Dosage regimens for orforglipron for treating subjects with type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity

Abstract

Disclosed herein are methods for treating subjects with T2D, obesity, or overweight with at least one weight-related comorbidity using a glucagon-like peptide-1 (GLP-1) receptor non-peptide agonist (NPA) via oral administration. Also disclosed herein are oral ascending doses for treating T2D, obesity, or overweight with at least one weight-related comorbidity using a GLP-1 receptor NPA. Also disclosed herein are pharmaceutical unit doses suitable for treating T2D, obesity, or overweight with at least one weight-related comorbidity. Further disclosed herein is the use of a GLP-1 receptor NPA for the manufacture of a medicament for treating T2D, obesity, or overweight with at least one weight-related comorbidity.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 432,197, filed December 13, 2022, and U.S. Provisional Patent Application No. 63 / 499,328, filed May 1, 2023, the contents of which are incorporated herein by reference in their entireties.

[0002] FIELD OF THE INVENTION Disclosed herein are methods for treating type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity using a glucagon-like peptide-1 (GLP-1) receptor non-peptide agonist (NPA) via oral administration. Also disclosed are oral administration regimens for treating subjects with T2D, obesity, or overweight with at least one weight-related comorbidity using a GLP-1 receptor NPA. Also disclosed are pharmaceutical unit doses suitable for treating subjects with T2D, obesity, or overweight with at least one weight-related comorbidity. Furthermore, disclosed is the use of a GLP-1 receptor NPA for the manufacture of a medicament for treating subjects with T2D, obesity, or overweight with at least one weight-related comorbidity. [Background technology]

[0003] Currently, there are GLP-1 receptor agonists (RAs) approved by health authorities for treating T2D, obesity, or overweight. Administration of peptides, such as GLP-1 RAs, is often via parenteral rather than oral routes due to several barriers, including enzymatic degradation in the gastrointestinal tract and intestinal mucosa, poor absorption from the intestinal mucosa, and first-pass metabolism in the liver. One available oral GLP-1 RA product, Rybelsus®, contains a peptide as an active agent, and its administration to patients involves restrictions, such as cumbersome food and water intake restrictions. Patients prefer medications that can be incorporated into their daily routines and habits, and oral medications with no or minimal food and / or water intake restrictions are generally preferred due to their ease of use. Therefore, improved methods for administering GLP-1 RAs or GLP-1 receptor NPAs are needed. Summary of the Invention [Means for solving the problem]

[0004] Disclosed herein is Compound 1, a GLP-1 receptor NPA compound having the following structure:

[0005] [ka] For treating a subject with T2D, obesity, or overweight with at least one weight-related comorbidity. As used herein, treating a subject with obesity or overweight with at least one weight-related comorbidity is also known as chronic weight management (CWM).

[0006] The specific doses and dose-escalation schemes disclosed herein provide an effective treatment option for T2D, obesity, or overweight with at least one weight-related comorbidity without the strict dosing restrictions associated with other GLP-1 RA products. [Brief explanation of the drawings]

[0007] [Figure 1] An overview of the clinical trial is shown below. [Figure 2] An overview of the clinical trial is shown below. [Figure 3-1] The effect of once-daily OFG compared to placebo on body weight is shown. Least squares means are shown in Figure 3. Panel A shows the percent change from baseline in body weight (efficacy estimate) by week. Panel B shows the change from baseline in body weight (kg) by week. Panels C and D show the proportion of patients achieving a weight loss of ≥ 5%, ≥ 10%, and ≥ 15% at 26 and 36 weeks, respectively. * = P value < 0.01 vs. placebo. Doses 36mg-1 and 36mg-2 were combined for 36mg, and doses 45mg-1 and 45mg-2 were combined for 45mg. [Figure 3-2] The effect of once-daily OFG compared to placebo on body weight is shown. Least squares means are shown in Figure 3. Panel A shows the percent change from baseline in body weight (efficacy estimate) by week. Panel B shows the change from baseline in body weight (kg) by week. Panels C and D show the proportion of patients achieving a weight loss of ≥ 5%, ≥ 10%, and ≥ 15% at 26 and 36 weeks, respectively. * = P value < 0.01 vs. placebo. Doses 36mg-1 and 36mg-2 were combined for 36mg, and doses 45mg-1 and 45mg-2 were combined for 45mg. [Figure 4] An overview of the clinical trial is shown below. [Figure 5-1] Figure 5A shows the LS mean change in HbA1c. [Figure 5-2] Figure 5B shows the LS mean change in HbA1c. [Figure 6-1] Figure 6A shows the LS mean change in body weight. [Figure 6-2] Figure 6B shows the LS mean change in body weight. [Figure 7] The percentage of subjects who achieved HbA1c and weight loss goals is shown. DETAILED DESCRIPTION OF THE INVENTION

[0008] GLP-1 RAs have many effects in the body that can be effective in lowering A1C (also known as "hemoglobin A1C" or "HbA1c") or inducing weight loss. However, available GLP-1 RA products have various limitations, such as the need for administration by injection and the restriction of food and water intake when administered orally. Compound 1 and the administration schemes disclosed herein are effective in lowering A1C levels and / or inducing weight loss. Oral administration of Compound 1 offers advantages over injectable GLP-1 RAs in that it is easy to use and easily incorporated into a patient's daily routine and habits. The administration regimens described herein also offer the advantage that Compound 1 can be administered at any time of day, with or without food, thereby providing improved convenience and reducing concerns about adequate drug absorption that affect orally delivered peptides.

[0009] Undesirable side effects are often associated with the treatment of T2D, obesity, or overweight with at least one weight-related comorbidity with GLP-1 RAs, and achieving a desirable or more tolerable side effect profile has been a significant challenge. The oral dosing scheme disclosed herein involves optimized dose escalation before reaching a maintenance dose, resulting in reduced treatment-related side effects.

[0010] In one embodiment, the dosing schemes disclosed herein, when used as an adjunct to diet and exercise, are effective in treating subjects with T2D, obesity, or overweight with at least one weight-related comorbidity, with reduced treatment-related side effects compared to using treatment doses without escalating doses or with a non-optimized escalating schedule.

[0011] In one embodiment, when used as an adjunct to diet and exercise, the dosing schemes disclosed herein are effective in treating subjects with T2D, obesity, or overweight with at least one weight-related comorbidity, with reduced side effects compared to using therapeutic doses without titration or with a non-optimized titration schedule, and without the strict food or water restrictions associated with other oral GLP-1 RA products.

[0012] In one embodiment, when used as an adjunct to diet and exercise, the dosing schemes disclosed herein for oral administration of Compound 1 result in reduced treatment-related adverse events, such as nausea, vomiting, or constipation, compared to the use of alternative dosing methods, e.g., using therapeutic doses without one or more escalating doses or with a non-optimized escalating schedule.

[0013] In one embodiment, when used as an adjunct to diet and exercise, a dosing regimen using a starting dose of 0.7 mg to 1.2 mg of Compound 1 results in reduced treatment-related side effects. In one embodiment, the starting dose is 0.75 mg to 1 mg of Compound 1. In one embodiment, the starting dose is 0.8 mg to 1 mg of Compound 1. In one embodiment, the starting dose is 0.8 mg to 0.9 mg of Compound 1. In one embodiment, the starting dose is 1 mg of Compound 1. In one embodiment, each dose is the free acid equivalent of Compound 1.

[0014] In one embodiment, when used as an adjunct to diet and exercise, a dosing regimen using one or more incremental doses, where each incremental dose is administered for 1, 2, 3, 4, 5, or 6 weeks, results in a reduction in treatment-related side effects. In one embodiment, each incremental dose is administered for 2, 3, 4, or 5 weeks. In one embodiment, each incremental dose is administered for 3, 4, or 5 weeks. In one embodiment, each incremental dose is administered for 4 weeks.

[0015] In one embodiment, when used as an adjunct to diet and exercise, a dosing regimen using a starting dose of Compound 1 of 0.7 mg to 1.2 mg and one or more escalating doses, where each escalating dose is administered for 1, 2, 3, 4, 5, or 6 weeks, results in reduced treatment-related side effects. In one embodiment, the dosing regimen includes a starting dose of Compound 1 of 0.75 mg to 1 mg and one or more escalating doses, where each escalating dose is administered for 2, 3, 4, or 5 weeks. In one embodiment, the dosing regimen includes a starting dose of Compound 1 of 0.8 mg to 1 mg and one or more escalating doses, where each escalating dose is administered for 4 weeks. In one embodiment, the dosing regimen includes a starting dose of Compound 1 of 0.8 mg to 0.9 mg and one or more escalating doses, where each escalating dose is administered for 4 weeks. In one embodiment, the dosing regimen includes a starting dose of Compound 1 of 1 mg and one or more escalating doses, where each escalating dose is administered for 4 weeks. In one embodiment, each dose is the free acid equivalent of Compound 1.

[0016] In one embodiment, a method for treating a subject having type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity in need of treatment comprises: The method comprises orally administering to a subject an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt is administered to a subject as a supplement to diet and exercise.

[0017] In one embodiment of the above method, the effective amount is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, and combinations of two or more of the listed doses. In one embodiment, each dose is the free acid equivalent of Compound 1. In one embodiment, each dose is administered once daily (QD). In one embodiment, one or more capsules containing Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0018] In one embodiment of the above method, the effective amount is selected from 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, and combinations of two or more of the recited doses. In one embodiment, each dose is the free acid equivalent of Compound 1. In one embodiment, each dose is administered QD. In one embodiment, one or more capsules containing Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or a pharmaceutically acceptable salt thereof, are administered to the subject.

[0019] In one embodiment, a subject is administered one or more tablets each containing an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or a pharmaceutically acceptable salt thereof, wherein each effective amount is equivalent to a corresponding capsule dose selected from the following: 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, and combinations of two or more of the listed doses. In one embodiment, each dose is the free acid equivalent of Compound 1. In one embodiment, each dose is administered once daily (QD). In one embodiment, the tablets are administered to a subject as a supplement to diet and exercise.

[0020] In one embodiment of the above method, in which one or more tablets are administered to a subject, the effective amount is selected from 0.7-1 mg, 2-3 mg, 4-6 mg, 8-12 mg, 9-20 mg, 13-30 mg, and combinations of two or more of the recited doses. In one embodiment, each dose is the free acid equivalent of Compound 1. In one embodiment, each dose is administered once daily (QD).

[0021] In one embodiment of the above method, in which one or more tablets are administered to a subject, the effective amount is selected from 0.75-0.9 mg, 2.2-2.8 mg, 4.2-5.5 mg, 7.5-10 mg, 10-17 mg, 14-19 mg, and combinations of two or more of the recited doses. In one embodiment, each dose is the free acid equivalent of Compound 1. In one embodiment, each dose is administered once daily (QD).

[0022] In one embodiment of the above method, in which one or more tablets are administered to a subject, the effective amount is selected from 0.8-0.9 mg, 2.3-2.7 mg, 4.5-5.3 mg, 8-9.5 mg, 11-16 mg, 14-18 mg, and combinations of two or more of the recited doses. In one embodiment, each dose is the free acid equivalent of Compound 1. In one embodiment, each dose is administered once daily (QD).

[0023] In one embodiment of the above method, when used as an adjunct to diet and exercise, the method is for treating a subject with T2D diabetes for improved glycemic control, and oral administration results in a reduction in A1C levels of at least about 1.5% compared to the subject's A1C level at the start of treatment.

[0024] In one embodiment of the above method, when used as an adjunct to diet and exercise, the method is for treating a subject having obesity or being overweight with at least one weight-related comorbidity, and oral administration results in a weight loss of at least about 5% compared to the subject's weight at the start of treatment.

[0025] In one embodiment of the above method, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is administered in the form of a capsule, tablet, sachet, or granules, wherein the capsule, tablet, sachet, or granules comprises Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0026] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject according to the following dosing regimen. Start with a dose of 1 mg QD and continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase to 3 mg QD and, if tolerated, continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase to 6 mg QD and, if tolerated, continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase to 12 mg QD and, if tolerated, continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase to 24 mg QD and, if tolerated, continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase to 36 mg QD and, if tolerated, administer this dose as a maintenance dose for at least 4 weeks. If the maximum tolerated dose (MTD) was reached at any of the following doses: 3 mg QD, 6 mg QD, 12 mg QD, 24 mg QD, and 36 mg QD, dose escalation was stopped at the MTD dose. The MTD dose was used as the maintenance dose and administered for at least 4 weeks.

[0027] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject according to the following dosing regimen. Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD and administered at this dose for 4 weeks. The dose was then increased to 6 mg QD and administered at this dose for 4 weeks. The dose was then increased to 12 mg QD and administered at this dose for 4 weeks. The dose was then increased to 24 mg QD and administered at this dose for 4 weeks. The dose is then increased to 36 mg QD and this dose is administered as a maintenance dose for at least 4 weeks. In one embodiment, each dose is the free acid equivalent of Compound 1.

[0028] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject according to the following dosing regimen. Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD and administered at this dose for 4 weeks. The dose was then increased to 6 mg QD and administered at this dose for 4 weeks. The dose is then increased to 12 mg QD and this dose is administered as a maintenance dose for at least 4 weeks. In one embodiment, each dose is the free acid equivalent of Compound 1.

[0029] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject according to the following dosing regimen. Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD and administered at this dose for 4 weeks. The dose is then increased to 6 mg QD and this dose is administered as a maintenance dose for at least 4 weeks. In one embodiment, each dose is the free acid equivalent of Compound 1.

[0030] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject according to the following dosing regimen. Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose is then increased to 3 mg QD and this dose is administered as a maintenance dose for at least 4 weeks. In one embodiment, each dose is the free acid equivalent of Compound 1.

[0031] In one embodiment of the above dosing regimen, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject as an adjunct to diet and exercise.

[0032] In one embodiment of the above method, the maintenance doses are administered QD for at least 16 weeks.

[0033] In one embodiment of the above method, the maintenance doses are administered QD for at least 20 weeks.

[0034] In one embodiment of the above method, the maintenance doses are administered QD for at least 32 weeks.

[0035] In one embodiment of the above method, the maintenance doses are administered QD for at least 52 weeks.

[0036] In one embodiment of the above method, the maintenance doses are administered QD for at least 84 weeks.

[0037] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject in tablet form according to the following dosing regimen: Start with a dose of 0.75-0.9 mg QD and continue at this dose for 4 weeks. The dose was then increased to 2.2-2.8 mg QD and administered at this dose for 4 weeks. The dose was then increased to 4.2-5.5 mg QD and administered at this dose for 4 weeks. The dose was then increased to 7.5-10 mg QD and administered at this dose for 4 weeks. The dose was then increased to 10.5-17 mg QD and administered at this dose for 4 weeks. The dose was then increased to 13–19 mg QD and administered as a maintenance dose for at least 4 weeks.

[0038] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject in tablet form according to the following dosing regimen: Start with a dose of 0.75-0.9 mg QD and continue at this dose for 4 weeks. The dose was then increased to 2.2-2.8 mg QD and administered at this dose for 4 weeks. The dose was then increased to 4.2-5.5 mg QD and administered at this dose for 4 weeks. The dose was then increased to 7.5–10 mg QD, and this dose was administered as a maintenance dose for at least 4 weeks.

[0039] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject in tablet form according to the following dosing regimen: Start with a dose of 0.75-0.9 mg QD and continue at this dose for 4 weeks. The dose was then increased to 2.2-2.8 mg QD and administered at this dose for 4 weeks. The dose was then increased to 4.2–5.5 mg QD, and this dose was administered as a maintenance dose for at least 4 weeks.

[0040] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject in tablet form according to the following dosing regimen: Start with a dose of 0.75-0.9 mg QD and continue at this dose for 4 weeks. The dose was then increased to 2.2–2.8 mg QD, and this dose was administered as a maintenance dose for at least 4 weeks.

[0041] In one embodiment of the dosing regimen using the tablet dosage form described above, each dose is the free acid equivalent of Compound 1.

[0042] In one embodiment of the dosing regimen using the tablet dosage form described above, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to a subject as an adjunct to diet and exercise.

[0043] In one embodiment of the above method, there is no restriction on the subject's intake of food or water within 30 minutes before or after oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, to the subject.

[0044] In one embodiment of the above method, the method is for treating a subject with T2D diabetes to improve glycemic control as an adjunct to diet and exercise, and oral administration results in a reduction in A1C levels of at least about 1.0% compared to the subject's starting A1C level (baseline) at the start of treatment. In one embodiment, the reduction in A1C levels is at least about 1.1%. In one embodiment, the reduction in A1C levels is at least about 1.2%. In one embodiment, the reduction in A1C levels is at least about 1.3%. In one embodiment, the reduction in A1C levels is at least about 1.4%. In one embodiment, the reduction in A1C levels is at least about 1.5%. In one embodiment, the reduction in A1C levels is at least about 1.6%. In one embodiment, the reduction in A1C levels is at least about 1.7%. In one embodiment, the reduction in A1C levels is at least about 1.8%. In one embodiment, the reduction in A1C levels is at least about 1.9%. In one embodiment, the reduction in A1C levels is at least about 2.0%. In one embodiment, the reduction in A1C levels is at least about 2.1%. In one embodiment, the reduction in A1C levels is at least about 2.2%.

[0045] In one embodiment of the above method, the method is for treating a subject with obesity or overweight with at least one weight-related comorbidity as an adjunct to diet and exercise, and oral administration results in a weight loss of at least about 5% compared to the subject's weight at the start of treatment (baseline). In one embodiment, the weight loss is at least about 6%. In one embodiment, the weight loss is at least about 7%. In one embodiment, the weight loss is at least about 7.5%. In one embodiment, the weight loss is at least about 8%. In one embodiment, the weight loss is at least about 9%. In one embodiment, the weight loss is at least about 10%. In one embodiment, the weight loss is at least about 11%. In one embodiment, the weight loss is at least about 12%.

[0046] In one embodiment of the above method, the method is for treating a subject with obesity or overweight with at least one weight-related comorbidity as an adjunct to diet and exercise, and oral administration results in a weight loss of at least about 3.5 kg compared to the subject's weight at the start of treatment (baseline). In one embodiment, the weight loss is at least about 4 kg. In one embodiment, the weight loss is at least about 4.5 kg. In one embodiment, the weight loss is at least about 5 kg. In one embodiment, the weight loss is at least about 5.5 kg. In one embodiment, the weight loss is at least about 6 kg. In one embodiment, the weight loss is at least about 6.5 kg. In one embodiment, the weight loss is at least about 7 kg. In one embodiment, the weight loss is at least about 7.5 kg. In one embodiment, the weight loss is at least about 8 kg. In one embodiment, the weight loss is at least about 8.5 kg. In one embodiment, the weight loss is at least about 9 kg. In one embodiment, the weight loss is at least about 9.5 kg. In one embodiment, the weight loss is at least about 10 kg.

[0047] In one embodiment of the above method, when Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is administered to adult subjects at high cardiovascular risk, with T2D, obesity, or overweight and at least one weight-related comorbidity, oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is non-inferior to insulin glargine treatment in the occurrence of MACE-4 events (non-inferiority margin of 1.8). In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is administered to the subject as an adjunct to diet and exercise.

[0048] In one embodiment of the above method, when Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is administered to adult subjects who are at high cardiovascular risk, have T2D, are obese, or are overweight with at least one weight-related comorbidity, oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof is superior to insulin glargine treatment in the occurrence of MACE-4 events (non-inferiority margin of 1.8).

[0049] In one embodiment of the above method, the method for treating a subject with type 2 diabetes in need of treatment comprises: orally administering to a subject Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, at a maintenance dose selected from 3 mg, 6 mg, 12 mg, and 36 mg; Before the maintenance dose is administered, an optional escalating dose according to the following regimen is administered. Start with a dose of 1-2 mg QD for several days or weeks, Optionally, if additional glycemic control is needed, increase the dose to 2-5 mg QD and administer at this dose for several days or weeks if tolerated. Optionally, if additional glycemic control is needed, increase the dose to 5-10 mg QD and administer at this dose for several days or weeks if tolerated. Optionally, if additional glycemic control is needed, increase the dose to 10-20 mg QD and administer at this dose for several days or weeks if tolerated. Optionally, if additional glycemic control is needed, increase the dose to 20-30 mg QD for several days or weeks if tolerated. Optionally, if additional glycemic control is needed, increase the dose to 30-40 mg QD and administer at this dose for several days or weeks if tolerated. If the maximum tolerated dose (MTD) is reached at any of the 2-5 mg QD, 5-10 mg QD, 10-20 mg QD, 20-30 mg QD, and 30-40 mg QD doses, dose escalation will stop at the MTD dose. The MTD dose was used as the maintenance dose.

[0050] In one embodiment of the above method for treating a subject with T2D to improve glycemic control, the maintenance dose is 3 mg QD, and before the maintenance dose is administered: A starting dose of 1 mg QD is administered for 2, 3, 4, 5, or 6 weeks. In one embodiment, a starting dose of 1 mg QD is administered for 4 weeks.

[0051] In one embodiment of the above method for treating a subject with T2D to improve glycemic control, the maintenance dose is 12 mg QD, and before the maintenance dose is administered: A starting dose of 1 mg QD was administered for 2, 3, 4, 5, or 6 weeks. The dose is then increased to 3 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks; The dose is then increased to 6 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks.

[0052] In one embodiment of the above method for treating a subject with T2D to improve glycemic control, the maintenance dose is 36 mg QD, and before the maintenance dose is administered: A starting dose of 1 mg QD was administered for 2, 3, 4, 5, or 6 weeks. The dose is then increased to 3 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks; The dose is then increased to 6 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks; The dose is then increased to 12 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks; The dose is then increased to 24 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks.

[0053] In one embodiment of the above method for treating a subject with T2D to improve glycemic control, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to the subject at a maintenance dose QD or an MTD dose QD for days, weeks, or years.

[0054] In one embodiment of the above-described method for treating a subject with T2D to improve glycemic control, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is administered to the subject at a maintenance dose QD or an MTD dose QD for at least 20, 28, 32, 36, 40, 44, 48, 50, 52, 60, 64, 68, 84, 92, 96, or 100 weeks.

[0055] In one embodiment of the above-described method for treating a subject with T2D to improve glycemic control, oral administration results in a reduction in the A1C level of at least about 1.5% compared to the subject's A1C level at the start of treatment. In one embodiment, the reduction in the A1C level is at least about 1.6%. In one embodiment, the reduction in the A1C level is at least about 1.7%. In one embodiment, the reduction in the A1C level is at least about 1.8%. In one embodiment, the reduction in the A1C level is at least about 1.9%. In one embodiment, the reduction in the A1C level is at least about 2.0%.

[0056] In one embodiment, a method for treating a subject with obesity or overweight with at least one weight-related comorbidity comprises: orally administering to a subject Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, at a maintenance dose selected from 6 mg, 12 mg, and 36 mg; Before the maintenance dose is administered, an optional escalating dose according to the following regimen is administered. Start with a dose of 1-2 mg QD for several days or weeks, Optionally, if additional weight control is needed, increase the dose to 2-5 mg QD and administer at this dose for several days or weeks if tolerated. Optionally, if additional weight control is needed, increase the dose to 5-10 mg QD and administer at this dose for several days or weeks if tolerated. Optionally, if additional weight control is needed, increase the dose to 10-20 mg QD and administer at this dose for several days or weeks if tolerated. Optionally, if additional weight control is needed, increase the dose to 20-30 mg QD and administer at this dose for several days or weeks if tolerated. If the maximum tolerated dose (MTD) is reached at any of the following doses: 2-5 mg QD, 5-10 mg QD, 10-20 mg QD, and 20-30 mg QD, dose escalation will stop at the MTD dose. The MTD dose was used as the maintenance dose.

[0057] In one embodiment of the above method for treating a subject with obesity or overweight with at least one weight-related comorbidity, the maintenance dose is 6 mg QD, and before the maintenance dose is administered: A starting dose of 1 mg QD was administered for 2, 3, 4, 5, or 6 weeks. The dose is then increased to 3 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks.

[0058] In one embodiment of the above method for treating a subject with obesity or overweight with at least one weight-related comorbidity, the maintenance dose is 12 mg QD, and before the maintenance dose is administered: A starting dose of 1 mg QD was administered for 2, 3, 4, 5, or 6 weeks. The dose is then increased to 3 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks; The dose is then increased to 6 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks.

[0059] In one embodiment of the above method for treating a subject with obesity or overweight with at least one weight-related comorbidity, the maintenance dose is 36 mg QD, and before the maintenance dose is administered: A starting dose of 1 mg QD was administered for 2, 3, 4, 5, or 6 weeks. The dose is then increased to 3 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks; The dose is then increased to 6 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks; The dose is then increased to 12 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks; The dose is then increased to 24 mg QD and administered at this dose for 2, 3, 4, 5, or 6 weeks.

[0060] In one embodiment of the methods described herein for treating a subject having obesity or overweight with at least one weight-related comorbidity, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is administered to the subject at a maintenance dose QD or an MTD dose QD for at least 20, 28, 32, 36, 40, 44, 48, 50, 52, 60, 64, 68, 84, 92, 96, or 100 weeks.

[0061] In one embodiment of the above dosing regimen for treating obesity or overweight with at least one weight-related comorbidity, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is administered to the subject as an adjunct to diet and exercise.

[0062] In one embodiment of the above method for treating a subject with obesity or overweight with at least one weight-related comorbidity, oral administration results in a weight loss of at least about 5% compared to the subject's weight at the start of treatment. In one embodiment, the weight loss is at least about 6%. In one embodiment, the weight loss is at least about 7%. In one embodiment, the weight loss is at least about 7.5%. In one embodiment, the weight loss is at least about 8%. In one embodiment, the weight loss is at least about 9%. In one embodiment, the weight loss is at least about 10%.

[0063] In one embodiment of the methods described herein, compound 1 has the following structure (compound 1a):

[0064] [ka] or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment of the methods described herein, the hemicalcium salt of compound 1a is used as the active agent.

[0066] In one embodiment of the methods described herein, the hemicalcium salt hydrate of Compound 1, having the following structure (Compound 1b), is used as the active agent:

[0067] [ka] In the formula, X is an integer or decimal number of 0.1 to 2. In one embodiment, X is 0.5 (hemihydrate). In one embodiment, X is 1 (monohydrate). In one embodiment, X is 2 (dihydrate).

[0068] Also disclosed herein is the treatment of a subject with T2D, obesity, or overweight with at least one weight-related comorbidity using Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or a pharmaceutically acceptable salt thereof, in combination with a second active agent.

[0069] In one embodiment, a method for treating a subject with T2D, obesity, or overweight with at least one weight-related comorbidity comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, in combination with a second active agent using a dosing regimen disclosed herein. In one embodiment, the second active agent is selected from the group consisting of amylin receptor non-peptide agonists, glucagon receptor non-peptide agonists, glucose-dependent insulinotropic polypeptide (GIP) non-peptide agonists, peptide tyrosine-tyrosine (PYY) non-peptide agonists, and mixtures thereof. In one embodiment, the second active agent is co-administered simultaneously with Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt. In one embodiment, the second active agent is co-administered sequentially with Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt.

[0070] In one embodiment, the co-administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, and a second active agent results in at least about a 10% weight loss, or more specifically, at least about a 15% weight loss, or even more specifically, at least about a 20% weight loss, compared to the subject's weight at the start of treatment.

[0071] In one embodiment, the combined administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, and a second active agent results in a reduction in A1C levels of at least about 2.0%, or more specifically, a reduction in A1C levels of at least about 2.1%, or more specifically, a reduction in A1C levels of at least about 2.2%, or even more specifically, a reduction in A1C levels of at least about 2.5%, compared to the subject's A1C level at the start of treatment.

[0072] In one embodiment, a method for treating a subject with type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity comprises: A subject is administered the free acid or hemicalcium salt of compound 1a having the structure:

[0073] [ka] The following dosing regimen: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. The dose is then increased to 36 mg QD and this dose is administered orally as a maintenance dose for at least 4 weeks. In one embodiment, the maintenance dose is administered for at least 20 weeks. In one embodiment, the maintenance dose is administered for at least 32 weeks. In one embodiment, the maintenance dose is administered for at least 52 weeks. In one embodiment, the maintenance dose is administered for at least 84 weeks.

[0074] In one embodiment, a method for treating a subject with type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity comprises: The subjects were orally administered the free acid or hemicalcium salt of Compound 1a according to the following dosing regimen: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose is then increased to 12 mg QD and this dose is administered as a maintenance dose for at least 4 weeks. In one embodiment, the maintenance dose is administered for at least 28 weeks. In one embodiment, the maintenance dose is administered for at least 40 weeks. In one embodiment, the maintenance dose is administered for at least 60 weeks. In one embodiment, the maintenance dose is administered for at least 92 weeks.

[0075] In one embodiment, a method for treating a subject with type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity comprises: The subjects were orally administered the free acid or hemicalcium salt of Compound 1a according to the following dosing regimen: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose is then increased to 6 mg QD and this dose is administered as a maintenance dose for at least 4 weeks. In one embodiment, the maintenance dose is administered for at least 32 weeks. In one embodiment, the maintenance dose is administered for at least 44 weeks. In one embodiment, the maintenance dose is administered for at least 64 weeks. In one embodiment, the maintenance dose is administered for at least 96 weeks.

[0076] In one embodiment, a method for treating a subject with type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity comprises: The subjects were orally administered the free acid or hemicalcium salt of Compound 1a according to the following dosing regimen: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose is then increased to 3 mg QD and this dose is administered as a maintenance dose for at least 4 weeks. In one embodiment, the maintenance dose is administered for at least 36 weeks. In one embodiment, the maintenance dose is administered for at least 48 weeks. In one embodiment, the maintenance dose is administered for at least 68 weeks. In one embodiment, the maintenance dose is administered for at least 100 weeks.

[0077] In one embodiment of the above method, each dose is the free acid equivalent of Compound 1a.

[0078] In one embodiment of the above method, the free acid or hemicalcium salt of Compound 1a is administered to the subject as an adjunct to diet and exercise.

[0079] In one embodiment, the method having a maintenance dose of 3 mg QD, 6 mg QD, 12 mg QD, or 36 mg QD is for improving glycemic control in a subject with T2D diabetes, wherein oral administration of the free acid or hemicalcium salt of Compound 1a results in a reduction in HbA1c levels in the subject by at least 1.0%. In one embodiment, the reduction in HbA1c levels is at least 1.1%. In one embodiment, the reduction in HbA1c levels is at least 1.2%. In one embodiment, the reduction in HbA1c levels is at least 1.3%. In one embodiment, the reduction in HbA1c levels is at least 1.4%. In one embodiment, the reduction in HbA1c levels is at least 1.5%.

[0080] In one embodiment of the above method for improved glycemic control in a subject with T2D diabetes, oral administration of the free acid or hemicalcium salt of Compound 1a further results in a weight loss of at least 5%. In one embodiment, the weight loss is at least 6%. In one embodiment, the weight loss is at least 7%. In one embodiment, the weight loss is at least 8%. In one embodiment, the weight loss is at least 9%. In one embodiment, the weight loss is at least 10%.

[0081] In one embodiment, the above method having a maintenance dose of 3 mg QD, 6 mg QD, 12 mg QD, or 36 mg QD is for treating a subject with obesity or overweight with at least one weight-related comorbidity, and oral administration of the free acid or hemicalcium salt of Compound 1a results in at least 5% weight loss. In one embodiment, the weight loss is at least 6%. In one embodiment, the weight loss is at least 7%. In one embodiment, the weight loss is at least 8%. In one embodiment, the weight loss is at least 9%. In one embodiment, the weight loss is at least 10%.

[0082] In one embodiment, the above method having a maintenance dose of 3 mg QD, 6 mg QD, 12 mg QD, or 36 mg QD is for treating a subject with obesity or overweight with at least one weight-related comorbidity, and oral administration of the free acid or hemicalcium salt of Compound 1a results in a weight loss of at least 5 kg. In one embodiment, the weight loss is at least 6 kg. In one embodiment, the weight loss is at least 7 kg. In one embodiment, the weight loss is at least 8 kg. In one embodiment, the weight loss is at least 9 kg. In one embodiment, the weight loss is at least 10 kg.

[0083] In one embodiment of the above method, the free acid or hemicalcium salt of Compound 1a is administered to the subject as an adjunct to diet and exercise.

[0084] In one embodiment of the above method having a maintenance dose of 3 mg QD, 6 mg QD, 12 mg QD, or 36 mg QD, the subject is not restricted from accessing food or water within 30 minutes before or after each oral administration of the free acid or hemicalcium salt of Compound 1a.

[0085] In one embodiment, the subject does not restrict food or water intake within 45 minutes before or after each oral administration of the free acid or hemicalcium salt of Compound 1a.

[0086] In one embodiment, the subject is not restricted from accessing food or water within one hour before and after each oral administration of the free acid or hemicalcium salt of Compound 1a.

[0087] In one embodiment of the above method having a maintenance dose of 3 mg QD, 6 mg QD, 12 mg QD, or 36 mg QD, oral administration of one or more escalating doses prior to administration of the maintenance dose results in a reduction in treatment-related side effects.

[0088] In one embodiment, oral administration of the free acid or hemicalcium salt of Compound 1a is co-administered simultaneously or sequentially with a second active agent.

[0089] In one embodiment, the second active agent is selected from the group consisting of amylin receptor non-peptide agonists, glucagon receptor non-peptide agonists, glucose-dependent insulinotropic polypeptide (GIP) non-peptide agonists, peptide tyrosine-tyrosine (PYY) non-peptide agonists, and mixtures thereof.

[0090] In one embodiment, disclosed herein is a use of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, for the treatment of a subject having type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity, in need of such treatment; Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is for oral administration to a subject; Doses are selected from 1 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, and combinations of two or more of the listed doses.

[0091] In one embodiment of the use, each administered dose is a QD dose.

[0092] In one embodiment of the use, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is for oral administration to a subject according to the following schedule: Start with a dose of 1-2 mg QD and administer at this dose for 2, 3, 4, 5, or 6 weeks. If additional glycemic or weight control is required, increase the dose to 2-5 mg QD and, if tolerated, administer at this dose for 2, 3, 4, 5, or 6 weeks. If additional glycemic or weight control is required, increase the dose to 5-10 mg QD and, if tolerated, administer at this dose for 2, 3, 4, 5, or 6 weeks. If additional glycemic or weight control is required, increase the dose to 10-20 mg QD and, if tolerated, administer at this dose for 2, 3, 4, 5, or 6 weeks. If additional glycemic or weight control is required, increase the dose to 20-30 mg QD and, if tolerated, administer at this dose for 2, 3, 4, 5, or 6 weeks. If additional glycemic or weight control is required, increase the dose to 30-40 mg QD and, if tolerated, administer this dose as a maintenance dose for at least 4 weeks. If the maximum tolerated dose (MTD) is reached at any of the following dose levels: 2-5 mg QD, 5-10 mg QD, 10-20 mg QD, and 20-30 mg QD, dose escalation will stop at the MTD dose without further escalation to the next dose level. The MTD dose was used as the maintenance dose and administered for at least 4 weeks.

[0093] In one embodiment of the use, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, is for oral administration to a subject according to the following schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase the dose to 3 mg QD and, if tolerated, continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase the dose to 6 mg QD and, if tolerated, continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase the dose to 12 mg QD and, if tolerated, continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase the dose to 24 mg QD and, if tolerated, continue at this dose for 4 weeks. If additional glycemic or weight control is required, increase the dose to 36 mg QD and, if tolerated, administer this dose as a maintenance dose for at least 4 weeks. If the maximum tolerated dose (MTD) is reached at any of 3 mg QD, 6 mg QD, 12 mg QD, 24 mg QD, and 36 mg QD, dose escalation will stop at the MTD dose without further escalation to the next dose level. The MTD dose was used as the maintenance dose and administered for at least 4 weeks.

[0094] In one embodiment, disclosed herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, for the treatment of a subject having T2D, obesity, or being overweight with at least one weight-related comorbidity, according to the following oral administration schedule: Start with a dose of 1 mg QD for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. The dose was then increased to 36 mg QD and administered as a maintenance dose for at least 4 weeks.

[0095] In one embodiment, the maintenance dose of 36 mg QD is administered for at least 20 weeks. In one embodiment, the maintenance dose of 36 mg QD is administered for at least 32 weeks. In one embodiment, the maintenance dose of 36 mg QD is administered for at least 52 weeks.

[0096] In one embodiment, disclosed herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, for the treatment of a subject having T2D, obesity, or being overweight with at least one weight-related comorbidity, according to the following oral administration schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD and administered as a maintenance dose for at least 4 weeks.

[0097] In one embodiment, a maintenance dose of 12 mg QD is administered for at least 28 weeks. In one embodiment, a maintenance dose of 12 mg QD is administered for at least 40 weeks. In one embodiment, a maintenance dose of 12 mg QD is administered for at least 60 weeks.

[0098] In one embodiment, disclosed herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, for the treatment of a subject having T2D, obesity, or being overweight with at least one weight-related comorbidity, according to the following oral administration schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD and administered as a maintenance dose for at least 4 weeks.

[0099] In one embodiment, a maintenance dose of 6 mg QD is administered for at least 32 weeks. In one embodiment, a maintenance dose of 6 mg QD is administered for at least 44 weeks. In one embodiment, a maintenance dose of 6 mg QD is administered for at least 64 weeks.

[0100] In one embodiment, disclosed herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, for the treatment of a subject having T2D, obesity, or being overweight with at least one weight-related comorbidity, according to the following oral administration schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD and administered as a maintenance dose for at least 4 weeks.

[0101] In one embodiment, a maintenance dose of 3 mg QD is administered for at least 36 weeks. In one embodiment, a maintenance dose of 3 mg QD is administered for at least 48 weeks. In one embodiment, a maintenance dose of 3 mg QD is administered for at least 68 weeks.

[0102] In one embodiment of the above use, each dose is the free acid equivalent of Compound 1.

[0103] In one embodiment of the above use, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is administered to a subject as an adjunct to diet and exercise.

[0104] In one embodiment, the use is for treating a subject with type 2 diabetes to improve glycemic control, and the administration results in a reduction in the A1C level of at least about 1.5% compared to the subject's A1C level at the start of treatment. In one embodiment, the reduction in the A1C level is at least about 1.6%. In one embodiment, the reduction in the A1C level is at least about 1.7%. In one embodiment, the reduction in the A1C level is at least about 1.8%. In one embodiment, the reduction in the A1C level is at least about 1.9%. In one embodiment, the reduction in the A1C level is at least about 2.0%.

[0105] In one embodiment, the use is for treating a subject with obesity or overweight with at least one weight-related comorbidity, and oral administration results in a weight loss of at least about 5% compared to the subject's weight at the start of treatment. In one embodiment, the weight loss is at least about 6%. In one embodiment, the weight loss is at least about 7%. In one embodiment, the weight loss is at least about 7.5%. In one embodiment, the weight loss is at least about 8%. In one embodiment, the weight loss is at least about 9%. In one embodiment, the weight loss is at least about 10%.

[0106] In one embodiment of the above uses, oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or of a pharmaceutically acceptable salt thereof, is an adjunct to diet and exercise.

[0107] In one embodiment, disclosed herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, for the manufacture of a medicament for treating a subject having T2D, obesity, or being overweight with at least one weight-related comorbidity; The pharmaceutical product is intended for oral administration to a subject of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt thereof; The once-daily dose is selected from 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, and combinations thereof.

[0108] In one embodiment of the above use, the medicament is for oral administration to a subject of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, according to the following administration schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD and administered as a maintenance dose for at least 4 weeks.

[0109] In one embodiment of the above use, the medicament is for oral administration to a subject of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, according to the following administration schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD and administered as a maintenance dose for at least 4 weeks.

[0110] In one embodiment of the above use, the medicament is for oral administration to a subject of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, according to the following administration schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD and administered as a maintenance dose for at least 4 weeks.

[0111] In one embodiment of the above use, the medicament is for oral administration to a subject of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt, according to the following administration schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. The dose was then increased to 36 mg QD and administered as a maintenance dose for at least 4 weeks.

[0112] In one embodiment, disclosed herein is a pharmaceutical unit dose comprising 1 mg to 36 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or a pharmaceutically acceptable salt thereof; the unit dose is suitable for oral administration to treat a subject with T2D, obesity, or overweight with at least one weight-related comorbidity; Multiple unit doses each containing a dose selected from 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, and combinations thereof are administered to the subject.

[0113] In one embodiment, multiple unit doses are administered to a subject according to the following dosing schedule: Start with a unit dose of 1 mg QD and administer at this dose for 4 weeks. The unit dose was then increased to 3 mg QD and this dose was administered as a maintenance dose for at least 4 weeks.

[0114] In one embodiment of the above unit dose, multiple unit doses are administered to a subject according to the following dosing schedule: Start with a unit dose of 1 mg QD and administer at this dose for 4 weeks. The unit dose was then increased to 3 mg QD and administered at this dose for 4 weeks. The unit dose was then increased to 6 mg QD and this dose was administered as a maintenance dose for at least 4 weeks.

[0115] In one embodiment of the above unit dose, multiple unit doses are administered to a subject according to the following dosing schedule: Start with a unit dose of 1 mg QD and administer at this dose for 4 weeks. The unit dose was then increased to 3 mg QD and administered at this dose for 4 weeks. The unit dose was then increased to 6 mg QD and administered at this dose for 4 weeks. The unit dose is then increased to 12 mg QD as a maintenance unit dose, and this dose is administered as a maintenance dose for at least 4 weeks.

[0116] In one embodiment of the above unit dose, multiple unit doses are administered to a subject according to the following dosing schedule: Start with a unit dose of 1 mg QD and administer at this dose for 4 weeks. The unit dose was then increased to 3 mg QD and administered at this dose for 4 weeks. The unit dose was then increased to 6 mg QD and administered at this dose for 4 weeks. The unit dose was then increased to 12 mg QD and administered at this dose for 4 weeks. The unit dose was then increased to 24 mg QD and administered at this dose for 4 weeks. The unit dose was then increased to 36 mg QD and this dose was administered as a maintenance dose for at least 4 weeks.

[0117] In one embodiment of the above uses or unit doses, each dose or unit dose is the free acid equivalent of Compound 1.

[0118] In one embodiment of the above uses or unit doses, the dose or unit dose is administered to a subject for a total treatment period selected from at least 40 weeks, at least 52 weeks, at least 72 weeks, and at least 104 weeks, wherein the total treatment period includes a dose escalation period and a dose maintenance period.

[0119] In one embodiment of the above uses or unit doses, the dose or unit dose is administered to a subject as an adjunct to diet and exercise.

[0120] In one embodiment of the above uses or unit doses, Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or pharmaceutically acceptable salt thereof, is the hemicalcium salt of Compound 1a or a hydrate thereof.

[0121] In one embodiment, disclosed herein is the use of the free acid or hemicalcium salt of compound 1a for the manufacture of a medicament for treating a subject having T2D, obesity, or being overweight with at least one weight-related comorbidity; The pharmaceutical preparation is for oral administration of the free acid or hemicalcium salt of Compound 1a to a subject according to the following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. The dose was then increased to 36 mg QD and administered as a maintenance dose for at least 4 weeks.

[0122] In one embodiment, the free acid or hemicalcium salt of Compound 1a is used to prepare one or more unit doses for treating a subject with T2D, obesity, or overweight with at least one weight-related comorbidity; each unit dose containing 1 mg, 3 mg, 6 mg, or 12 mg of the free acid or hemicalcium salt of Compound 1a; Multiple unit doses are administered to a subject according to the following dosing schedule: Start with a unit dose of 1 mg QD and administer at this dose for 4 weeks. The unit dose was then increased to 3 mg QD and administered at this dose for 4 weeks. The unit dose was then increased to 6 mg QD and administered at this dose for 4 weeks. The unit dose was then increased to 12 mg QD and this dose was administered as a maintenance dose for at least 4 weeks.

[0123] One embodiment is the use of the free acid or hemicalcium salt of compound 1a for the manufacture of a medicament for treating a subject with T2D, obesity, or overweight with at least one weight-related comorbidity, The pharmaceutical preparation is for oral administration of the free acid or hemicalcium salt of Compound 1a to a subject according to the following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD and administered as a maintenance dose for at least 4 weeks.

[0124] One embodiment is the use of the free acid or hemicalcium salt of compound 1a for the manufacture of a medicament for treating a subject with T2D, obesity, or overweight with at least one weight-related comorbidity, The pharmaceutical preparation is for oral administration of the free acid or hemicalcium salt of Compound 1a to a subject according to the following dosing schedule:

[0125] Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD and administered as a maintenance dose for at least 4 weeks.

[0126] In one embodiment of the use of the free acid or hemicalcium salt of compound 1a above, oral administration is for a total treatment period selected from at least 40 weeks, at least 52 weeks, at least 72 weeks, and at least 104 weeks, wherein the total treatment period includes a dose escalation period and a dose maintenance period.

[0127] In one embodiment of the use of the free acid or hemicalcium salt of compound 1a above, oral administration is an adjunct to diet and exercise.

[0128] In one embodiment of the use or unit dose having the above-mentioned 3 mg QD, 6 mg QD, 12 mg QD, or 36 mg QD maintenance dose, the subject is not restricted from eating or drinking within 30 minutes before or after oral administration of the free acid or hemicalcium salt of Compound 1a.

[0129] In one embodiment of the use or unit dose having a maintenance dose of 3 mg QD, 6 mg QD, 12 mg QD, or 36 mg QD described above, administration of the escalating doses results in a reduction in treatment-related side effects compared to treatment with the respective maintenance dose without the escalating dose.

[0130] In one embodiment, the pharmaceutical composition is prepared as a dosage form, the dosage form comprising 1 mg to 45 mg of Compound 1 having the formula:

[0131] [ka] or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or of the pharmaceutically acceptable salt thereof, wherein the unit dosage form is suitable for oral administration.

[0132] In one embodiment, the method, unit dose, or use described herein is for treating a subject with type 2 diabetes mellitus (T2D) to improve glycemic control. In one embodiment, the subject is not receiving insulin therapy before being treated with the compound. In one embodiment, the subject is already taking metformin before being treated with the compound. In one embodiment, the subject is receiving baseline therapy with metformin, SGLT-2, and / or sulfonylurea and has elevated cardiovascular risk. In one embodiment, the subject has type 2D diabetes mellitus and has inadequate glycemic control with diet and exercise alone or in combination with oral antihyperglycemic agents. In one embodiment, the subject has T2D and is receiving baseline therapy with adjusted insulin glargine with or without metformin and / or SGLT-2.

[0133] In one embodiment, the method, unit dose, or use described herein is for treating a subject who is overweight and has a BMI (body mass index) of ≧27 kg / m2. In one embodiment, the subject has T2D and a BMI (body mass index) of ≧27 kg / m2. In one embodiment, the subject has a weight-related comorbidity other than T2D and a BMI (body mass index) of ≧27 kg / m2. In one embodiment, a suitable subject is obese and has a BMI of ≧30 kg / m2. In one embodiment, a suitable subject is T2D and obese with a BMI of ≧30 kg / m2.

[0134] In one embodiment, the method, unit dose, or use described herein is for treating a subject with T2D and an HbA1c level of ≥7.0% to ≤9.5%. In one embodiment, the subject's HbA1c level is reduced by at least 1.0% after a 40-week treatment period according to a Compound 1 or Compound 1a dosing regimen described herein, the 40-week treatment period including both a dose-titration period and a dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced by at least 1.5%. In one embodiment, the subject's HbA1c level is reduced by at least 2.0%. In one embodiment, the subject's HbA1c level is reduced to <7.0% after 40 weeks of treatment according to a Compound 1 or Compound 1a dosing regimen. In one embodiment, treatment of T2D according to a dosing regimen disclosed herein is superior to comparable treatment with a placebo. In one embodiment, a higher percentage of subjects treated with the dosing regimen achieve HbA1c levels <7.0% compared to a comparable placebo group. In one embodiment, the treatment also results in at least a 5% weight loss after a 40-week treatment period, including dose escalation and dose maintenance periods. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%.

[0135] In one embodiment, the method, unit dose, or use described herein is for treating a subject with T2D, obesity, or an overweight subject with elevated cardiovascular risk. In one embodiment, treatment with the dosing regimen of Compound 1 or Compound 1a described herein is non-inferior to insulin glargine QD treatment in the occurrence of MACE-4 events after a 52-week treatment period (non-inferiority margin of 1.8), which includes both a dose-escalation period and a dose-maintenance period. In one embodiment, the treatment is superior to insulin glargine QD treatment in the occurrence of MACE-4 events. In one embodiment, the treatment also results in at least 5% weight loss after a 52-week treatment period, including a dose-escalation and dose-maintenance period. In one embodiment, the weight loss is at least 10% after 52 weeks.

[0136] In one embodiment, the method, unit dose, or use described herein is for treating a subject with obesity or overweight with at least one weight-related comorbidity. In one embodiment, the subject has obesity without T2D. In one embodiment, the subject has obesity with T2D. In one embodiment, the subject is overweight with at least one weight-related comorbidity selected from hypertension, dyslipidemia, MASLD / MASH, cardiovascular disease, obstructive sleep apnea, osteoarthritis, prediabetes, increased risk of cancer, and increased risk of premature death. In one embodiment, the subject is overweight with T2D.

[0137] In one embodiment, the method, unit dose, or use described herein is for treating a subject who has obesity with T2D or is overweight with T2D, wherein treatment with Compound 1 or Compound 1a according to the dosing regimen described herein results in at least 5% weight loss after a 72-week treatment period, the 72-week treatment period including both the dose escalation period and the dose maintenance period. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%.

[0138] In one embodiment, the method, unit dose, or use described herein is for treating an overweight subject with obesity without T2D or with at least one weight-related comorbidity selected from cardiovascular disease, obstructive sleep apnea, osteoarthritis, increased risk of cancer, and increased risk of premature death. In one embodiment, treatment with the dosing regimen of Compound 1 or Compound 1a described herein results in at least 5% weight loss after a 72-week treatment period, which includes both a dose-escalation period and a dose-maintenance period. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%.

[0139] In one embodiment, the dosing regimens of Compound 1 or 1a, uses of Compound 1 or 1a, and pharmaceutical dosage forms comprising Compound 1 or 1a disclosed herein can be used to treat a subject with obstructive sleep apnea (OSA). OSA is associated with obesity or overweight, and treatment of obesity or overweight as disclosed herein can further improve the subject's OSA condition.

[0140] In one embodiment of the methods, unit dosage forms, or uses described herein, for each of the dosing schedules having maintenance doses of 3 mg QD, 6 mg QD, 12 mg QD, and 36 mg QD, the total treatment period, including dose escalation and dose maintenance, is at least 40 weeks. In one embodiment, the total treatment period is at least 52 weeks. In one embodiment, the total treatment period is at least 72 weeks. In one embodiment, the total treatment period is at least 104 weeks.

[0141] In one embodiment, a method for treating an adult subject with type 2 diabetes and obesity or overweight at increased cardiovascular risk comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose is then increased to 3 mg QD and, if tolerated, maintained at this dose for 4 weeks. The dose is then increased to 6 mg QD and, if tolerated, maintained at this dose for 4 weeks. The dose is then increased to 12 mg QD and, if tolerated, maintained at this dose for 4 weeks. The dose is then increased to 24 mg QD and, if tolerated, maintained at this dose for 4 weeks. The dose was then increased to 36 mg QD as a maintenance dose. If 3 mg QD, 6 mg QD, 12 mg QD, or 24 mg QD is not tolerated, the dose will be stopped at the maximum tolerated dose (MTD) and maintained at the MTD dose. administering a maintenance dose to the subject for at least 32 weeks or until the occurrence of at least about 122 MACE-4 events; Treatment with compound 1a is non-inferior to insulin glargine treatment in the occurrence of MACE-4 (NIM 1.8). In one embodiment, treatment with compound 1a is superior to insulin glargine treatment in the occurrence of MACE-4 (NIM 1.8). In an embodiment, the total treatment period is at least 52 weeks, including dose escalation and dose maintenance. In an embodiment, the total treatment period is at least 104 weeks, including dose escalation and dose maintenance. In one embodiment, the treatment is a diet and exercise supplement.

[0142] In one embodiment, a method for treating an adult subject with type 2 diabetes and obesity or overweight at increased cardiovascular risk comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. The dose was then increased to 36 mg QD as a maintenance dose. administering a maintenance dose to the subject for at least 32 weeks or until the occurrence of about 122 MACE-4 events; Treatment with compound 1a is non-inferior to insulin glargine treatment in the occurrence of MACE-4 (NIM 1.8). In one embodiment, treatment with compound 1a is superior to insulin glargine QD treatment in the occurrence of MACE-4 (NIM 1.8). In one embodiment, the total treatment period is at least 52 weeks, including dose escalation and dose maintenance. In one embodiment, the total treatment period is at least 104 weeks, including dose escalation and dose maintenance. In one embodiment, the treatment is a diet and exercise supplement.

[0143] In one embodiment, a method for treating an adult subject with type 2 diabetes who has inadequate glycemic control with diet and exercise alone comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. then increasing the dose to 36 mg QD and administering this dose as a maintenance dose for at least 20 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 20-week dose-escalation period and a 20-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after 40 weeks of treatment.

[0144] In one embodiment, a method for treating an adult subject with type 2 diabetes who has inadequate glycemic control with diet and exercise alone comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. then increasing the dose to 12 mg QD and administering this dose as a maintenance dose for at least 28 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 12-week dose-escalation period and a 28-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after a 40-week treatment period.

[0145] In one embodiment, a method for treating an adult subject with type 2 diabetes who has inadequate glycemic control with diet and exercise alone comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. then increasing the dose to 3 mg QD and administering this dose as a maintenance dose for 36 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 4-week dose-titration period and a 36-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after a 40-week treatment period.

[0146] In one embodiment, the method for treating an adult subject with type 2 diabetes who is inadequately controlled with metformin includes: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. then increasing the dose to 36 mg QD and administering this dose as a maintenance dose for at least 20 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 20-week dose-titration period and a 20-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after a 40-week treatment period. In one embodiment, treatment with Compound 1a after a 36 mg maintenance dose is non-inferior to 10 mg QD oral dapagliflozin treatment in glycemic control.

[0147] In one embodiment, the method for treating an adult subject with type 2 diabetes who is inadequately controlled with metformin includes: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. then increasing the dose to 12 mg QD and administering this dose as a maintenance dose for at least 28 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 12-week dose-titration period and a 28-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after 40 weeks of treatment. In one embodiment, treatment with Compound 1a after a 12 mg maintenance dose is non-inferior to 10 mg QD oral dapagliflozin treatment in glycemic control.

[0148] In one embodiment, the method for treating an adult subject with type 2 diabetes who is inadequately controlled with metformin includes: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. then increasing the dose to 3 mg QD and administering this dose as a maintenance dose for at least 36 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 4-week dose-titration period and a 36-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after a 40-week treatment period. In one embodiment, treatment with Compound 1a after a 3 mg maintenance dose is non-inferior to 10 mg QD oral dapagliflozin treatment in glycemic control.

[0149] In one embodiment, the method for treating an adult subject with type 2 diabetes who is inadequately controlled with metformin includes: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. then increasing the dose to 36 mg QD and administering this dose as a maintenance dose for at least 32 weeks; and The subject's HbA1c level was reduced to less than 7% after a 52-week treatment period, including a 20-week dose-escalation period and a 32-week dose-maintenance period; Treatment with compound 1a is non-inferior to 7 mg QD semaglutide treatment (with 4 weeks of 3 mg QD semaglutide titration) in glycemic control. In one embodiment, treatment with compound 1a is non-inferior to 14 mg QD semaglutide treatment (with successive 3 mg QD and 7 mg QD semaglutide titrations each for 4 weeks) in glycemic control.

[0150] In one embodiment, the method for treating an adult subject with type 2 diabetes who is inadequately controlled with metformin includes: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. then increasing the dose to 12 mg QD and administering this dose as a maintenance dose for at least 40 weeks; and The subject's HbA1c level was reduced to less than 7% after a 52-week treatment period, including a 12-week dose-escalation period and a 40-week dose-maintenance period; Treatment with compound 1a is non-inferior to 7mg QD semaglutide treatment (with an initial 3mg QD semaglutide titration over 4 weeks) in glycemic control. In one embodiment, treatment with compound 1a is non-inferior to 14mg QD semaglutide treatment (with an initial continuous 3mg QD for 4 weeks and 7mg QD semaglutide titration over 4 weeks).

[0151] In one embodiment, the method for treating an adult subject with type 2 diabetes and inadequate glycemic control with insulin glargine, with or without metformin and / or an SGLT-2, comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. then increasing the dose to 36 mg QD and administering this dose as a maintenance dose for at least 20 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 20-week dose-escalation period and a 20-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after a 40-week treatment period. In one embodiment, treatment with compound 1a is superior to placebo in glycemic control.

[0152] In one embodiment, the method for treating an adult subject with type 2 diabetes and inadequate glycemic control with insulin glargine, with or without metformin and / or an SGLT-2, comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. then increasing the dose to 12 mg QD and administering this dose as a maintenance dose for at least 28 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 12-week dose-escalation period and a 28-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after a 40-week treatment period. In one embodiment, treatment with compound 1a is superior to placebo in glycemic control.

[0153] In one embodiment, the method for treating an adult subject with type 2 diabetes and inadequate glycemic control with insulin glargine, with or without metformin and / or an SGLT-2, comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. then increasing the dose to 3 mg QD and administering this dose as a maintenance dose for at least 36 weeks; and The subject's HbA1c level is reduced to less than 7% after a 40-week treatment period, including a 4-week dose-titration period and a 36-week dose-maintenance period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after a 40-week treatment period. In one embodiment, treatment with compound 1a is superior to placebo in glycemic control.

[0154] In one embodiment, a method for treating an adult subject with obesity or overweight with at least one weight-related comorbidity other than T2D comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. then increasing the dose to 36 mg QD and administering this dose as a maintenance dose for at least 52 weeks; and Oral administration of Compound 1a results in a weight loss of at least 5% after a 72-week treatment period, including a 20-week dose-escalation period and a 52-week dose-maintenance period. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%. In one embodiment, the weight loss is at least 20%.

[0155] In one embodiment, a method for treating an adult subject with obesity or overweight with at least one weight-related comorbidity other than T2D comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. then increasing the dose to 12 mg QD and administering this dose as a maintenance dose for at least 60 weeks; and Oral administration of Compound 1a results in a weight loss of at least 5% after a 72-week treatment period, including a 12-week dose-escalation period and a 60-week dose-maintenance period. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%. In one embodiment, the weight loss is at least 20%.

[0156] In one embodiment, a method for treating an adult subject with obesity or overweight with at least one weight-related comorbidity other than T2D comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. then increasing the dose to 6 mg QD and administering this dose as a maintenance dose for at least 64 weeks; and Oral administration of Compound 1a results in a weight loss of at least 5% after a 72-week treatment period, including an 8-week dose-escalation period and a 64-week dose-maintenance period. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%.

[0157] In one embodiment, the method for treating an overweight adult subject with obesity or T2D comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. The dose was then increased to 12 mg QD for 4 weeks. The dose was then increased to 24 mg QD for 4 weeks. then increasing the dose to 36 mg QD and administering this dose as a maintenance dose for at least 52 weeks; and Oral administration of Compound 1a results in at least a 5% weight loss after a 72-week treatment period, including a 20-week dose-escalation period and a 52-week dose-maintenance period. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%. In one embodiment, oral administration of Compound 1a further results in at least a 1.0% reduction in the subject's HbA1c level. In one embodiment, the reduction in the HbA1c level is at least 1.2%. In one embodiment, the reduction in the HbA1c level is at least 1.5%. In one embodiment, the subject's HbA1c level is reduced to less than 7.0% after the 72-week treatment period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after the 72-week treatment period.

[0158] In one embodiment, the method for treating an overweight adult subject with obesity or T2D comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. The dose was then increased to 6 mg QD for 4 weeks. then increasing the dose to 12 mg QD and administering this dose as a maintenance dose for at least 60 weeks; and Oral administration of Compound 1a results in a weight loss of at least 5% after a 72-week treatment period, including a 12-week dose-escalation period and a 60-week dose-maintenance period. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%. In one embodiment, oral administration of Compound 1a further results in a reduction in the subject's HbA1c level of at least 1.0%. In one embodiment, the reduction in HbA1c level is at least 1.2%. In one embodiment, the reduction in HbA1c level is at least 1.5%. In one embodiment, the subject's HbA1c level is reduced to less than 7.0% after the 72-week treatment period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after the 72-week treatment period.

[0159] In one embodiment, the method for treating an overweight adult subject with obesity or T2D comprises: The following dosing schedule: Start with a dose of 1 mg QD and continue at this dose for 4 weeks. The dose was then increased to 3 mg QD for 4 weeks. then increasing the dose to 6 mg QD and administering this dose as a maintenance dose for at least 64 weeks; and Oral administration of Compound 1a results in a weight loss of at least 5% after a 72-week treatment period, including an 8-week dose-escalation period and a 64-week dose-maintenance period. In one embodiment, the weight loss is at least 10%. In one embodiment, the weight loss is at least 15%. In one embodiment, oral administration of Compound 1a further results in a reduction in the subject's HbA1c level of at least 1.0%. In one embodiment, the reduction in HbA1c level is at least 1.2%. In one embodiment, the reduction in HbA1c level is at least 1.5%. In one embodiment, the subject's HbA1c level is reduced to less than 7.0% after the 72-week treatment period. In one embodiment, the subject's HbA1c level is reduced to less than 6.5% after the 72-week treatment period.

[0160] In one embodiment, the hemicalcium salt of compound 1a or a hydrate thereof is used in the manufacture of a medicament for treating a subject with T2D, obesity, or overweight with at least one weight-related comorbidity according to a dosing schedule as described in the above embodiment.

[0161] In one embodiment, the treatment period is preceded by a screening or run-in period. In one embodiment, the treatment period is followed by an additional treatment or safety follow-up period.

[0162] As used herein, an "effective amount" or "effective dose" of a GLP-1 receptor NPA refers to an amount sufficient to cure, alleviate, or partially halt the clinical symptoms of a given disease or condition and its complications. An amount sufficient to accomplish this is defined as an "effective amount" or "effective dose." The effective amount for each purpose depends on the severity of the disease or condition and the weight and general condition of the subject.

[0163] As used herein, the term "maximum tolerated dose" or "MTD" means the highest dose of a drug or treatment that does not cause unacceptable side effects. In one embodiment, the maximum tolerated dose is determined in a clinical trial by testing increasing doses in different groups of people until the highest dose with tolerable side effects is found.

[0164] As used herein, the term "treatment" or "treating" refers to the management and care of a subject for the purpose of combating a condition, such as a disease or disorder. In one embodiment, the term "treatment" or "treating" is intended to include the full range of treatments for a given condition from which a subject is afflicted, such as the administration of an active GLP-1 receptor NPA to alleviate symptoms or complications, slow the progression of, or cure or eliminate a disease, disorder, or condition.

[0165] As used herein, the terms "Compound LY" and "Compound 1" are used interchangeably.

[0166] As used herein, the term "OFG" refers to the hemicalcium salt of compound 1a or a hydrate thereof, as the context will dictate.

[0167] As used herein, the terms "dose escalation" and "escalating dose" are used interchangeably with "dose titration" and "titration dose," respectively. Similarly, dose "escalation" and "titration" are used interchangeably.

[0168] As used herein, the terms "titrate" and "escalate" when referring to a change in dose are used interchangeably.

[0169] As used herein, the terms "dosing schedule" and "dosing regimen" are used interchangeably.

[0170] As used herein, the term "at the start of treatment" refers to the point in time at which dose escalation or treatment begins after a screening / run-in period. A subject's weight or HbA1C level at the start of treatment may also be referred to as the subject's baseline weight or baseline HbA1C level.

[0171] As used herein, "weight loss" and "weight reduction" are used interchangeably. [Example]

[0172] Capsule formulation of Compound 1 (Ca 0.5 hydrate) In one embodiment, Compound 1 is administered to a subject in a capsule. In one embodiment, capsules containing Compound 1 can be prepared as described in Examples 1 and 2 below.

[0173] Example 1 Compound 1a Ca0.5 hydrate SDD preparation Compound 1a Ca sesquihydrate was dissolved in ethanol and denatured with methanol (5% v / v or w / w). A 20% w / w solid solution was prepared with a 30% w / w (free acid basis) solid fraction consisting of the title compound, with the remainder consisting of PVP-VA. This translated into 6% Compound 1a (free acid basis), 14% PVP-VA, and 80% denatured ethanol SDA-3A (all fractions w / w). After spray drying, the solid formed consisted of 30% w / w (free acid basis) of the solid fraction consisting of Compound 1a, with the remainder consisting of PVP-VA. The percentage values ​​are shown in Table 1 below.

[0174] Example 1 - Compound 1a SDD

[0175] [Table 1]

[0176] A solution was prepared and pumped into a spray dryer where the solution was atomized upon entry. Heated drying gas was admitted cocurrently to the atomized liquid at the top of the spray-drying chamber at a spray solution-to-drying gas ratio of approximately 0.044 kg / kg. The inlet temperature was adjusted to provide an outlet temperature of 35-45°C. Solids formed in the spray dryer were collected from a cyclone as well as a filter housing above the gas stream. The gas was passed through a condenser maintained at -3°C to remove the solvent (to a dew point of -3°C). The gas was then heated to the inlet temperature and returned to the spray dryer.

[0177] Example 2 - Exemplary Capsule Formulation Compound 1a Ca 0.5 hydrate, 1 mg and 15 mg capsule formulations SDD, NaHCO3, microcrystalline cellulose (MCC PH-102), and SiO2 were dispensed into separate low-density polyethylene (LDPE) bags. The NaHCO3 and MCC PH-102 were sequentially passed through a screen (30 mesh) into separate LDPE bags. ∼25% of the sieved NaHCO3 was added to a 10-L mixing vessel. The sieved MCC was added to the bag containing SDD and mixed by hand for at least 2 minutes. SiO2 was then added to the blend of MCC and SDD and mixed by hand for at least another 2 minutes. The blend was sieved into a vessel through a 30-mesh screen. The LDPE bag of blend was rinsed with the remaining NaHCO3 and sieved into a vessel through a 30-mesh screen, after which it was blended at 20 RPM for 15 minutes. The blend was sieved through a 30-mesh screen and blended again at 20 RPM for 15 minutes. The blend was filled into empty No. 0 capsule shells to the target fill weight using a semi-automatic filling machine (eg, Dott-Bonapace).

[0178] [Table 2]

[0179] Tablet and capsule formulations of Compound 1a Ca 0.5 hydrate In one embodiment, Compound 1a is administered to a subject in a tablet. In one embodiment, an exemplary tablet containing Compound 1a can be prepared as described in the Examples below.

[0180] Example 3 Exemplary Tablets and Alternative Capsules Compound 1a SDD Preparation 1 30% Compound 1a SDD was prepared by dissolving 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one Ca sesquihydrate (8.7 g, 92% potency) and PVP-VA (also known as copovidone, CAS# 25086-89-9;) (18.7 g) in EtOH (200 mL) at room temperature. After dissolution of the solids, the solution was spray dried in a conventional spray dryer equipped with a pressure nozzle. The following parameters in the table below were used to prepare the dispersion using a lab-scale spray dryer. Spray drying began when the spray dryer temperature exceeded 33°C. The material was collected and dried overnight under vacuum at 50°C to give the title compound (21.99 g, 7.0 g, 92% titer, 80% recovery), which was observed by optical microscopy to be microscopically non-birefringent particles approximately 5-25 μm in diameter.

[0181] [Table 3]

[0182] Compound 1a SDD Preparation 2 Compound 1a was dissolved in EtOH and modified with MeOH (5% v / v or w / w). A 20% w / w solid solution was prepared with a 30% w / w (free acid basis) solid fraction consisting of the title compound, with the remainder consisting of PVP-VA. This translated to 6% title compound (free acid basis), 14% PVP-VA, and 80% modified EtOH SDA-3A (all fractions as w / w). After spray drying, the resulting solid consisted of 30% w / w (free acid basis) of the solid fraction consisting of the title compound, with the remainder consisting of PVP-VA. The percentage values ​​are shown in the table below.

[0183] [Table 4]

[0184] A solution was prepared and pumped into a spray dryer where the solution was atomized. Heated drying gas was admitted cocurrently to the atomized liquid at the top of the spray-drying chamber at a spray solution-to-drying gas ratio of approximately 0.044 kg / kg. The inlet temperature was adjusted to provide an outlet temperature of 35-45°C. Solids formed in the spray dryer were collected from a cyclone as well as a filter housing above the gas stream. The gas was passed through a condenser maintained at -3°C to remove the solvent (to a dew point of -3°C). The gas was then heated to the inlet temperature and returned to the spray dryer.

[0185] Preparation 3 Compound 1a capsule formulation Capsules were prepared by first adding sodium bicarbonate (600 mg) to a size 0 hypromellose capsule, followed by SDD of Preparation 3 (54 mg).

[0186] [Table 5]

[0187] Compound 1a tablet formulation Preparation of Core Tablet Composition To prepare the core tablets, Compound 1a (13.33% w / w) SDD and excipients (described below) except magnesium stearate were sieved through a 600 μm sieve before use. The materials were added to a container (1000 mL) and mixed using a mixer at 32 rpm for approximately 10 minutes. The blend was passed through a 600 μm sieve and mixed again using a mixer at 32 rpm for approximately 10 minutes. Magnesium stearate was added, and the blend was mixed at 32 rpm for approximately 3 minutes. The blend was compressed on a single-station tablet press using 14.10 × 7.75 mm oval tablet tooling to produce tablets (400.0 mg) with a hardness of 30 kP.

[0188] Tablet compositions were prepared substantially as described herein above using the parameters in the following table to prepare corresponding Examples (Compositions T1, T2, A, B, C, D, and E). Each Example included an IR coating substantially as described herein and further included an enteric coating. The tablet of Example 7E included only an IR coating.

[0189] [Table 6]

[0190] [Table 7]

[0191] [Table 8]

[0192] [Table 9]

[0193] [Table 10]

[0194] [Table 11]

[0195] [Table 12]

[0196] Example 4 - Clinical Data The clinical pharmacology, PK, and PD of compound 1a were confirmed in two completed Phase 1 studies in healthy volunteers and subjects with T2D. Results from these studies demonstrated a PK profile suitable for once-daily oral administration, allowing administration without food or water intake or time-of-day-related restrictions. PK of compound 1a plasma concentrations increased approximately proportionally with dose over the dose range of 9 mg QD to 45 mg QD.

[0197] In these Phase 1 studies, GI AEs of nausea, vomiting, and constipation were the most commonly reported AEs. PD results from one study showed clinically meaningful improvements in HbA1c of up to -1.4% and weight loss of up to -5.8 kg after 12 weeks of treatment with compound 1a at 9 mg QD to 45 mg QD in people with T2D.

[0198] Two Phase 2 studies evaluated the safety and efficacy of compound 1a: one for the treatment of type 2 disease, and the other for the treatment of obesity or overweight with at least one weight-related comorbidity. In one study, 26 weeks of compound 1a treatment at doses of 3 mg to 45 mg QD resulted in a mean change from baseline in HbA1c of up to -2.1% (treatment difference vs. placebo: -1.7%) and a mean weight loss of up to 10 kg (treatment difference vs. placebo: 8 kg).

[0199] In another Phase 2 study in obese or overweight individuals with at least one weight-related comorbidity, a mean weight loss of up to 13% from baseline (11% compared with placebo) was observed at week 26 of compound 1a treatment, the primary endpoint. The most common TEAEs were GI-related (nausea, vomiting, diarrhea, and constipation).

[0200] Detailed results of these two Phase 2 trials are provided in more detail below in Examples 4A and 4B.

[0201] Example 4A - Phase 2 Clinical Data A randomized, double-blind, Phase 2 clinical trial enrolled 272 adults with obesity or overweight with at least one weight-related comorbidity other than diabetes to evaluate the weight loss efficacy and safety of four dose levels (12 mg, 24 mg, 36 mg, and 45 mg) of Compound 1a hemicalcium salt ("OFG") compared with placebo administered once daily for 36 weeks. The primary endpoint was percent change in body weight from baseline to week 26, and the secondary endpoint was at week 36.

[0202] Test Design A 36-week, multicenter, phase 2, randomized, double-blind, parallel-group, placebo-controlled study was designed to investigate the efficacy and safety of four dose levels of once-daily Compound 1a compared with once-daily placebo in subjects with obesity or overweight with at least one weight-related comorbidity. A total of 272 patients were randomized 5:5:5:3:3:3:3 to receive either once-daily placebo or Compound 1a maintenance doses of 12 mg, 24 mg, 36 mg (36-1, 36-2), or 45 mg (45-1, 45-2). The 36 mg and 45 mg cohorts were subdivided into 36 mg-1 and 36 mg-2 and 45 mg-1 and 45 mg-2, respectively, and different starting doses, dose escalations, and dose titration procedures were investigated in these subgroup cohorts (Figure 2). Different dose escalations were performed to evaluate maintenance doses and titration procedures for future studies.

[0203] subject Eligible male or female subjects were >18 years of age, had an HbA1c <6.5% (48 mmol / mol) and a BMI >30 kg / m², or >27 kg / m² and <30 kg / m², and had at least one of the following weight-related comorbidities: hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea. Subjects had a stable weight (<5% weight gain and / or loss) for the 3 months prior to randomization.

[0204] procedure The study consisted of a 2-week screening / run-in period, a 36-week treatment period, and a 2-week safety follow-up period after withdrawal. During the treatment period, doses were titrated for all treatment groups. The dose titration period ranged from 0 to 16 weeks depending on the dose group. The initial dose was 2 or 3 mg, followed by additional titration steps depending on the assigned cohort (Figure 2). Compound 1a or a matching placebo was administered daily via oral capsule. All subjects were provided with education on healthy diet and exercise by the study personnel throughout the study period.

[0205] Evaluation items The primary endpoint was percent change in body weight from baseline at week 26. Secondary endpoints included percent change in body weight from baseline at week 36, change from baseline in body weight (kg), BMI (kg / m2), and waist circumference (cm), and the proportion of subjects achieving a ≥ 5% weight loss (kg) and a ≥ 10% weight loss (kg) at weeks 26 and 36. Key safety endpoints included adverse events, blood pressure, heart rate, safety laboratory values, PK parameters, and patient-reported outcomes.

[0206] statistical analysis A sample size of 270 subjects was calculated to provide at least 90% power to test the superiority of Compound 1 over placebo in the primary endpoint. The estimator used for efficacy analysis was the "efficacy estimator," which represents the average treatment effect of the randomized population if treatment were administered as intended. Therefore, it includes data from all randomized subjects who received at least one dose of study drug and excludes data from subjects who permanently discontinued study drug. All tests of treatment effect were performed at a two-sided alpha level of 0.05 without correction for multiple comparisons, and two-sided 95% CIs were calculated. To test the efficacy of Compound 1a with adequate statistical power for the 36 mg and 45 mg doses, the primary endpoint was assessed by pooling the two dose-escalation regimens (combining 36 mg-1 and 36 mg-2 for 36 mg and 45 mg-1 and 45 mg-2 for 45 mg).

[0207] Safety analyses were performed by comparing the safety of Compound 1a with placebo, regardless of adherence to the study drug. Safety analyses were performed using the safety analysis population, which included all randomized subjects who received at least one dose of study drug. Results are presented with summary statistics, point estimates, and 95% confidence intervals, as well as p-values ​​for between-treatment comparisons.

[0208] result At baseline, mean body weight was 108.7 kg, and mean BMI was 37.9 kg / m². The mean percent change in body weight from baseline ranged from -8.6% to -12.6% at week 26 and -9.4% to -14.7% at week 36 in a dose-dependent manner, compared with -2.0% and -2.3% for placebo (Figure 3). The percentage of patients with a ≥10% weight loss at week 36 ranged from 47% to 75% compared with 9% for placebo. At the highest dose of compound 1a (45 mg), 48% of patients had a ≥15% weight loss at week 36 compared with 1% for placebo. Treatment with compound 1a resulted in improvements in all prespecified weight and cardiometabolic measures. The most common adverse events with compound 1a were gastrointestinal, mild to moderate in severity, and occurred primarily during dose escalation. The tolerability and safety profile is consistent with the GLP-1 RA class.

[0209] Across all treatment groups, there was a statistically significant, dose-dependent progressive decrease in placebo-corrected body weight from baseline to weeks 26 and 36, ranging from -6.9 kg to -11.2 kg at week 26 (all groups p<0.001) and from -7.4 kg to -13.0 kg at week 36 (all groups p<0.001) (Figure 3).

[0210] Additional Treatment Outcomes In the compound 1a group, there was a mean reduction in systolic blood pressure (SBP) from baseline to week 26 (range: -4.8 to -10.5 mmHg) and from baseline to week 36 (range: -6.7 to -10.5 mmHg), compared with -3.6 and -1.8 for placebo, respectively. SBP tended to decrease in all compound 1a groups compared with placebo throughout the study. No differences were observed in diastolic blood pressure (DBP) compared with placebo. Benefits from compound 1a were observed with respect to changes in fasting lipids (triglycerides, total cholesterol, non-HDL cholesterol, LDL, and VLDL), but there was no significant change in HDL cholesterol compared with placebo at week 36. Compound 1a-treated subjects reported greater improvements in measures of health-related quality of life and physical activity compared with placebo.

[0211] The changes in systolic or diastolic blood pressure and mean pulse rate compared to placebo were consistent with the results seen in the Phase 2 study described in Example 4B. The prevalence, incidence, and time to onset of nausea, vomiting, diarrhea, and constipation observed in this study were also generally consistent with the results seen in Example 4B.

[0212] Tolerability and safety Nausea, constipation, vomiting, diarrhea, and belching were the most common events reported with Compound 1a and were more frequent with Compound 1a than with placebo. Most gastrointestinal events were mild to moderate in severity, occurred primarily during initial titration, were transient, and resolved without permanently discontinuing treatment. Overall, the proportion of patients reporting AEs was slightly higher in the Compound 1a group (86%-90.2%) compared with placebo (76.0%). The most frequent GI reactions did not increase dose-dependently with Compound 1a doses above 3 mg. The 3 mg starting dose had higher GI AE events throughout the study compared with the 2 mg starting dose. Dose escalation every 3 weeks compared with every 1-2 weeks was well tolerated. Overall, after the titration phase, Compound 1a was well tolerated across all arms. Liver function tests did not increase significantly in subjects receiving Compound 1a compared with placebo.

[0213] Example 4B - Phase 2 Clinical Data Test Design A 26-week, multicenter, phase 2, randomized, double-blind, parallel-group, placebo-controlled study was designed to investigate the efficacy and safety of five dose levels of once-daily OFG compared with once-daily placebo and once-weekly dulaglutide. Patients were randomized 5:5:5:5:5:3:3:3:3 to receive once-daily placebo, once-weekly dulaglutide plus oral placebo, or maintenance doses of 3 mg, 12 mg, 24 mg, 36 mg (36-1, 36-2), or 45 mg (45-1, 45-2) OFG. The 36 mg and 45 mg cohorts were subdivided into 36 mg-1 and 36 mg-2 and 45 mg-1 and 45 mg-2, respectively, and different starting doses, dose escalation, and dose escalation procedures were investigated in these subgroup cohorts (Figure 4).

[0214] subject Eligible male or female subjects were >18 years of age, had T2D with HbA1c 7.0%-10.5% and body mass index (BMI) ≥23 kg / m2, were treated with diet and exercise alone or with a stable dose of metformin, and had a stable weight (≤5% weight gain and / or loss) for at least 3 months prior to Screening / Visit 1.

[0215] procedure The study period included a 2-week screening / run-in period and a 26-week treatment period. During the treatment period, doses were titrated for all treatment groups. The dose titration period ranged from 4 to 12 weeks depending on the dose group. The initial dose was 2 or 3 mg, followed by additional titration steps depending on the assigned cohort (Figure 4). All subjects received one capsule (OFG or matching placebo) orally daily and one subcutaneous injection (dulaglutide 1.5 mg or matching placebo) once weekly. All subjects received education on healthy diet and exercise by the study personnel throughout the study period.

[0216] Evaluation items The primary endpoint was the change in HbA1c from baseline at week 26, comparing OFG doses versus placebo. Secondary endpoints included the proportion of subjects with HbA1c ≤ 6.5% and < 7.0% at week 26, change from baseline in fasting plasma glucose at week 26, change from baseline in body weight, and the effect of OFG versus dulaglutide on change from baseline in HbA1c at week 26. Key safety and tolerability endpoints included the frequency of patient- and investigator-reported adverse events, the rate and incidence of hypoglycemic events (glucose < 70 mg / dL [3.9 mmol / L] and ≥ 54 mg / dL [3.0 mmol / L], or glucose < 54 mg / dL [3.0 mmol / L]), and changes in safety laboratory parameters, electrocardiograms, and vital signs.

[0217] statistical analysis A sample size of 370 subjects was calculated to provide at least 90% power to test the superiority of OFG over placebo on the primary endpoint. The estimator used for efficacy analyses was the "efficacy estimator," which represents the average treatment effect in the randomized population if treatment had been administered as intended; therefore, it includes data from all randomized subjects who received at least one dose of study drug and excludes data from subjects who permanently discontinued study drug. All tests of treatment effect were performed at a two-sided alpha level of 0.05 without correction for multiple comparisons, and two-sided 95% CIs were calculated. To test the efficacy of OFG with adequate statistical power for the 36 mg and 45 mg doses, the primary endpoint was assessed by pooling the two dose-escalation regimens (combining 36 mg-1 and 36 mg-2 for 36 mg and 45 mg-1 and 45 mg-2 for 45 mg).

[0218] Safety analyses were performed by comparing the safety of OFG with placebo and dulaglutide, regardless of adherence to study drug. Safety analyses were performed using the safety analysis population, which included all randomized subjects who received at least one dose of study drug. Results are presented with summary statistics, point estimates, and 95% confidence intervals, as well as p-values ​​for between-treatment comparisons.

[0219] result At baseline, the mean HbA1c was 8.1%. The mean change in HbA1c from baseline with OFG treatment ranged from -0.77% to -1.67% at week 26 in a dose-dependent manner, compared with -0.43% for placebo and -1.1% for dulaglutide 1.5 mg. The proportion of patients achieving an HbA1c of 7% or less at week 26 ranged from 65.2% to 95.8% compared with 24.3% for placebo and 64.1% for dulaglutide 1.5 mg. OFG treatment resulted in significant improvements in fasting glucose compared with placebo. The most common adverse events with OFG were gastrointestinal, mild to moderate in severity, and occurred primarily during dose escalation. HbA1c results are shown in Figure 5.

[0220] At baseline, mean body weight was 100.3 kg (SD 21.5). At week 26, mean change from baseline in body weight for subjects receiving OFG was -3.7 kg (0.79) for 3 mg, -6.5 kg (0.76) for 12 mg, -9.7 kg (0.85) for 24 mg, -9.5 kg (0.73) for 36 mg, and -10.1 kg (0.71) for 45 mg, compared with -3.9 kg (0.76) for dulaglutide and -2.2 kg (0.74) for placebo (Figure 6). OFG was significantly more effective than placebo (ETD, -4.3 kg [95% CI -6.4 to -2.2] for 12 mg, 7.6 kg [-9.8 to -5.3] for 24 mg, -7.4 kg [-9.4 to -5.3] for 36 mg, and -7.9 kg [-9.9 to -5.9] for 45 mg; p<0.0001 for OFG 12 mg and above) and dulaglutide (ETD, -2.6 kg [-4.7 to -0.5] for 12 mg, -5.9 kg [-8.1 to -3.6] for 24 mg, -5.7 kg [-7.8 to -3.6] for 36 mg, and -6.2 kg [-8.3 to -4.2] for 45 mg; p=0.0153 for OFG 12 mg, p=0.0153 for OFG 12 mg, p=0.0153 for OFG 45 mg). p<0.0001 for 24 mg, 36 mg, and 45 mg.

[0221] The percentage of subjects who achieved HbA1c and weight loss goals in the various groups is shown in Figure 7.

[0222] Additional Treatment Outcomes At week 26, no statistically significant differences in systolic or diastolic blood pressure were observed compared with dulaglutide or placebo. Increases in mean pulse rate were reported in all OFG treatment groups, with the greatest changes occurring around week 12. At week 26, subjects receiving OFG had a change from baseline of +3.0 to +6.1 bpm compared with +2.3 and -1.6 bpm for dulaglutide and placebo, respectively. More detailed vital sign parameters are provided in the table below.

[0223] [Table 13] Abbreviations: CFB = change from baseline, Dula = dulaglutide, HbA1c = hemoglobin A1c; LSM = least squares mean, MMRM = mixed model repeated measures scale, n = number of subjects in a particular category, SE = standard error. A Safety Analysis - All available data, including data from both the treatment period and safety follow-up, will be included in the safety analysis. B For OFG 36 mg, OFG 36 mg-1 and OFG 36 mg-2 were combined, and for OFG 45 mg, OFG 45 mg-1 and OFG 45 mg-2 were combined. c MMRM model for post-baseline measurements: log(actual / baseline) = log(baseline) + country + baseline HbA1c group (≤8.0%, >8.0%) + treatment + time + treatment × time (type III sum of squares). Variance-covariance structure (actual) = unstructured. Note 1: Analyses included only subjects with no missing baseline values ​​for the response variable and at least one nonmissing value from baseline onwards. Note 2: Model estimates for the pooled treatment group are estimated by linear contrasts averaging estimates from the individual treatment groups. Summary statistics for the pooled treatment group are calculated based on the observed data without linear contrasts.

[0224] Tolerability and safety Gastrointestinal adverse events occurred more frequently in subjects receiving a high initial dose or rapid dose escalation; for example, in the OFG 36 mg treatment group, 70.4% of subjects in the 36 mg-1 treatment group experienced a gastrointestinal adverse event compared to 44.1% in the 36 mg-2 treatment group.

[0225] [Table 14-1]

[0226] [Table 14-2]

[0227] [Table 14-3] Abbreviations: Dula = dulaglutide, N = number of subjects in a particular treatment group.

[0228] Note: Incidence refers to the proportion of subjects with an event during a certain time interval. Incidence refers to the proportion of subjects with a new event during a certain time interval. Onset refers to the time interval when a subject with an event first occurred. After first dose, it refers to the interval from week 0 to the end of the treatment period.

[0229] Example 5 - Phase 3 Clinical Trial In this Phase 3 clinical trial, OFG (compound 1a hemicalcium salt) will be administered to subjects according to the clinical trial protocol described herein to compare the effects of OFG and insulin glargine on the incidence of MACE-4 in individuals at high risk for cardiovascular (CV) events, who have type 2 disease, obesity, or are overweight with at least one weight-related comorbidity. A summary of this trial is provided in the table below.

[0230] [Table 14-4]

[0231] A detailed description of this study is provided below.

[0232] [Table 15]

[0233] [Table 16]

[0234] A schematic showing patient visit dates and treatment schedules, including time, duration and dose, is shown in Figure 1.

[0235] Abbreviations and footnotes used in Figure 1 are listed below. FTV=last treatment visit date; MACE = major adverse cardiovascular events; QD = once daily. a) All subjects will be receiving stable treatment with at least one and no more than three oral antihyperglycemic agents (metformin, sodium-glucose cotransporter 2 inhibitors, or sulfonylureas). b) The starting dose of insulin glargine is 10 IU / day titrated to FBG ≦100 mg / dL (≦5.6 mmol / L) according to the insulin dosing schedule. Subjects will be titrated weekly for insulin glargine dose and titrated by the investigator (by phone or in-clinic) for the first 8 weeks. From Weeks 8 through 16, subjects will continue weekly titration and will have biweekly phone calls or in-clinic visits to confirm accurate dosing based on the algorithm. c) Subjects will receive the study intervention for at least 12 months and continue until study completion criteria are met. d) Subjects who reach 104 weeks of treatment before the end of the study will continue to visit every 12 weeks until study completion criteria are met. e) All subjects will attend Visit 801 two weeks after FTV.

[0236] Study population - inclusion criteria Subject type and disease characteristics 1. Clinically diagnosed with T2D according to the World Health Organization classification or other regionally applicable diagnostic criteria. 2.HbA1c value at Visit 1 screening. a. If the underlying diabetes medication does not contain sulfonylureas, ≥ 7.0% (53 mmol / mol) to ≤ 10.5% (91 mmol / mol), or b. If the underlying diabetes medication contains a sulfonylurea, the concentration is ≥ 7.5% (58 mmol / mol) to ≤ 10.5% (91 mmol / mol). 3. Receiving stable treatment with at least one but no more than three oral antihyperglycemic agents for at least 90 days prior to screening at Visit 1. Acceptable antihyperglycemic agents metformin (required dose ≥ 1500 mg / day, unless a lower dose is required by country-specific indications based on eGFR or other indices of renal function); SGLT-2 inhibitors, or Sulfonylureas. 4. Increased risk of CV events.

[0237] Study interventions and combination therapies This table lists the interventions used in this clinical trial.

[0238] [Table 17]

[0239] Subjects randomized to OFG The starting dose of OFG is 1 mg QD for 4 weeks, followed by increasing the dose to 36 mg QD every 4 weeks, as outlined in this table.

[0240] [Table 18] OFG is administered orally once daily.

[0241] Subjects randomized to insulin glargine The starting dose of insulin glargine is 10 IU / day, and subjects must administer the daily dose at a time agreed upon between the subject and the investigator, typically before bedtime. Insulin glargine will be titrated to achieve an FBG of ≤100 mg / dL (≤5.6 mmol / L) according to the insulin titration schedule in the Treat-to-Target trial (adapted from Riddle et al. 2003).

[0242] [Table 19] a Based on the last three fasting SMBG readings. b The dose should also be reduced by 2 to 4 units in the following situations: Multiple episodes of non-severe hypoglycemia were recorded at any time during the evaluation period, and / or At least one episode of severe hypoglycemia (an event requiring assistance with treatment) or associated with an SMBG value <54 mg / dL (<3.0 mmol / L) was recorded during the evaluation period. c If only one hypoglycemic episode is documented with an SMBG value ≥ 54 mg / dL (≥ 3.0 mmol / L) and < 70 mg / dL (< 3.9 mmol / L), the insulin dose should not be changed.

[0243] Efficacy evaluation Evaluation for primary purpose The primary objective of this study is to demonstrate that OFG is non-inferior to insulin glargine (non-inferiority margin 1.8) in the incidence of MACE-4 events, including CEC-confirmed MI, stroke, hospitalization for unstable angina, and CV death.

[0244] Example 6 - Phase 1 Clinical Data Randomized, open-label, crossover phase 1 clinical trials A and B evaluated the effect of food on OFG concentrations in healthy adults after a single 3 mg dose (Study A) and after a 16 mg daily dose achieved by weekly dose escalation starting from 2 mg (Study B).

[0245] Based on statistical analysis, Cmax was reduced by 23% (Study A) and 21% (Study B) in the fed state. AUC(0-∞) and AUC(0-24) were reduced by 24% (Study A) and 18% (Study B) when administered with food. Tmax and T1 / 2 were similar regardless of whether food was administered or not. In Studies A and B, treatment-emergent adverse events (TEAEs) were mild. In Study B, TEAEs occurred most frequently at the starting dose and decreased with dose escalation. The most common TEAEs in Study B were decreased appetite (69.7%), nausea (48.5%), and vomiting (45.5%).

[0246] Overall mean exposure to OFG based on Cmax and AUC was numerically reduced when administered with food, with little effect on Tmax and T1 / 2. These PK differences between fed and fasted administration are not expected to result in clinically meaningful differences in the safety and efficacy of OFG based on the exposure-response relationship.

[0247] [Table 20] a Mean (SD), b Geometric LS average (geometric CV%), c AUC (0-∞)、 d AUC (0-24) , e Median (range), f Geometric mean (range)

[0248] Examples 7-12 - Additional Phase 3 Clinical Trials Examples 7-12 describe additional Phase 3 clinical trials summarized below in Table 21. OFG (the hemicalcium salt of compound 1a) was administered to subjects according to the respective clinical trial protocols, the contents of which are incorporated herein by reference, to test the efficacy of OFG for treating individuals with T2D, obesity, or overweight with at least one weight-related comorbidity.

[0249] [Table 21-1]

[0250] [Table 21-2]

Claims

1. 1. A method for treating a subject having type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity in need of such treatment, comprising: The subject is administered a compound 1 having the following structure: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, orally administering a once daily (QD) dose selected from 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, and combinations thereof.

2. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following administration schedule: Starting at a dose of 1 mg QD and continuing at that dose for 1, 2, 3, 4, 5, or 6 weeks; The dose is then increased to 3 mg QD and maintained at that dose for 1, 2, 3, 4, 5, or 6 weeks. The dose is then increased to 6 mg QD and maintained at that dose for 1, 2, 3, 4, 5, or 6 weeks. The dose is then increased to 12 mg QD and maintained at that dose for 1, 2, 3, 4, 5, or 6 weeks. The dose was then increased to 24 mg QD and maintained at that dose for 1, 2, 3, 4, 5, or 6 weeks. The dose is then increased to 36 mg QD and administered as a maintenance dose for at least 4 weeks; The method of claim 1, wherein the subject is administered according to

3. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following administration schedule: Start with a dose of 1 mg QD and administer at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered at that dose for 4 weeks; The dose is then increased to 6 mg QD and administered at that dose for 4 weeks; The dose was then increased to 12 mg QD and administered at that dose for 4 weeks; The dose was then increased to 24 mg QD and administered at that dose for 4 weeks, and then increasing the dose to 36 mg QD and administering that dose as a maintenance dose for at least 4 weeks.

4. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following administration schedule: Starting at a dose of 1 mg QD and continuing at that dose for 1, 2, 3, 4, 5, or 6 weeks; The dose is then increased to 3 mg QD and maintained at that dose for 1, 2, 3, 4, 5, or 6 weeks. The dose is then increased to 6 mg QD and maintained at that dose for 1, 2, 3, 4, 5, or 6 weeks. The dose is then increased to 12 mg QD and administered as a maintenance dose for at least 4 weeks; The method of claim 1, wherein the administration is performed according to the formula:

5. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following administration schedule: Starting at a dose of 1 mg QD and administering at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered at that dose for 4 weeks; The dose is then increased to 6 mg QD and administered at that dose for 4 weeks; The dose is then increased to 12 mg QD and administered as a maintenance dose for at least 4 weeks; The method of claim 4, wherein the subject is administered according to

6. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following administration schedule: Starting at a dose of 1 mg QD and administering at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered at that dose for 4 weeks; The dose is then increased to 6 mg QD and administered as a maintenance dose for at least 4 weeks; The method of claim 1, wherein the subject is administered according to

7. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following administration schedule: Starting at a dose of 1 mg QD and administering at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered as a maintenance dose for at least 4 weeks; The method of claim 1, wherein the administration is performed according to the formula:

8. administering the dose to the subject for a total treatment period selected from at least 40 weeks, at least 52 weeks, at least 72 weeks, and at least 104 weeks; 8. The method of any one of claims 1 to 7, wherein the total treatment period comprises a dose escalation period and a dose maintenance period.

9. the method is for treating a subject with T2D diabetes for improved glycemic control; 9. The method of any one of claims 1-8, wherein oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, results in a decrease in HbA1c levels in said subject of at least 1.0%.

10. 10. The method of claim 9, wherein the reduction in HbA1c level is at least 1.2%.

11. the method is for treating a subject having obesity or overweight with at least one weight-related comorbidity; 9. The method of any one of claims 1 to 8, wherein oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, results in at least 5% weight loss.

12. 12. The method of claim 11, wherein the weight loss is at least 10%.

13. 14. The method of claim 13, wherein the weight loss is at least 5 kg.

14. 14. The method of any one of claims 1 to 13, wherein the subject does not restrict food or water intake within 30 minutes before and after each oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt.

15. 15. The method of any one of claims 2 to 14, wherein oral administration of one or more ascending doses prior to administration of a maintenance dose results in a reduction of treatment-related side effects.

16. Oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is co-administered simultaneously or sequentially with a second active agent; 16. The method of any one of claims 1 to 15, wherein the second active agent is selected from the group consisting of amylin receptor non-peptide agonists, glucagon receptor non-peptide agonists, glucose-dependent insulinotropic polypeptide (GIP) non-peptide agonists, peptide tyrosine-tyrosine (PYY) non-peptide agonists, and mixtures thereof.

17. 1. A method for treating a subject having type 2 diabetes (T2D), obesity, or overweight with at least one weight-related comorbidity in need of such treatment, comprising: administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt; orally administered at a once daily (QD) dose selected from 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, and combinations thereof; wherein the subject is not restricted in food or water intake within 30 minutes before or after the oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt.

18. one or more escalating doses are administered to the subject prior to administration of a maintenance dose; 18. The method of claim 17, wherein said administration of said escalating doses results in a reduction in treatment-related side effects compared to treatment without escalating doses.

19. The maintenance dose is 36 mg QD, and Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following dosing schedule: Starting at a dose of 1 mg QD and administering at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered at that dose for 4 weeks; The dose is then increased to 6 mg QD and administered at that dose for 4 weeks; The dose was then increased to 12 mg QD and administered at that dose for 4 weeks; The dose was then increased to 24 mg QD and administered at that dose for 4 weeks, The dose is then increased to 36 mg QD and administered as a maintenance dose for at least 4 weeks; 20. The method of claim 18, wherein the subject is administered according to

20. 20. The method of any one of claims 1 to 19, wherein each dose is the free acid equivalent of Compound 1.

21. 21. The method according to any one of claims 1 to 20, wherein Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is the hemicalcium salt of the following compound or a hydrate of said hemicalcium salt: 【Chemistry 2】

22. 22. The method of any one of claims 1 to 21, wherein Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered to said subject as an adjunct to diet and exercise.

23. Use of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, at a once daily (QD) dose selected from 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg, and combinations thereof, for the treatment of a subject with T2D, obesity, or overweight with at least one weight-related comorbidity.

24. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following administration schedule: Starting at a dose of 1 mg QD and administering at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered as a maintenance dose for at least 4 weeks; 24. The use according to claim 23, for oral administration to the subject according to

25. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt is administered according to the following administration schedule: Starting at a dose of 1 mg QD and administering at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered at that dose for 4 weeks; The dose is then increased to 6 mg QD and administered as a maintenance dose for at least 4 weeks; 24. The use according to claim 23, for oral administration to the subject according to

26. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is administered according to the following administration schedule: Starting at a dose of 1 mg QD and administering at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered at that dose for 4 weeks; The dose is then increased to 6 mg QD and administered at that dose for 4 weeks; The dose is then increased to 12 mg QD and administered as a maintenance dose for at least 4 weeks; 24. The use according to claim 23, for oral administration to the subject according to

27. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt is administered according to the following administration schedule: Starting at a dose of 1 mg QD and administering at that dose for 4 weeks, The dose is then increased to 3 mg QD and administered at that dose for 4 weeks; The dose is then increased to 6 mg QD and administered at that dose for 4 weeks; The dose was then increased to 12 mg QD and administered at that dose for 4 weeks; The dose was then increased to 24 mg QD and administered at that dose for 4 weeks, The dose is then increased to 36 mg QD and administered as a maintenance dose for at least 4 weeks; Therefore, the use according to claim 23 is for oral administration to the subject.

28. The use according to any one of claims 23 to 27, wherein each dose is the free acid equivalent of Compound 1.

29. The total oral administration period is selected from at least 40 weeks, at least 52 weeks, at least 72 weeks, and at least 104 weeks; The use according to any one of claims 23 to 28, wherein the total administration period comprises a dose escalation period and a dose maintenance period.

30. 30. The use according to any one of claims 23 to 29, wherein the dose is administered to the subject as an adjunct to diet and exercise.

31. The use according to any one of claims 23 to 30, wherein Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of said compound or said pharmaceutically acceptable salt, is the hemicalcium salt of the following compound or a hydrate of said hemicalcium salt: 【Transformation 3】

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