% w / w to about 15% w / w, about 0.001% w / w to about 10% w / w, about 0.001% w / w to about 5% w / w, about 0.001% w / w to about 4% w / w, about 0.001% w / w to about 3% w / w, about 0.001% w / w to about 2% w / w, about 0.001% w / w to about 1% w / w, about 0.01% w / w to about 25% w / w, about 0.01% w / w to about 20% w / w, about 0.01% w / w to about 15% w / w, about 0.01% w / w to about 10 % w / w, about 0.01% w / w to about 5% w / w, about 0.01% w / w to about 4% w / w, about 0.01% w / w to about 3% w / w, about 0.01% w / w to about 2% w / w. about 0.01% w / w to about 1% w / w, about 0.1% w / w to about 25% w / w. about 0.1% w / w to about 20% w / w, about 0. 1% w / w to about 15% w / w, about 0.1% w / w to about 10 % w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 4% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0. 1% w / w to about 1% w / w, about 0.5% w / w to about 25% w / w, about 0.5% w / w to about 20% w / w, about 0.5% w / w to about 15% w / w, about 0.5% w / w to about 10 % w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 4% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w. about 1% w / w to about 25% w / w, about 1% w / w to about 20% w / w, about 1% w / w to about 15% w / w, about 1% w / w to about 10 % w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 1% w / w to about 1.5% w / w.

[0062] In various embodiments, the GLP-1 agonist (e.g., semaglutide) is present in the topical formulation in an amount of about 0.001% w / w, about 0.01% w / w, about 0.05% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w. about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w. about 1.4% w / w, about 1.5% w / w. about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w. about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4. 1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w. about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w. about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w / , about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, or about 25% w / w.

[0063] Tire topical composition can be formulated as a transdermal patch, gel (an aqueous or nonaqueous), cream, ointment, lotion, foam, solution, suspension, emulsion, drops, sprayable liquid, dispersion, salve, paste, liposome, micelle, or giant micelle. In various embodiments, the topical formulation is a transdermal patch in a first embodiment, a gel a second embodiment, a cream in a third embodiment, an ointment in a fourth embodiment, a lotion in a sixth embodiment, and a foam in a seventh embodiment.

[0064] Tire topical compositions of the disclosure can be made according to procedures well known in the art in the fonnulation of dermatological compositions. In general, the base formulation is prepared first and then the GLP-1 agonist (e.g., semaglutide) or a pharmaceutically acceptable salt thereof is added and mixed thoroughly. If necessary, the pH of the topical composition can be adjusted.

[0065] In one embodiment, the topical composition further comprises an additional therapeutic agent. The additional therapeutic agent can be a corticosteroid, an immunomodulator, a calcineurin inhibitor, a JAK inhibitor, a retinoid, a vitamin or analog thereof, a dietary supplement and any combination thereof. Examples of additional therapeutic agents that can be used include, but are not limited to, alclometasone, amcinonide, betamethasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, mometasone, prednicarbate. triamcinolone, tacrolimus, pimecrolimus. ruxolitinib (sold under OPZELURA™), tofacitinib, calcipotriene, beta carotene, alpha carotene, tretinoin, vitamin A, vitamin C, vitamin E, vitamin Bl 2, vitamin D, folic acid, cartenoids (such as lycopene), and any combination thereof.

[0066] 3.3 Methods Of Using GLP-1 Agonists And Compositions Thereof

[0067] The present disclosure provides a method for treating or preventing vitiligo. In one embodiment, the method comprises administering a GLP-1 agonist or a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the GLP-1 agonist or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In one aspect, the method is for treating vitiligo in a subject in need thereof and in a second aspect, the method is for preventing vitiligo in a subject in need thereof. The GLP-1 agonists can be any described in Section 3.2.

[0068] In another embodiment, the method comprises administering semaglutide or a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising semaglutide or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In one aspect, the method is for treating vitiligo in a subject in need thereof and in a second aspect, the method is for preventing vitiligo in a subject in need thereof.

[0069] The GLP-1 agonists (e.g., semaglutide) used in the methods of the disclosure may be formulated for oral or topical administration. Oral formulations of semaglutide arc known and can be prepared as described in U.S. Patent Nos. 9,278,123 and 10,086,047. Topical compositions of GLP-1 agonists are described in Section 3.2, and any can be used in the methods of the disclosure.

[0070] When treating vitiligo topically, the topical composition of the disclosure is administered directly to the vitiligo-affected area of the skin (i.e., the white patches of skin) of the subject in need thereof.

[0071] Prior to topically administering the GLP-1 agonist composition to the subject, the vitiligo- affected skin can optionally be pre -treated, e.g., by cleaning the skin with soap and water or an alcohol- based cleanser.

[0072] The compositions disclosed herein can be administered prior to, at substantially the same time with, or after administration of an additional therapeutic agent. The administration regimen can include pretreatment and / or co-administration with the additional therapeutic agent. In such case, the GLP-1 agonist composition and the additional therapeutic agent can be administered simultaneously, separately, or sequentially.

[0073] Examples of administration regimens include without limitation: administration of each the GLP- 1 agonist composition and therapeutic agent in a sequential manner; and co-administration of the GLP- 1 agonist composition and therapeutic agent in a substantially simultaneous manner (e.g., as in a single unit dosage form) or in multiple, separate unit dosage forms for the GLP-1 agonist composition and the therapeutic agent.

[0074] The additional therapeutic agent can be a corticosteroid, an immunomodulator, a calcineurin inhibitor, a JAK inhibitor, a retinoid, a vitamin or analog thereof, an antioxidant and any combination thereof. Examples of additional therapeutic agents that can be used include, but are not limited to alclometasone, amcinonide, betamethasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, mometasone, prednicarbate, triamcinolone, tacrolimus, pimecrolimus, ruxolitinib (sold under OPZELURA™), tofacitinib, calcipotriene, beta carotene, alpha carotene, tretinoin, vitamin A, vitamin C, vitamin E, vitamin B 12, vitamin D, folic acid, cartenoids (such as lycopene), and any combination thereof.

[0075] In various embodiments, the methods of the disclosure further comprise exposing the vitiligo- affected skin to phototherapy. Phototherapy includes exposure to sunlight or to radiation of specific wavelengths, for example, UV radiation, including UVA and U VB radiation.

[0076] 3.4 Administration Regimens and Dose Levels As described in Section 3.3, the GLP-1 agonist and compositions thereof can be administered by oral or topical administration.

[0077] The amount of the GLP-1 agonist or composition thereof used to treat or prevent vitiligo will vary depending on the severity and progression of vitiligo, the specific formulation used, the administration route, the age and body weight of the subject, the sex and general health of the subject, the judgment of the treating physician and the like.

[0078] When a composition comprising a GLP-1 agonist is administered, dosages are expressed based on the amount of the GLP-1 agonist.

[0079] In embodiments in which the GLP-1 agonist is administered topically, a topical GLP-1 agonist composition is applied topically to the vitiligo-affected skin. Preferably, the topical formulation is applied in a thin layer.

[0080] The topical GLP-1 agonist composition is administered topically in a range of about 0.001 mg / day to about 2000 mg / day, about 0.01 mg / day to about 2000 mg / day, about 0.1 mg / day to about 2000 mg / day, about 1.0 mg / day to about 2000 mg / day, about 10 mg / day to about 2000 mg / day, about 100 mg / day to about 2000 mg / day, about 1000 mg / day to about 2000 mg / day, about 1100 mg / day to about 2000 mg / day, about 1200 mg / day to about 2000 mg / day, about 1300 mg / day to about 2000 mg / day, about 1400 mg / day to about 2000 mg / day, about 1500 mg / day to about 2000 mg / day, about 1600 mg / day to about 2000 mg / day, about 1700 mg / day to about 2000 mg / day, about 1800 mg / day to about 2000 mg / day, about 1900 mg / day to about 2000 mg / day, about 0.001 mg / day to about 1900 mg / day, about 0.001 mg / day to about 1800 mg / day, about 0.001 mg / day to about 1700 mg / day, about 0.001 mg / day to about 1600 mg / day, about 0.001 mg / day to about 1500 mg / day, about 0.001 mg / day to about 1400 mg / day, about 0.001 mg / day to about 1300 mg / day, about 0.001 mg / day to about 1200 mg / day, about 0.001 mg / day to about 1100 mg / day, about 0.001 mg / day to about 1000 mg / day, about 0.001 mg / day to about 900 mg / day, about 0.001 mg / day to about 800 mg / day, about 0.001 mg / day to about 700 mg / day, about 0.001 mg / day to about 600 mg / day, about 0.001 mg / day to about 500 mg / day, about 0.001 mg / day to about 400 mg / day, about 0.001 mg / day to about 300 mg / day, about 0.001 mg / day to about 200 mg / day, about 0.001 mg / day to about 100 mg / day, about 0.001 mg / day to about 10 mg / day, about 0.001 mg / day to about 1 mg / day, about 0.001 mg / day to about 0. 10 mg / day, or about 0.001 mg / day to about 0.010 mg / day.

[0081] In various embodiments, the topical GLP-1 agonist composition is administered topically in an amount of about 0.001 mg / day, about 0.01 mg / day, about 0.1 mg / day, about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 200 mg / day, about 300 mg / day, about 400 mg / day, about 500 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day, about 1100 mg / day, about 1200 mg / day, about 1300 mg / day, about 1400 mg / day, about 1500 mg / day, about 1600 mg / day, about 1700 mg / day, about 1800 mg / day, about 1900 mg / day, or about 2000 mg / day.

[0082] The topical GLP-1 agonist composition may be applied once or more times daily, for example, 1 to 6 times daily. The duration of the treatment will depend on the severity of the vitiligo symptoms and the state of the disease and can be easily adjusted by the treating physician. Typically, the treatment may be for several weeks, several months, or longer.

[0083] In embodiments in which the GLP-1 agonist is administered orally, the GLP-1 agonist or a composition thereof is administered in a range of about 0.1 mg / kg / week to about 3 mg / kg / week, about 0.1 mg / kg / week to about 2.5 mg / kg / week, about 0. 1 mg / kg / week to about 2 mg / kg / week, about 0.1 mg / kg / week to about 1.5 mg / kg / week, about 0. 1 mg / kg / week to about 1 mg / kg / week, about 0. 1 mg / kg / week to about 0.5 mg / kg / week, about 0. 1 mg / kg / week to about 0.25 mg / kg / week, about 0. 1 mg / kg / week to about 0.2 mg / kg / week, about 0.2 mg / kg / week to about 3 mg / kg / week, about 0.25 mg / kg / week to about 3 mg / kg / week, about 0.5 mg / kg / week to about 3 mg / kg / week, about 1 mg / kg / week to about 3 mg / kg / week, about 1 .5 mg / kg / week to about 3 mg / kg / week, about 2 mg / kg / week to about 3 mg / kg / week, or about 2.5 mg / kg / week to about 3 mg / kg / week.

[0084] In various embodiments, the oral GLP- 1 agonist or composition thereof is administered in an amount of about 0.1 mg / kg / week, about 0.15 mg / kg / week, about 0.2 mg / kg / week, about 0.25 mg / kg / week, about 0.3 mg / kg / week, about 0.35 mg / kg / week, about 0.4 mg / kg / week, about 0.45 mg / kg / week, about 0.5 mg / kg / week, about 0.55 mg / kg / week, about 0.6 mg / kg / week, about 0.65 mg / kg / week, about 0.7 mg / kg / week, about 0.75 mg / kg / week, about 0.8 mg / kg / week, about 0.85 mg / kg / week, about 0.9 mg / kg / week, about 0.95 mg / kg / week, about 1.0 mg / kg / week, about 1.1 mg / kg / week, about 1.2 mg / kg / week, about 1.3 mg / kg / week, about 1.4 mg / kg / week, about 1.5 mg / kg / week, about 1.6 mg / kg / week, about 1.7 mg / kg / week, about 1.8 mg / kg / week, about 1.9 mg / kg / week, about 2.0 mg / kg / week, about 2.1 mg / kg / week, about 2.2 mg / kg / week, about 2.3 mg / kg / week, about 2.4 mg / kg / week, about 2.5 mg / kg / week, about 2.6 mg / kg / week, about 2.7 mg / kg / week, about 2.8 mg / kg / week, about 2.9 mg / kg / week, or about 3 mg / kg / week.

[0085] The oral GLP-1 agonist composition may be administered once or more times weekly, for example, 1 to 6 times a week. The duration of the oral treatment will depend on the severity of the vitiligo symptoms and the state of the disease and can be easily adjusted by the treating physician. Typically, the treatment may be for several weeks, several months, or longer. 3.5 Kits Comprising the Pharmaceutical Compositions

[0086] The disclosure provides kits comprising a composition disclosed herein. The topical composition of the disclosure may be presented in a pack, dispenser device, patch, bottle jar, tube, or packet. When the topical composition is provided in a patch, it is on the side of the patch that directly contacts the skin. Dermatologically acceptable adhesives may be used to attach the patch to skin for the desired amount of time.

[0087] In various embodiments, the kit further comprises an additional therapeutic agent as described in Section 3.2.

[0088] In one embodiment, the kit further comprises instructions for use in accordance with any of the methods described herein. The instructions can comprise a description of the administration of the composition for treating or preventing vitiligo as described herein. The instructions can include information as to dosage and dosing schedule.

[0089] The instructions included in the kit can be in any appropriate form, such as written instructions on a label or a package insert, or an electronic storage medium (e.g., magnetic diskette or optical disk).

[0090] In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

[0091] 4. EXAMPLES

[0092] 4.1 Example 1 - Preparation of a Composition of the Disclosure

[0093] A topical ointment (or a lotion, gel, or the like) is prepared by mixing semaglutide (prepared as described in Example 4 of W02006 / 097537) with at least one dermatologically acceptable excipient, such as mineral oil, paraffin, propylene carbonate, white petrolatum or white wax, optionally with buffering agents, stabilizing agents, scent ingredients, emulsifiers, oils, alcohols, or other excipients.

[0094] 4.2 Example 2 - Preparation of a Composition of the Disclosure

[0095] A 0.5 % semaglutide topical ointment was prepared by mixing semaglutide powder (obtained from Facron, Inc.) with ethyl alcohol 200 proof 129 ml / 100 gm, Polysorbate 80 NF Liquid, and Hydrophilic anhydrous base (ointment).

[0096] 4.3 Example 3 - Treatment of Vitiligo with Oral Semaglutide Compositions

[0097] Case 1: A 42-year-old woman with a medical history of type 2 diabetes and long standing, stable untreated vitiligo began treatment with Ozempic® (semaglutide) at a dose of 0.25 mg once weekly. Within a month from the start of treatment, the patient was noted to develop peri-follicular repigmentation in her vitiligo patches. As with empiric and FDA approved treatments for vitiligo, peri-follicular repigmentation is the first sign of a therapeutic response.

[0098] Case 2: A 37-year-old man with a medical history of type 2 diabetes and long standing, stable untreated vitiligo began treatment with Ozempic® (semaglutide) at a dose of 0.25 mg once weekly. Within a month from the start of treatment, the patient was noted to develop peri-follicular repigmentation in her vitiligo patches.

[0099] 4.4 Example 4 - Treatment of Vitiligo with Topical Semaglutide Compositions

[0100] Case 3: An 82-year-old man with a medical history of untreated, stable for greater than 6 months vitiligo, began treatment with the semaglutide ointment of Example 2 by applying the semaglutide ointment 2 times per day to facial vitiligo macules. After 5 months of treatment, the patient was noted to have detectable improvement.

[0101] Case 4: A 53-year-old woman with a medical history of untreated, stable for greater than 6 months vitiligo, began treatment with the semaglutide ointment of Example 2 by applying the semaglutide ointment 2 times per day to facial vitiligo macules. After 6 months of treatment, the patient was noted to develop several new perfolicular macules in the vitiligo areas.

[0102] Case 5: A 73-year-old woman with a medical history of untreated, stable for greater than 6 months vitiligo began treatment with the semaglutide ointment of Example 2 by applying the semaglutide ointment 2 times per day to facial vitiligo macules. After two months of treatment, the patient was noted to develop several new perfolicular macules in the vitiligo areas.

[0103] 4.5 Example 5 - Treatment of Vitiligo with Topical Semaglutide Compositions

[0104] An open-label, nonrandomized study in which patients with a medical history of vitiligo are treated with a topical composition of the disclosure (2% semaglutide ointment) once daily on their vitiligo patches, excluding perioral and periocular areas, for 20 weeks. Study participants will have a minimum of 1% body surface area (BSA) affected by vitiligo.

[0105] The primary outcome will be determined as improvement in Vitiligo Area Scoring Index (VASI) at week 20. VAS1 scores (possible range, 0-100) are calculated by multiplying the affected BSA (estimated with the use of hand units) by the degree of depigmentation (0-100%) within each hand unit.

[0106] The secondary outcomes will be determined as improvement in the Vitiligo European Task Force (VETF) scoring, Physician Global Vitiligo Assessment, BSA, and Dermatology Life Quality Index. VETF is a validated tool that grades vitiligo on extent of disease, staging, and spread. Extent of disease is calculated by use of the “rule of nines” to estimate BSA, staging is assessed through degree of depigmentation on a 0 (no depigmentation) to 4 (complete depigmentation) scale, and spread is scored on a simple scale (+1 : progressive; 0: stable; —1 : regressive). Physician Global Vitiligo Assessment is determined through a 5-point scale ranging from 0 (clear) to 4 (severe disease). Total BSA is calculated using a handprint (palm plus the volar surface of fingertips) to estimate 1% BSA.

[0107] While particular materials, formulations, operational sequences, process parameters, and end products have been set forth to describe and exemplify this invention, they are not intended to be limiting. Rather, it should be noted by those ordinarily skilled in the art that the written disclosures are exemplary only and that various other alternatives, adaptations, and modifications may be made within the scope of the present disclosure.

Claims

WHAT IS CLAIMED IS:

1. A topical composition comprising a GLP-1 agonist or a pharmacally salt thereof and at least one dermatologically acceptable excipient.

2. A topical composition comprising semaglutide or a pharmaceutically salt thereof and at least one dermatologically acceptable excipient.

3. The topical composition of claim 1 or claim 2, wherein the composition is formulated as a transdermal patch, a gel, a cream, an ointment, a lotion or a foam.

4. The topical composition of any of claims 1 to 3. wherein the at least one dermatologically acceptable excipient is mineral oil, paraffin, propylene carbonate, white petrolatum, white wax, hydrophilic petrolatum, or any combination thereof.

5. The topical composition of any of claims 1 to 4, further comprising an additional therapeutic agent.

6. Tire topical composition of claim 5, wherein the additional therapeutic agent is a corticosteroid, an immunomodulator, a calcincurin inhibitor, a JAK inhibitor, a retinoid, a vitamin or analog thereof, a dietary supplement or any combination thereof.

7. The topical composition of claim 5, wherein the additional therapeutic agent is alclometasone, amcinonide, betamethasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, mometasone, prednicarbate, triamcinolone, tacrolimus, pimecrolimus. ruxolitinib, tofacitinib, calcipotriene, beta carotene, alpha carotene, tretinoin, vitamin A, vitamin C. vitamin E, vitamin B 12, vitamin D, folic acid, cartenoids (such as lycopene), or any combination thereof.

8. A method of treating or preventing vitiligo comprising administering an effective amount of a GLP-f agonist or a pharmacally acceptable salt thereof to a subject in need thereof.

9. A method of treating or preventing vitiligo comprising administering an effective amount of semaglutide or a pharmacally acceptable salt thereof to a subject in need thereof.

10. The method of claim 8 or 9, wherein the GLP-1 agonist or semaglutide or a pharmaceutically acceptable salt thereof is administered orally.

11. The method of any of claims 8 to 10, further comprising exposing the vitiligo-affected skin to phototherapy.

12. A method of treating or preventing vitiligo comprising administering an effective amount of a composition comprising a GLP-1 agonist or a pharmaceutically salt thereof to a subject in need thereof.

13. A method of treating or preventing vitiligo comprising administering an effective amount of a composition comprising semaglutide or a pharmaceutically salt thereof to a subject in need thereof.

14. The method of claim 12 or claim 13, wherein the composition is administered orally.

15. The method of claim 12 or claim 13, wherein the composition is administered topically.

16. The method of any of claims 12 to 15, further comprising exposing the vitiligo-affected skin to phototherapy.

17. A kit comprising the topical formulation of any of claims 1 to 7.

18. Use of a GLP- 1 agonist for the manufacture of a medicament useful for treating vitiligo.

19. Use of semaglutide for the manufacture of a medicament useful for treating vitiligo.

20. Use of a topical composition of any of claims 1 -7 for the manufacture of a medicament useful for treating vitiligo.

21. A GLP- 1 agonist for use in the treatment of vitiligo .

22. Semaglutide for use in the treatment of vitiligo.

23. A topical composition any one of claims 1 to 7 for use in the treatment of vitiligo.