Compounds for use in the treatment of obesity and metabolic disorders

Abstract

Provided herein are methods of treating obesity and metabolic disorders using Compound 1 or pharmaceutically acceptable salts thereof.

Description

COMPOUNDS FOR USE IN THE TREATMENT OF OBESITY AND METABOLICDISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 674,746 filed July 23, 2024, which is incorporated herein by reference in its entirety.REFERENCE TO THE SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SeqListing_VIKNG.034WO.xml created July 3, 2025, which is 3,699 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.BACKGROUNDField

[0003] The present disclosure relates generally to the fields of chemistry and medicine. More specifically, the present disclosure relates to compounds and methods of using said compounds for the treatment of obesity and metabolic disorders.Description of the Related Art

[0004] Excess body weight represents one of the most prevalent and fastest growing chronic health conditions in the United States and worldwide. Excess body weight and obesity are not simply cosmetic issues; rather, they are associated with increased mortality (Kuk et al. Clin Obes, 8(5), 305-312 and increased risks of medical conditions that include type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, strokes, sleep apnea, some cancers, and arthritis, as well as psychosocial difficulties (Apovian, Am J Manag Care, 22(& Suppl), S176-185.); (Kinlen et al. QJM, 111(1), 437-443; Khaodiar et al. Clin Cornerstones, 2(3), 17-31.).

[0005] Fortunately, interventional and epidemiological studies have clearly shown that reduction of excess body weight can reduce morbidity and mortality, and that this reduction is correlated with the magnitude of weight loss. Weight loss of as little as 5-10% is associated with reductions in outcomes like new onset type 2 diabetes or come cancers, andimprovements in sleep apnea, hypertension, dyslipidemia, hyperglycemia, osteoarthritis of the knee and polycystic ovary disease. Franz et al. J Acad Nutri Diet, 115(9), 1447-1463; Clifton, P. Pathology, 57(2), 222-226; Van Gaal et al. J Obes Relat Metab Disord, 27(Suppl 1), S5-9; Goldstein, Int J Obese Relat Metab Disord, 16(6), 397-415; Tahrani et al., Obesity, 30(4), 802- 840. The magnitude of benefits appears correlated with the magnitude of weight loss.

[0006] Incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide- 1 (GLP-1) are metabolic hormones. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet 0-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of 0-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1 -receptor activation is associated with weight loss in both preclinical and clinical studies. Accordingly, a need exists for methods of treating obesity, metabolic disorders, and other diseases and disorders using GIP / GLP1 dual agonist compounds.SUMMARY

[0007] In one aspect of the present disclosure, Provided herein is a method for treating obesity or a metabolic disease or disorder, said method comprising:(i) administering a first dose of Compound 1or a pharmaceutically acceptable salt thereof to a subject in need thereof, at a first dosing frequency, for a first period of time during a first phase of administration;(ii) administering a second dose of Compound 1, or a pharmaceutically acceptable salt thereof for a second period of time, at a second dosing frequency, during a second phase of administration;(iii) optionally administering a third dose of Compound 1, or a pharmaceutically acceptable salt thereof, at a third dosing frequency, for a third period of time during a third phase of administration; and(iv) optionally administering a fourth dose of Compound 1, or a pharmaceutically acceptable salt thereof, at a fourth dosing frequency, for a fourth period of time during a fourth phase of administration.

[0008] In some embodiments, the first dose is from about 0.5 mg to about 30 mg. In some embodiments, the first dose is from about 1 mg to about 20 mg. In some embodiments, the first dose is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 17.5 mg, or about 20 mg.

[0009] In some embodiments, the first dosing frequency is once every about 1 day to about two months. In some embodiments, the first dosing frequency is once every about one week to about six weeks. In some embodiments, the first dosing frequency is about once every week, about once every two weeks, about once every three weeks, about once every four weeks, or about once a month.

[0010] In some embodiments, the first period of time is from about 1 day to about 8 weeks. In some embodiments, the first period of time is from about 1 week to about 6 weeks. In some embodiments, the first period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about one month. In some embodiments, the first phase is repeated 1, 2, 3, or 4 times.

[0011] In some embodiments, the second dose is from about 0.5 mg to about 30 mg. In some embodiments, the second dose is from about 1 mg to about 20 mg. In some embodiments, the second dose is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 17.5 mg, or about 20 mg.

[0012] In some embodiments, the second dosing frequency is once every about 1 day to about two months. In some embodiments, the second dosing frequency is once every about one week to about six weeks. In some embodiments, the second dosing frequency is about once every week, about once every two weeks, about once every three weeks, about once every four weeks, or about once a month.

[0013] In some embodiments, the second period of time is from about 1 day to about 8 weeks. In some embodiments, the second period of time is from about 1 week to about 6 weeks. In some embodiments, the second period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about one month. In some embodiments, the second phase is repeated 1, 2, 3, or 4 times.

[0014] In some embodiments, the method comprises the third phase of administration.

[0015] In some embodiments, the third dose is from about 0.5 mg to about 30 mg. In some embodiments, the third dose is from about 1 mg to about 20 mg. In some embodiments, the third dose is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 17.5 mg, or about 20 mg.

[0016] In some embodiments, the third dosing frequency is once every about 1 day to about two months. In some embodiments, the third dosing frequency is once every about one week to about six weeks. In some embodiments, the third dosing frequency is about once every week, about once every two weeks, about once every three weeks, about once every four weeks, or about once a month.

[0017] In some embodiments, the third period of time is from about 1 day to about 8 weeks. In some embodiments, the third period of time is from about 1 week to about 6 weeks. In some embodiments, the third period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about one month. In some embodiments, the third phase is repeated 1, 2, 3, or 4 times.

[0018] In some embodiments, the method comprises the fourth phase of administration.

[0019] In some embodiments, the fourth dose is from about 0.5 mg to about 30 mg. In some embodiments, the fourth dose is from about 1 mg to about 20 mg. In some embodiments, the fourth dose is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 17.5 mg, or about 20 mg.

[0020] In some embodiments, the fourth dosing frequency is once every about 1 day to about two months. In some embodiments, the fourth dosing frequency is once every about one week to about six weeks. In some embodiments, the fourth dosing frequency is about once every week, about once every two weeks, about once every three weeks, about once every four weeks, or about once a month.

[0021] In some embodiments, the fourth period of time is from about 1 day to about 8 weeks. In some embodiments, the fourth period of time is from about 1 week to about 6 weeks. In some embodiments, the fourth period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about one month. In some embodiments, the fourth phase is repeated 1, 2, 3, or 4 times.

[0022] In another aspect of the present disclosure, provided herein is a method for treating obesity or a metabolic disease or disorder, said method comprising, administering a final dose of Compound 1or a pharmaceutically acceptable salt thereof to a subject in need thereof, once every four weeks or once a month.

[0023] In some embodiments, the method further comprises, prior to administering the final dose, administering one or more lower dose to the subject, wherein the lower dose is lower than the final dose.

[0024] In some embodiments, the final dose is from about 0.5 mg to about 30 mg. In some embodiments, the final dose is from about 1 mg to about 20 mg. In some embodiments, the final dose is about 10 mg, about 15 mg, about 17.5 mg, or about 20 mg.

[0025] In some embodiments, the one or more lower dose is from about 0.5 mg to about 20 mg. In some embodiments, the one or more lower dose is from about 2.5 mg to about 15 mg. In some embodiments, the one or more lower dose is about 2.5 mg, about 5 mg, about 7.5 mg, or about 10 mg.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 is a graph depicting the mean plasma concentration of Compound 1 versus time profile by treatment group over a period of 49 days. The lower limit of quantification (LLOQ) is 5 ng / mL.

[0027] FIG. 2 is a graph depicting weight percent change from baseline by treatment group versus time profile by treatment group over the 13 -week study.DETAILED DESCRIPTION

[0028] In some embodiments, provided herein is a method of treating obesity or metabolic disorders, said method comprising administering Compound 1 :or a pharmaceutically acceptable salt thereof to a subject in need thereof. The indicator indicates a chiral carbon, which may be in the “S” configuration, the “R” configuration, or a racemic mixture. The preparation of Compound 1 has been described in International Patent Publication No. WO 2022 / 159395, which is incorporated by reference herein in its entirety.

[0029] Some embodiments provided herein include administering Compound 1 wherein indicates a chiral carbon with “S” configuration.

[0030] Some embodiments provided herein include administering Compound 1 wherein indicates a chiral carbon with “R” configuration.

[0031] In some embodiments, the methods described herein may be used to treat patients with obesity (i.e., patients having a body mass index (BMI) > 30 kg / m2). In some embodiments, the methods described herein may be used to treat patients that are overweight (i.e., patients having a BMI > 27 kg / m2) in the presence of other comorbid conditions. In some embodiments, the methods described herein may be used to treat patients having a BMI of greater than about 25, 26, 27, 28, 29, or 30 kg / m2.

[0032] Metabolic disorders are conditions that affect any aspect of metabolism. In some embodiments, the methods described herein may be used to treat metabolic disorders, wherein the metabolic disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, or Prader-Willi syndrome.

[0033] Administration of Compound 1 or a pharmaceutically acceptable salt thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.

[0034] In some embodiments provided herein, the method comprises a dosing schedule that requires (i) administering a first dose of Compound 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof, at a first dosing frequency, for a first period of time during a first phase of administration; (ii) administering a second dose of Compound 1, or a pharmaceutically acceptable salt thereof for a second period of time, at a second dosing frequency, during a second phase of administration; optionally administering a third dose of Compound 1 , or a pharmaceutically acceptable salt thereof, at a third dosing frequency, for a third period of time during a third phase of administration; and optionally administering a fourth dose of Compound 1, or a pharmaceutically acceptable salt thereof, at a fourth dosing frequency, for a fourth period of time during a fourth phase of administration. In some such embodiments, the method comprises a third phase. In other such embodiments, the method comprises a third and fourth phase.

[0035] In some embodiments provided herein, the method comprising, administering a final dose of Compound 1 :or a pharmaceutically acceptable salt thereof to a subject in need thereof, once every four weeks or once a month.Definitions

[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0037] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, / ?-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).

[0038] The term “mammal” is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other species.

[0039] “Subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0040] Treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition.Dosing and Administration

[0041] According to the methods disclosed herein, Compound 1 or a pharmaceutically acceptable salt thereof may be administered to a subject in need thereof in several phases of dosing. In some embodiments, the dosage amount may escalate after each phase of dosing. In some embodiments, a final dose of Compound 1 or a pharmaceutically acceptable salt thereof may be administered to a subject in need thereof. In some such embodiments, prior to administering the final dose of Compound 1 or a pharmaceutically acceptable salt thereof, one or more lower doses Compound 1 or a pharmaceutically acceptablesalt thereof may be administered to the subject, wherein the lower dose is lower than the final dose. In some embodiments, where there is more than one lower dose administered to the subject, each of the lower doses may be the same. In other embodiments, each or subsets of the lower doses may be different.

[0042] In some embodiments described herein, a first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof, at a first dosing frequency, for a first period of time during a first phase of administration.

[0043] In some embodiments, the first dose of Compound 1, or a pharmaceutically acceptable salt thereof may be about 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16.0 mg, 16.5 mg, 17.0 mg, 17.5 mg, 18.0 mg, 18.5 mg, 19.0 mg, 19.5 mg, 20.0 mg 20.5 mg, 21.0 mg, 21.5 mg, 22.0mg, 22.5 mg, 23.0 mg, 23.5 mg, 24.0 mg, 24.5 mg, 25.0 mg, 25.5 mg, 26.0 mg, 26.5 mg, 27.0 mg, 27.5 mg, 28.0 mg, 28.5 mg, 29.0 mg, 29.5 mg, 30.0 mg or more, or within a range defined by any two of the aforementioned values. In some embodiments, the first dose of Compound 1 or a pharmaceutically acceptable salt thereof may be from about 0.5 to about 30 mg, about 1 mg to about 20, about 0.5 mg to about 10 mg, or about 1 mg to about 5 mg.

[0044] In some embodiments, the first dosing frequency of the first dose of Compound 1 , or a pharmaceutically acceptable salt thereof may be about once daily, about once every two days, about once every three days, about once every four days, about once every five days, about once every six days, about once weekly, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, once every seven weeks, about every eight weeks, about once a month, or about once every two months, or within a range defined by any two of the aforementioned times. For example, dosing frequency of the first dose of Compound 1, or a pharmaceutically acceptable salt thereof may be once every about 1 day to about two months, once every about one week to about six weeks, or once every about 1 week to about one month.

[0045] In some embodiments, the first period of time for the first phase may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about sixweeks, about seven weeks, about eight weeks, or more, or within a range defined by any two of the aforementioned times. In some embodiments, the first period of time may be from about 1 day to about eight weeks, about one week to about six weeks, or about two weeks to about four weeks. In some embodiments, the first phase may repeated 1, 2, 3, or 4 times, or more.

[0046] In some embodiments described herein, a second dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof, at a second dosing frequency, for a second period of time during a second phase of administration.

[0047] In some embodiments, the second dose of Compound 1, or a pharmaceutically acceptable salt thereof may be about 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16.0 mg, 16.5 mg, 17.0 mg, 17.5 mg, 18.0 mg, 18.5 mg,19.0 mg, 19.5 mg, 20.0 mg 20.5 mg, 21.0 mg, 21.5 mg, 22.0mg, 22.5 mg, 23.0 mg, 23.5 mg,24.0 mg, 24.5 mg, 25.0 mg, 25.5 mg, 26.0 mg, 26.5 mg, 27.0 mg, 27.5 mg, 28.0 mg, 28.5 mg,29.0 mg, 29.5 mg, 30.0 mg or more, or within a range defined by any two of the aforementioned values. In some embodiments, the second dose of Compound 1 or a pharmaceutically acceptable salt thereof may be from about 0.5 to about 30 mg, about 1 mg to about 20, about 0.5 mg to about 10 mg, or about 1 mg to about 5 mg.

[0048] In some embodiments, the second dosing frequency of the second dose of Compound 1 , or a pharmaceutically acceptable salt thereof may be about once daily, about once every two days, about once every three days, about once every four days, about once every five days, about once every six days, about once weekly, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, once every seven weeks, about every eight weeks, about once a month, or about once every two months, or within a range defined by any two of the aforementioned times. For example, dosing frequency of the second dose of Compound 1, or a pharmaceutically acceptable salt thereof may be once every about 1 day to about two months, once every about one week to about six weeks, or once every about 1 week to about one month.

[0049] In some embodiments, the second period of time for the second phase may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about sixweeks, about seven weeks, about eight weeks, or more, or within a range defined by any two of the aforementioned times. In some embodiments, the second period of time may be from about 1 day to about eight weeks, about one week to about six weeks, or about two weeks to about four weeks. In some embodiments, the second phase may repeated 1, 2, 3, or 4 times, or more.

[0050] In some embodiments described herein, a third dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof, at a third dosing frequency, for a third period of time during a third phase of administration.

[0051] In some embodiments, the third dose of Compound 1, or a pharmaceutically acceptable salt thereof may be about 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16.0 mg, 16.5 mg, 17.0 mg, 17.5 mg, 18.0 mg, 18.5 mg, 19.0 mg, 19.5 mg, 20.0 mg 20.5 mg, 21.0 mg, 21.5 mg, 22.0mg, 22.5 mg, 23.0 mg, 23.5 mg, 24.0 mg, 24.5 mg, 25.0 mg, 25.5 mg, 26.0 mg, 26.5 mg, 27.0 mg, 27.5 mg, 28.0 mg, 28.5 mg, 29.0 mg, 29.5 mg, 30.0 mg or more, or within a range defined by any two of the aforementioned values. In some embodiments, the third dose of Compound 1 or a pharmaceutically acceptable salt thereof may be from about 0.5 to about 30 mg, about 1 mg to about 20, about 0.5 mg to about 10 mg, or about 1 mg to about 5 mg.

[0052] In some embodiments, the third dosing frequency of the third dose of Compound 1 , or a pharmaceutically acceptable salt thereof may be about once daily, about once every two days, about once every three days, about once every four days, about once every five days, about once every six days, about once weekly, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, once every seven weeks, about every eight weeks, about once a month, or about once every two months, or within a range defined by any two of the aforementioned times. For example, dosing frequency of the third dose of Compound 1, or a pharmaceutically acceptable salt thereof may be once every about 1 day to about two months, once every about one week to about six weeks, or once every about 1 week to about one month.

[0053] In some embodiments, the third period of time for the third phase may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about oneweek, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, or more, or within a range defined by any two of the aforementioned times. In some embodiments, the third period of time may be from about 1 day to about eight weeks, about one week to about six weeks, or about two weeks to about four weeks. In some embodiments, the third phase may repeated 1, 2, 3, or 4 times, or more.

[0054] In some embodiments described herein, a fourth dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof, at a fourth dosing frequency, for a fourth period of time during a fourth phase of administration.

[0055] In some embodiments, the fourth dose of Compound 1, or a pharmaceutically acceptable salt thereof may be about 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16.0 mg, 16.5 mg, 17.0 mg, 17.5 mg, 18.0 mg, 18.5 mg,19.0 mg, 19.5 mg, 20.0 mg 20.5 mg, 21.0 mg, 21.5 mg, 22.0mg, 22.5 mg, 23.0 mg, 23.5 mg,24.0 mg, 24.5 mg, 25.0 mg, 25.5 mg, 26.0 mg, 26.5 mg, 27.0 mg, 27.5 mg, 28.0 mg, 28.5 mg,29.0 mg, 29.5 mg, 30.0 mg or more, or within a range defined by any two of the aforementioned values. In some embodiments, the fourth dose of Compound 1 or a pharmaceutically acceptable salt thereof may be from about 0.5 to about 30 mg, about 1 mg to about 20, about 0.5 mg to about 10 mg, or about 1 mg to about 5 mg.

[0056] In some embodiments, the fourth dosing frequency of the fourth dose of Compound 1 , or a pharmaceutically acceptable salt thereof may be about once daily, about once every two days, about once every three days, about once every four days, about once every five days, about once every six days, about once weekly, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, once every seven weeks, about every eight weeks, about once a month, or about once every two months, or within a range defined by any two of the aforementioned times. For example, dosing frequency of the fourth dose of Compound 1, or a pharmaceutically acceptable salt thereof may be once every about 1 day to about two months, once every about one week to about six weeks, or once every about 1 week to about one month.

[0057] In some embodiments, the fourth period of time for the fourth phase may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, or more, or within a range defined by any two of the aforementioned times. In some embodiments, the fourth period of time may be from about 1 day to about eight weeks, about one week to about six weeks, or about two weeks to about four weeks. In some embodiments, the fourth phase may repeated 1, 2, 3, or 4 times, or more.

[0058] In some embodiments, a final dose of Compound 1 or a pharmaceutically acceptable salt thereof may be administered to a subject in need thereof. In some such embodiments, prior to administering the final dose of Compound 1 or a pharmaceutically acceptable salt thereof, one or more lower doses Compound 1 or a pharmaceutically acceptable salt thereof may be administered to the subject, wherein the lower dose is lower than the final dose. In some embodiments, where there is more than one lower dose administered to the subject, each of the lower doses may be the same. In other embodiments, each or subsets of the lower doses may be different.

[0059] In some embodiments, the final dose of Compound 1 or a pharmaceutically acceptable salt thereof about 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0mg, 12.5 mg, 13.0 mg,13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16.0 mg, 16.5 mg, 17.0 mg, 17.5 mg, 18.0 mg,18.5 mg, 19.0 mg, 19.5 mg, 20.0 mg 20.5 mg, 21.0 mg, 21.5 mg, 22.0mg, 22.5 mg, 23.0 mg,23.5 mg, 24.0 mg, 24.5 mg, 25.0 mg, 25.5 mg, 26.0 mg, 26.5 mg, 27.0 mg, 27.5 mg, 28.0 mg,28.5 mg, 29.0 mg, 29.5 mg, 30.0 mg or more, or within a range defined by any two of the aforementioned values. In some embodiments, the final dose of Compound 1 or a pharmaceutically acceptable salt thereof may be from about 10 to about 30 mg, about 10 mg to about 20, about 15 mg to about 25 mg, or about 15 mg to about 20 mg.

[0060] In some embodiments, the final dose frequency of Compound 1, or a pharmaceutically acceptable salt thereof, may be about once daily, about once every two days, about once every three days, about once every four days, about once every five days, about once every six days, about once weekly, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, once every seven weeks, about every eight weeks, about once a month, or about once everytwo months, or within a range defined by any two of the aforementioned times. For example, dosing frequency of the final dose of Compound 1, or a pharmaceutically acceptable salt thereof, may be once every about 1 day to about two months, once every about one week to about six weeks, or once every about 1 week to about one month. In some embodiments, the final dose frequency of Compound 1, or a pharmaceutically acceptable salt thereof, is once every about 4 weeks or about once a month.

[0061] In some embodiments, the one or more lower dose of Compound 1 or a pharmaceutically acceptable salt thereof may include one, two, three, four, or more lower doses. In some embodiments, each or subsets of the lower doses may be different. In some embodiments, each of the lower doses may the same. In some embodiments, the one or more lower dose may be about 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, or 15.0 mg, or within a range defined by any two of the aforementioned values. In some embodiments, the one or more lower dose of Compound 1 or a pharmaceutically acceptable salt thereof may be from about 0.5 to about 10 mg, about 1 mg to about 10, about 2.5 mg to about 10 mg, or about 3 mg to about 15 mg.

[0062] In some embodiments, the lower dose frequency of Compound 1, or a pharmaceutically acceptable salt thereof, may be about once daily, about once every two days, about once every three days, about once every four days, about once every five days, about once every six days, about once weekly, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, once every seven weeks, about every eight weeks, about once a month, or about once every two months, or within a range defined by any two of the aforementioned times. For example, dosing frequency of the lower doses of Compound 1, or a pharmaceutically acceptable salt thereof, may be once every about 1 day to about two months, once every about one week to about six weeks, or once every about 1 week to about one month.

[0063] To further illustrate aspects of this disclosure, the following examples are included. The examples should not, of course, be construed as specifically limiting the disclosure. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the disclosure asdescribed, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the disclosure without exhaustive examples. The following examples will further describe the present disclosure, and are used for the purposes of illustration only, and should not be considered as limiting.EXAMPLESExample 1 - Clinical Study of Compound 1 for Weight Management

[0064] A phase 2, 13-week, randomized, double-blind, placebo-controlled, parallel arm dose finding study was performed that evaluated the safety, tolerability, weight loss efficacy, pharmacodynamic effects, and pharmacokinetics of Compound 1 in adults who are obese (BMI >30 kg / m2) or who are overweight (BMI >27 kg / m2) with at least one weight- related co-morbid condition. The total duration of study participation for each subject was approximately 19-23 weeks, to include a screening period of up to 4 weeks, 13 weeks study intervention administration, and an approximately 6-week safety follow-up period.

[0065] Subjects were randomly assigned in approximately a 1: 1: 1: 1:1 ratio to receive one of four Compound 1 doses or matched placebo. Compound 1 and placebo were administered once weekly by subcutaneous (SC) injection. The dose level for Group 1 (Trt 1) remained at 2.5 mg throughout the dosing period. For Group 2 (Trt 2), the dose was escalated to 5 mg starting at Week 3. The dose was escalated every 3 weeks for Treatment Groups 3 (Trt 3) and 4 (Trt 4) until the final target dose was reached in each Treatment Group. Subjects received the final dose level for 4 weeks (administered at Weeks 9, 10, 11 and 12). Subjects received doses on the first day of each study week, starting from Week 0. The dosing summary is provided in Table 1.Table 1 - Clinical Study Dosing Summary

[0066] Plasma samples were collected to evaluate the steady state pharmacokinetics of Compound 1. Samples were collected immediately prior to beginning the study (day 1 of Week 0) and were collected at day 22 + / - 1 day, 43+ / - 1 day, 64+ / - 1 day and 92 + / - 1 day (i.e., at the start of Weeks 3, 6, 9, and 13). The summary of plasma pharmacokinetics for each of the treatment groups after 13 consecutive weekly doses is provided in Table 2. The plasma concentration of Compound 1 is dose dependent, with higher doses of Compound 1 corresponding to increased mean plasma levels of Compound 1 at all timepoints. These results are consistent with patterns observed for AUCo- tau and AUCo-inf , further demonstrating a dose-dependent relationship for Compound 1 plasma pharmacokinetic parameters. Median half-life averaged between 148 to 171 hours across treatment groups.Table 2 - Plasma Pharmacokinetic Summary for Compound 1

[0067] Additionally, a subset of subjects continued to be evaluated for 7 weeks (i.e., 1176 hours) after the final administration of Compound 1 in the 13 -week study. The post-study data is provided in Table 3 and FIG. 1. The post-study evaluation showed highplasma concentration of Treatment Groups 3 and 4 even four weeks (672 hours) after the final administration of Compound 1, with Treatment Groups 2-4 all displaying detectible levels of Compound 1 after 7 weeks post dosing. The data suggests that Compound 1 can be administered at longer intervals (e.g., monthly) once the final dose is reached and maintain a therapeutic effect. For example, the blood level of Compound 1 in Treatment Group 4 (15 mg dose) four weeks after final dose was 205 ng / mL, which is comparable with the pre-final dose level of 316 ng / mL in Treatment Group 1 (2.5 mg). Thus, once every 4 weeks, or once monthly, dosing at a level of 15 mg to 20 mg (e.g., 17 mg, 17.5 mg, or 18 mg) can be expected to provide a therapeutic effect.Table 3 - Post-Study Pharmacokinetic Evaluation for Compound 1Example 2 - Efficacy of Compound 1 for Weight Management

[0068] For the phase 2 study described in Example 1, the efficacy of the compound was determined for reducing body weight for subjects in each treatment groups. Each of the treatment groups demonstrated statistically significant differences in percent change of baseline body weight, with treatment group 4 exhibiting the largest percent weight reduction. Additionally, efficacy of Compound 1 was demonstrated by the percent of participants achieving weight loss thresholds of 5% body weight, 10% body weight, and 15 % body weight at week 13. These results are presented in Table 4 and FIG. 2.Table 4 - Efficacy Evaluation for Compound 1

[0069] Notably, Treatment Group 1 (2.5 mg) achieved approximately 10% weight loss at drug levels comparable to the levels obtained up to four weeks post dosing at higher doses (e.g., Treatment Groups 3 and 4), further supporting that once every 4 weeks, or once monthly, dosing at a dose of 15 mg to 20 mg can achieve statistically significant weight loss.

[0070] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0071] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosedherein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0072] All publications, patent applications, issued patents, and other documents (for example, journals, articles and / or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Claims

WHAT IS CLAIMED IS:

1. A method for treating obesity or a metabolic disease or disorder, said method comprising(i) administering a first dose of Compound 1or a pharmaceutically acceptable salt thereof to a subject in need thereof, at a first dosing frequency, for a first period of time during a first phase of administration;(ii) administering a second dose of Compound 1, or a pharmaceutically acceptable salt thereof for a second period of time, at a second dosing frequency, during a second phase of administration;(iii) optionally administering a third dose of Compound 1, or a pharmaceutically acceptable salt thereof, at a third dosing frequency, for a third period of time during a third phase of administration; and(iv) optionally administering a fourth dose of Compound 1, or a pharmaceutically acceptable salt thereof, at a fourth dosing frequency, for a fourth period of time during a fourth phase of administration.

2. The method of Claim 1 , wherein the first dose is from about 0.5 mg to about 30 mg.

3. The method of Claim 1 or 2, wherein the first dose is from about 1 mg to about 20 mg.

4. The method of any one of Claims 1 to 3, wherein the first dose is about 2.5 mg.

5. The method of any one of Claims 1 to 3, wherein the first dose is about 5 mg.

6. The method of any one of Claims 1 to 3, wherein the first dose is about 7.5 mg.

7. The method of any one of Claims 1 to 3, wherein the first dose is about 10 mg.

8. The method of any one of Claims 1 to 3, wherein the first dose is about 15 mg.

9. The method of any one of Claims 1 to 3, wherein the first dose is about 17.5 mg.

10. The method of any one of Claims 1 to 3, wherein the first dose is about 20 mg.

11. The method of any one of Claims 1 to 10, wherein the first dosing frequency is once every about 1 day to about two months.

12. The method of any one of Claims 1 to 10, wherein the first dosing frequency is once every about one week to about six weeks.

13. The method of any one of Claims 1 to 10, wherein the first dosing frequency is about once every week.

14. The method of any one of Claims 1 to 10, wherein the first dosing frequency is about once every two weeks.

15. The method of any one of Claims 1 to 10, wherein the first dosing frequency is about once every three weeks.

16. The method of any one of Claims 1 to 10, wherein the first dosing frequency is about once every four weeks.

17. The method of any one of Claims 1 to 10, wherein the first dosing frequency is about once a month.

18. The method of any one of Claims 1 to 17, wherein the first period of time is from about 1 day to about 8 weeks.

19. The method of any one of Claims 1 to 17, wherein the first period of time is from about 1 week to about 6 weeks.

20. The method of any one of Claims 1 to 17, wherein the first period of time is about1 week.

21. The method of any one of Claims 1 to 17, wherein the first period of time is about2 weeks.

22. The method of any one of Claims 1 to 17, wherein the first period of time is about3 weeks.

23. The method of any one of Claims 1 to 17, wherein the first period of time is about4 weeks.

24. The method of any one of Claims 1 to 17, wherein the first period of time is about 5 weeks.

25. The method of any one of Claims 1 to 17, wherein the first period of time is about one month.

26. The method of any one of Claims 1 to 18, wherein the first phase is repeated 1 , 2, 3, or 4 times.

27. The method of any one of Claims 1 to 26, wherein the second dose is from about 0.5 mg to about 30 mg.

28. The method of any one of Claims 1 to 26, wherein the second dose is from about 1 mg to about 20 mg.

29. The method of any one of Claims 1 to 26, wherein the second dose is about 2.5 mg.

30. The method of any one of Claims 1 to 26, wherein the second dose is about 5 mg.

31. The method of any one of Claims 1 to 26, wherein the second dose is about 7.5 mg.

32. The method of any one of Claims 1 to 26, wherein the second dose is about 10 mg.

33. The method of any one of Claims 1 to 26, wherein the second dose is about 15 mg.

34. The method of any one of Claims 1 to 26, wherein the second dose is about 17.5 mg.

35. The method of any one of Claims 1 to 26, wherein the second dose is about 20 mg.

36. The method of any one of Claims 1 to 35, wherein the second dosing frequency is once every about 1 day to about two months.

37. The method of any one of Claims 1 to 35, wherein the second dosing frequency is once every about one week to about six weeks.

38. The method of any one of Claims 1 to 35, wherein the second dosing frequency is about once every week.

39. The method of any one of Claims 1 to 35, wherein the second dosing frequency is about once every two weeks.

40. The method of any one of Claims 1 to 35, wherein the second dosing frequency is about once every three weeks.

41. The method of any one of Claims 1 to 35, wherein the second dosing frequency is about once every four weeks.

42. The method of any one of Claims 1 to 35, wherein the second dosing frequency is about once a month.

43. The method of any one of Claims 1 to 42, wherein the second period of time is from about 1 day to about 8 weeks.

44. The method of any one of Claims 1 to 42, wherein the second period of time is from about 1 week to about 6 weeks.

45. The method of any one of Claims 1 to 42, wherein the second period of time is about 1 week.

46. The method of any one of Claims 1 to 42, wherein the second period of time is about 2 weeks.

47. The method of any one of Claims 1 to 42, wherein the second period of time is about 3 weeks.

48. The method of any one of Claims 1 to 42, wherein the second period of time is about 4 weeks.

49. The method of any one of Claims 1 to 42, wherein the second period of time is about 5 weeks.

50. The method of any one of Claims 1 to 42, wherein the second period of time is about one month.

51. The method of any one of Claims 1 to 50, wherein the second phase is repeated 1, 2, 3, or 4 times.

52. The method of any one of Claims 1 to 51, comprising the third phase of administration.

53. The method of any one of Claims 1 to 52, wherein the third dose is from about 0.5 mg to about 30 mg.

54. The method of any one of Claims 1 to 52, wherein the third dose is from about 1 mg to about 20 mg.

55. The method of any one of Claims 1 to 54, wherein the third dose is about 2.5 mg.

56. The method of any one of Claims 1 to 54, wherein the third dose is about 5 mg.

57. The method of any one of Claims 1 to 54, wherein the third dose is about 7.5 mg.

58. The method of any one of Claims 1 to 54, wherein the third dose is about 10 mg.

59. The method of any one of Claims 1 to 54, wherein the third dose is about 15 mg.

60. The method of any one of Claims 1 to 54, wherein the third dose is about 17.5 mg.

61. The method of any one of Claims 1 to 54, wherein the third dose is about 20 mg.

62. The method of any one of Claims 1 to 61, wherein the third dosing frequency is once every about 1 day to about two months.

63. The method of any one of Claims 1 to 61, wherein the third dosing frequency is once every about one week to about six weeks.

64. The method of any one of Claims 1 to 61, wherein the third dosing frequency is about once every week65. The method of any one of Claims 1 to 61, wherein the third dosing frequency is about once every two weeks.

66. The method of any one of Claims 1 to 61, wherein the third dosing frequency is about once every three weeks.

67. The method of any one of Claims 1 to 61, wherein the third dosing frequency is about once every four weeks.

68. The method of any one of Claims 1 to 61, wherein the third dosing frequency is about once a month.

69. The method of any one of Claims 1 to 68, wherein the third period of time is from about 1 day to about 8 weeks.

70. The method of any one of Claims 1 to 68, wherein the third period of time is from about 1 week to about 6 weeks.

71. The method of any one of Claims 1 to 68, wherein the third period of time is about1 week.

72. The method of any one of Claims 1 to 68, wherein the third period of time is about2 weeks.

73. The method of any one of Claims 1 to 68, wherein the third period of time is about3 weeks.

74. The method of any one of Claims 1 to 68, wherein the third period of time is about4 weeks.

75. The method of any one of Claims 1 to 68, wherein the third period of time is about5 weeks.

76. The method of any one of Claims 1 to 68, wherein the third period of time is about one month.

77. The method of any one of Claims 1 to 76, wherein the third phase is repeated 1, 2, 3, or 4 times.

78. The method of any one of Claims 1 to 77, comprising the fourth phase of administration.

79. The method of any one of Claims 1 to 78, wherein the fourth dose is from about 0.5 mg to about 30 mg.

80. The method of any one of Claims 1 to 78, wherein the fourth dose is from about 1 mg to about 20 mg.

81. The method of any one of Claims 1 to 78, wherein the fourth dose is about 2.5 mg.

82. The method of any one of Claims 1 to 78, wherein the fourth dose is about 5 mg.

83. The method of any one of Claims 1 to 78, wherein the fourth dose is about 7.5 mg.

84. The method of any one of Claims 1 to 78, wherein the fourth dose is about 10 mg.

85. The method of any one of Claims 1 to 78, wherein the fourth dose is about 15 mg.

86. The method of any one of Claims 1 to 78, wherein the fourth dose is about 17.5 mg.

87. The method of any one of Claims 1 to 78, wherein the fourth dose is about 20 mg.

88. The method of any one of Claims 1 to 78, wherein the fourth dosing frequency is once every about 1 day to about two months.

89. The method of any one of Claims 1 to 78, wherein the fourth dosing frequency is once every about one week to about six weeks.

90. The method of any one of Claims 1 to 78, wherein the fourth dosing frequency is about once every week.

91. The method of any one of Claims 1 to 78, wherein the fourth dosing frequency is about once every two weeks.

92. The method of any one of Claims 1 to 78, wherein the fourth dosing frequency is about once every three weeks.

93. The method of any one of Claims 1 to 78, wherein the fourth dosing frequency is about once every four weeks.

94. The method of any one of Claims 1 to 78, wherein the fourth dosing frequency is about once a month.

95. The method of any one of Claims 1 to 94, wherein the fourth period of time is from about 1 day to about 8 weeks.

96. The method of any one of Claims 1 to 94, wherein the fourth period of time is from about 1 week to about 6 weeks.

97. The method of any one of Claims 1 to 94, wherein the fourth period of time is about1 week.

98. The method of any one of Claims 1 to 94, wherein the fourth period of time is about2 weeks.

99. The method of any one of Claims 1 to 94, wherein the fourth period of time is about3 weeks.

100. The method of any one of Claims 1 to 94, wherein the fourth period of time is about 4 weeks.

101. The method of any one of Claims 1 to 94, wherein the fourth period of time is about 5 weeks.

102. The method of any one of Claims 1 to 94, wherein the fourth period of time is about one month.

103. The method of any one of Claims 1 to 103, wherein the fourth phase is repeated 1, 2, 3, or 4 times.

104. A method for treating obesity or a metabolic disease or disorder, said method comprising, administering a final dose of Compound 1or a pharmaceutically acceptable salt thereof to a subject in need thereof, once every four weeks or once a month.

105. The method of Claim 104, further comprising, prior to administering the final dose, administering one or more lower dose to the subject, wherein the lower dose is lower than the final dose.

106. The method of Claim 104 or 105, wherein the final dose is from about 0.5 mg to about 30 mg.

107. The method of any one of Claims 104 to 106, wherein the final dose is from about 1 mg to about 20 mg.

108. The method of any one of Claims 104 to 106, wherein the final dose is about 10 mg.

109. The method of any one of Claims 104 to 106, wherein the final dose is about 15 mg.

110. The method of any one of Claims 104 to 106, wherein the final dose is about 17.5 mg.

111. The method of any one of Claims 104 to 106, wherein the final dose is about 20 mg.

112. The method of any one of Claims 104 to 111, wherein the one or more lower dose is from about 0.5 mg to about 20 mg.

113. The method of any one of Claims 104 to 111, wherein the one or more lower dose is from about 2.5 mg to about 15 mg.

114. The method of any one of Claims 104 to 111, wherein the one or more lower dose is about 2.5 mg.

115. The method of any one of Claims 104 to 111, wherein the one or more lower dose is about 5 mg.

116. The method of any one of Claims 104 to 111, wherein the one or more lower dose is about 7.5 mg.

117. The method of any one of Claims 104 to 111, wherein the one or more lower dose is about 10 mg.

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