GLP-1 NPA therapies for maintaining body weight loss or reduced HBA1c levels following a prior GLP-1 ra treatment

Abstract

Disclosed herein are methods for treating a subject with T2DM, obesity, or overweight with at least one weight related comorbidity using a glucagon-like peptide-1 (GLP-1) receptor non-peptide agonist (NPA) compound selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and hydrates of the compounds and pharmaceutically acceptable salts, by oral administration to maintain body weight loss or reduced HbA1c levels resulting from a prior treatment with a GLP-1 RA. Also disclosed herein are uses of a GLP-1 receptor NPA compound for the manufacture of a medicament for treating a subject with T2DM, obesity, or overweight with at least one weight related comorbidity to maintain body weight loss or reduced HbA1c levels resulting from a prior treatment with a GLP-1 RA.

Description

GLP-1 NPA THERAPIES FOR MAINTAINING BODY WEIGHT LOSS OR REDUCED HBA1C LEVELS FOLLOWING A PRIOR GLP-1 RA TREATMENT TECHNICAL FIELD

[0001] Disclosed herein are methods for treating a subject with T2DM, obesity, or overweight with at least one weight related comorbidity using a glucagon-like peptide-1 (GLP-1) receptor non-peptide agonist (NPA) compound, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, by oral administration to maintain body weight loss or reduced HbA1c levels resulting from a prior treatment with a GLP-1 receptor agonist (RA) peptide. Also disclosed herein are uses of a GLP-1 receptor NPA compound for the manufacture of an oral medicament for treating a subject with T2DM, obesity, or overweight with at least one weight related comorbidity to maintain body weight loss or reduced HbA1c levels resulting from a prior treatment with a GLP-1 RA peptide. INTRODUCTION

[0002] Currently there are GLP-1 receptor agonist (RA) peptides approved by health authorities for treating T2DM, obesity, or overweight. Administration of peptides, such as GLP-1 RA, is often through parenteral routes rather than oral administration due to several barriers, such as enzymatic degradation in the gastrointestinal tract and intestinal mucosa, insufficient absorption from the intestinal mucosa, and first pass metabolism in the liver. An available oral GLP-1 RA product Rybelsus® contains a peptide as an active agent and its administration to patients comes with restrictions such as food and water intake limitations. Patients prefer oral medications that they can integrate into their lives and daily routines, and oral medications with no or less restrictive food and / or water intake limitations are generally preferred as they are simple to use. SUMMARY

[0003] Disclosed herein are GLP-1 receptor NPA compounds selected from Compound 1, Compound 2, and Compound 3:Compound 1 Compound 2 Compound 3 pharmaceutically acceptable salts thereof, and hydrates of the GLP-1 receptor NPA compounds and the pharmaceutically acceptable salts for treating a subject. The GLP-1 receptor NPA compounds also contemplate their isotopologues, including where2D deuterium is used in place of one or more1H hydrogen.

[0004] Inthe GLP-1 receptor NPA compounds are used to treat subjects with type 2 diabetes mellitus (T2DM), obesity, or overweight with at least one weight related comorbidity. In some embodiments, they are used to maintain a therapeutic effect, such as body weight reduction or reduced HbA1c level, from a prior GLP-1 RA peptide treatment.

[0005] The substituents for Compound 3 are: W is -N= or –CRa=; Rais selected from a hydrogen atom and a halogen atom; X is -N= or –CRa=; Rais selected from a hydrogen atom and a halogen atom; Y is selected from -C(=O)- and -CHRa-; R1is selected from a hydrogen atom and C1-6alkyl; R2is selected from a hydrogen atom and C1-6 alkyl; R3is selected from a hydrogen atom and C1-6 alkyl; R4is selected from a hydrogen atom and C1-6alkyl; R5is selected from a hydrogen atom and C1-6 alkyl; R6is selected from a hydrogen atom and C1-6 alkyl; R7and R8together with the carbon atom to which they are attached form a C3-15cycloalkane ring, optionally substituted with 1 to 3 C1-6alkyl;R9is selected from a group represented by Formula (IIa), (IIb), (IIc), and (IId): ; R9a, R9b, R9c, atom and C1-6alkyl; n1 is an integer of 0 to 3; n2 is an integer of 0 to 5; Q1is C6-10 aryl, optionally substituted with 1 to 5 substituents independently selected from a halogen atom and C1-6 alkyl; Q2is a 3 to 12 membered heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from a halogen atom and C1-6 alkyl; O *N **Z1is a group represented by Formula (IIIa); and Z2is selected from:(a) C6-10aryl, optionally substituted with 1 to 3 substituents independently selected from: ^ halogen, ^ -NRzaRzb, wherein Rzaand Rzbare independently selected from a hydrogen atom and C1-6alkyl, ^ -C(=O)-NRzaRzb, ^ -S(=O)0-2-Rzc, wherein Rzcis a hydrogen atom, C1-6alkyl, or C3-8cycloalkyl; ^ -S(=O)(=NRzd)-Rze; wherein Rzdis C1-6 alkyl; and Rzeis C1-6 alkyl or C3-8 cycloalkyl; ^ -P(=O)-RzfRzg, wherein Rzfand Rzgare independently selected from C1-6alkyl; and ^ -P(=O)2-Rzh, wherein Rzgis C1-6 alkyl; and (b) 5 to 10 membered heteroaryl, optionally substituted with 1 to 5 substituents independently selected from a halogen atom, C1-6alkyl, and C3-8cycloalkyl.

[0006] In some embodiments of Compound 3, W is -N= or –CRa=; and Rais a hydrogen atom; X is –CRa=; and Rais a hydrogen atom; Y is -C(=O)-; R1is a hydrogen atom; R2is a hydrogen atom; R3is C1-6alkyl; R4is a hydrogen atom; R5is a hydrogen atom; R6is a hydrogen atom; R7and R8together with the carbon atom to which they are attached form a cyclopropyl, optionally substituted with 1 to 3 C1-6 alkyl; R9is a group represented by Formula H; n1 is 0;n2 is 0; Q1is phenyl, optionally substituted with 1 to 3 substituents independently selected from a halogen atom and C1-6alkyl; Q2is tetrahydropyranyl, optionally substituted with 1 to 3 C1-6alkyl; Z1is a group represented by Formula (IIIa); and Z2is C6-10 aryl, optionally substituted withindependently selected from: (a) halogen, (b) -NRzaRzb, wherein Rzaand Rzbare independently selected from a hydrogen atom and C1-6 alkyl, (c) -S(=O)(=NRzd)-Rze; wherein Rzdis C1-6alkyl; and Rzeis C1-6alkyl or C3-8cycloalkyl; and (d) -P(=O)-RzfRzg, wherein Rzfand Rzgare independently selected from C1-6 alkyl.

[0007] In some embodiments of Compound 3, W is -N= or –CRa=; and Rais a hydrogen atom; X is –CRa=; and Rais a hydrogen atom; Y is -C(=O)-; R1is a hydrogen atom; R2is a hydrogen atom; R3is C1-6alkyl; R4is a hydrogen atom; R5is a hydrogen atom; R6is a hydrogen atom; R7and R8together with the carbon atom to which they are attached form a cyclopropyl, optionally substituted with 1 to 3 C1-6 alkyl; R9is a group represented by Formula H; n1 is 0;n2 is 0; Q1is phenyl, optionally substituted with 1 to 3 substituents independently selected from a halogen atom and C1-6alkyl; Q2is tetrahydropyranyl, optionally substituted with 1 to 3 C1-6alkyl; Z1is a group represented by Formula (IIIa); and Z2is 5 to 10 membered heteroaryl,with 1 to 5 substituents independently selected from a halogen atom, C1-6alkyl, and C3-8cycloalkyl.

[0008] In some embodiments, Compound 3 is selected from: Compound 3a Compound 3b Compound 3c Compound 3d Compound 3e Compound 3f Compound 3g Compound 3h , pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.

[0009] The specific doses and treatment methodologies disclosed herein provide effective treatment options for a subject with T2DM, obesity, or overweight with at least one weight related comorbidity while providing flexible dosing options. 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). As described herein, the treatment methodologies include continuing to treat a patient who, at the initiation of a prior GLP-1 RA treatment, had at least onecondition selected from T2DM, obesity, and overweight with at least one weight related comorbidity; but who, following the prior GLP-1 RA treatment had the condition controlled such that they no longer meet one or more defining criteria of the condition, e.g., for T2DM their HbA1c may be less than 6.5%; for obesity and overweight they may have a BMI lower than characteristic of obesity or overweight.

[0010] The specific doses and treatment methodologies disclosed herein can be integrated with a treatment regimen using a GLP-1 RA such as tirzepatide or semaglutide. In some embodiments, the GLP-1 receptor NPA compound dosing methodologies disclosed herein are used directly following a prior GLP-1 RA treatment (e.g., tirzepatide or semaglutide), and maintain the body weight loss or reduced HbA1c level resulting from the prior GLP-1 RA treatment.

[0011] The doses and dose escalation methodologies disclosed herein for Compound 1 or a related compound (e.g., Compound 1a) can also be implemented with a treatment regimen using a GLP-1 receptor NPA compound selected from Compound 2 and Compounds 3a to 3h: Compound 2 Compound 3a Compound 3b Compound 3c Compound 3d Compound 3eCompound 3f Compound 3g Compound 3h GLP-1 agonists reported to be potent and / or useful for treating GLP-1 associated diseases, disorders, and conditions. See U.S. Patent No. 11,492,365; U.S. Patent No. 12,291,529; U.S. Patent No. 11,584,751; and U.S. Patent No. 12,234,236.

[0012] For example, consistent with the dose and treatment methodologies provided for Compound 1, the starting dose can be selected based on its ability to provide a therapeutic effect, such as body weight reduction or reduced HbA1c level, in patients naïve to or not directly following treatment with a prior GLP-1 RA peptide treatment, and bypassing extended dose titration regimen used in treatment naïve patients to develop tolerance to side effects, such as gastrointestinal side effects. For example, as discussed further herein (Example 5), Compound 1 can be started at a dose of 12 mg QD, shown in Phase 3 trials results to provide a 1.6% A1C reduction from baseline of 8.0% and a 6.1 % (5.5 kg) weight reduction from baseline of 90.2 kg (198.9 lbs), or higher doses. In contrast to the treatment-naïve patients in that trial where escalation doses steps of 1 mg, 3 mg, and 6 mg were used prior to the 12 mg dose, according to the present methods of treating patients directly following a prior GLP-1 RA peptide treatment to maintain an obtained therapeutic effect, the titration steps begin at a much higher dose (e.g., 12 mg QD of Compound 1 instead of 1 mg for a standard non-switching dosing regimen), thereby preventing loss of the obtained therapeutic effect that would otherwise occur if the lower Compound 1 doses were used directly following the prior GLP-1 RA peptide treatment. Similarly, directly following prior GLP-1 RA peptide treatment, other NPA compounds, and likewise other formulations of Compound 1, can be initiated at higher and more therapeutically effective doses than used for treatment-naïve patients.BRIEF DESCRIPTION OF DRAWINGS

[0013] Fig. 1 shows a clinical trial schema.

[0014] Fig. 2 shows a clinical trial schema.

[0015] Fig. 3 shows the effect of once-daily OFG as compared with placebo on body weight. In Fig. 3, least square means are presented. Panel A shows the percentage change from baseline in body weight by week (efficacy estimand). Panel B shows change from baseline in body weight (kg) by week. Panels C and D show percentage of patients achieving ≥5%, ≥10%, and ≥15% weight reduction at 26-weeks 36-weeks respectively. * = P-value <0.01 versus placebo. Doses 36 mg-1 and 36 mg-2 were combined for 36 mg and doses 45 mg-1 and 45 mg-2 were combined for 45 mg.

[0016] Fig. 4 shows a clinical trial schema.

[0017] Fig. 5 shows LS Mean change in HbA1c.

[0018] Fig. 6 shows LS Mean change in body weight.

[0019] Fig. 7 shows the percentage of participants achieving HbA1c and weight loss targets.

[0020] Fig. 8 shows a clinical trial schema. DESCRIPTION

[0021] GLP-1 RA peptides have many actions in the body that may make them effective at lowering A1C (also known as “hemoglobin A1C” or “HbA1c”) or providing weight loss. Available GLP-1 RA peptide products include: Class Medication Dosage Form GLP-1 RA Trulicity® (dulaglutide) injectable GLP-1 RA Saxenda® (liraglutide) injectable GLP-1 RA Ozempic®, Wegovy® (semaglutide) injectable GLP-1 RA Byetta® (exenatide) injectable GLP-1 RA Victoza® (liraglutide) injectable GLP-1 RA Adlyxin® (lixisenatide) injectable GLP-1 RA Rybelsus® (semaglutide) oral GLP-1 / GIP RA Mounjaro®, Zepbound® (tirzepatide) injectableHowever, available GLP-1 RA peptide products are generally administered through injections (e.g., Trulicity®, Saxenda®, Ozempic®, Wegovy®, Byetta®, Victoza®, Adlyxin®, Mounjaro®, and Zepbound®) or involve inconvenient food restrictions (e.g., Rybelsus®).

[0022] Adherence to pharmacologic therapies poses a significant challenge for treating chronic diseases. In the context of obesity and diabetes care, discontinuation of medication is pervasive, particularly when patients encounter a body weight or HbA1c plateaus after an initial reduction. Obesity and diabetes management involves diverse patient factors, including variable phenotypes and biopsychosocial considerations. Given this complexity, there is a need for different therapies that can sustain long-term weight reduction and / or reduced HbA1c levels with a tolerable side effect profile.

[0023] One option involves transitioning from an injectable medication to an oral medication. One option involves transitioning from an oral medication to a different oral medication. One option involves transitioning from an injectable peptide medication to an oral non-peptide medication. One option involves transitioning from an oral peptide medication to an oral non- peptide medication.

[0024] One option involves transitioning from an injectable GLP-1 RA to an oral GLP-1 RA. One option involves transitioning from an oral GLP-1 RA to a different oral GLP-1 RA. One option involves transitioning from an injectable peptide GLP-1 RA to an oral non-peptide GLP-1 RA. One option involves transitioning from an oral peptide GLP-1 RA to an oral non-peptide GLP-1 RA.

[0025] The dosing methodologies disclosed herein for a GLP-1 receptor NPA compound selected from Compound 1, Compound 2, and Compound 3 are effective in further lowering HbA1c level and / or further providing body weight reduction from a prior GLP-1 RA treatment such as a prior tirzepatide or semaglutide treatment. Additionally, the dosing methodologies disclosed herein are also effective in maintaining body weight reduction or reduced HbA1c levels resulting from a prior GLP-1 RA treatment such as a prior tirzepatide or semaglutide treatment. Oral administration of Compound 1, Compound 2, or Compound 3 provides advantages over injectable GLP-1 RA in that they are simple to use and can be integrated into patients’ lives and daily routines. The dosing regimens herein also provide advantages over oral peptide GLP-1 RA in that the GLP-1 receptor NPA compound can be taken at any time of theday with or without food, which provides improved convenience and compliance, and reduces concerns about adequate drug absorption that affect orally delivered peptides. The oral administration dosing methodologies disclosed herein involve no, reduced, or minimal dose escalations before reaching a maintenance dose, which results in a favorable treatment related side effect profile and improved efficacy such as in maintaining the treatment effect of a prior GLP-1 RA.

[0026] Peptides offer several advantages over small molecules, including high specificity and good efficacy. Their larger size and more flexible backbone enable them to act as potent inhibitors of protein-protein interactions. By contrast, small molecules generally have low specificity compared with peptide drugs. Moreover, it is generally difficult for small molecule drugs to inhibit large surface interactions, such as protein-protein interactions. Wang, L. et al. Sig. Transduct. Target Ther. 7, 48 (2022). Without wishing to be bound by theory, it is believed that dosing regimens disclosed herein comprising switching from a peptide GLP-1 RA (e.g., semaglutide or tirzepatide) to a non-peptide GLP-1 RA (e.g., Compound 1, Compound 2, or Compound 3) nevertheless result in superior long-term maintenance of body weight reduction and / or reduced HbA1c levels. Without wishing to be bound by theory, it is believed that a GLP- 1 receptor NPA compound can maintain the reduced body weight and / or reduced HbA1c levels of a prior peptide GLP-1 RA treatment and can do so with no, reduced, or minimal dose escalations before reaching a maintenance dose. For example, it is believed that switching from once-weekly injectable semaglutide treatment to daily oral Compound 1 treatment in subjects with obesity or overweight and at least one weight related comorbidity (without T2D) can lead to superior long-term maintenance of body weight reduction and / or reduced HbA1c levels compared to switching to placebo.

[0027] Therapeutics that target multiple receptors in the incretin pathway have proven to be more effective at reducing body weight and / or HbA1c levels than therapeutics that target single receptors. For example, tirzepatide, an injectable dual GLP-1 / GIP RA, has been shown to have more pronounced effects than semaglutide, an injectable GLP-1 RA, in reducing body weight and HbA1c levels in people with type 2 diabetes. Karagiannis, T. et al. Diabetologia 67, 1206– 1222 (2024). Without wishing to be bound by theory, it is nevertheless believed that dosing regimens disclosed herein comprising switching from a dual GLP-1 / GIP RA (e.g., tirzepatide) to a GLP-1-only RA (e.g., Compound 1, Compound 2, or Compound 3) result in superior long-termmaintenance of body weight reduction and / or reduced HbA1c levels with no, reduced, or minimal dose escalations before reaching a maintenance dose. Accordingly, it is believed that a GLP-1-only RA can maintain the reduced body weight and / or reduced HbA1c levels of a prior dual GLP-1 / GIP RA such as tirzepatide. For example, it is believed that switching from once- weekly injectable tirzepatide treatment to daily oral Compound 1 treatment with no, reduced, or minimal dose escalations before reaching a maintenance dose in subjects with obesity or overweight and at least one weight related comorbidity (without T2D) can lead to superior long- term maintenance of body weight reduction and / or reduced HbA1c levels compared to switching to placebo.

[0028] Without being bound by theory, it is believed that transitioning from any peptide medications targeting the incretin pathway to the non-peptide medications disclosed herein, would similarly result in superior long-term maintenance of body weight reduction and / or reduced HbA1c levels with no, reduced, or minimal dose escalations before reaching a maintenance dose.

[0029] Without being bound by theory, the inventors hypothesize that transitioning from any medications directed to multiple targets in the incretin pathway to the single-target medications disclosed herein, would similarly result in superior long-term maintenance of body weight reduction and / or reduced HbA1c levels with no, reduced, or minimal dose escalations before reaching a maintenance dose. Dosing Regimen

[0030] The disclosure provides a method of treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, the method comprising starting with orally administering to the subject a first therapeutically effective dose level of a GLP-1 receptor NPA compound for a first duration.

[0031] In some embodiments, the subject who has received a prior GLP-1 RA treatment has completed the prior GLP-1 RA treatment.

[0032] In some embodiments, the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, and Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. In some embodiments, the Compound 3 is selected from Compounds 3a to 3h. In some embodiments, the GLP-1 receptor NPA compound is Compound 1. In some embodiments, the GLP-1 receptor NPA compound is Compound 1a. In someembodiments, the GLP-1 receptor NPA compound is a pharmaceutically acceptable salt of Compound 1a. In some embodiments, the GLP-1 receptor NPA compound is a solvate of a pharmaceutically acceptable salt of Compound 1a. In some embodiments, the GLP-1 receptor NPA compound is a hydrate of a pharmaceutically acceptable salt of Compound 1a. In some embodiments, the GLP-1 receptor NPA compound is Compound 1a hemicalcium salt hydrate (Compound 1a 0.5 Ca hydrate). In some embodiments, the GLP-1 receptor NPA compound is Compound 2. In some embodiments, the GLP-1 receptor NPA compound is selected from Compounds 3a to 3h.

[0033] In some embodiments, administering the first therapeutically effective dose level for the first duration is sufficient to substantially maintain the therapeutic effect. In some embodiments, administering the first therapeutically effective dose level for the first duration is insufficient to substantially maintain the therapeutic effect.

[0034] In some embodiments, the first duration is about 2 weeks. In some embodiments, the first duration is at least about 2 weeks. In some embodiments, the first duration is about 4 weeks. In some embodiments, the first duration is at least about 4 weeks. In some embodiments, the first duration is about 26 weeks. In some embodiments, the first duration is at least about 26 weeks. In some embodiments, the first duration is about 48 weeks. In some embodiments, the first duration is at least about 48 weeks. In some embodiments, the first duration is about 52 weeks. In some embodiments, the first duration is at least about 52 weeks.

[0035] In some embodiments, the method of treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment further comprises orally administering a second therapeutically effective dose level of the GLP-1 receptor NPA compound for a second duration, wherein the second therapeutically effective dose level is greater than the first therapeutically effective dose level.

[0036] In some embodiments, the second therapeutically effective dose level for the second duration is sufficient to substantially maintain the therapeutic effect. In some embodiments, the second therapeutically effective dose level for the second duration is insufficient to substantially maintain the therapeutic effect.

[0037] In some embodiments, the second duration is about 2 weeks. In some embodiments, the second duration is at least about 2 weeks. In some embodiments, the second duration is about 4 weeks. In some embodiments, the second duration is at least about 4 weeks. In someembodiments, the second duration is about 26 weeks. In some embodiments, the second duration is at least about 26 weeks. In some embodiments, the second duration is about 48 weeks. In some embodiments, the second duration is at least about 48 weeks. In some embodiments, the second duration is about 52 weeks. In some embodiments, the second duration is at least about 52 weeks.

[0038] In some embodiments, the first duration and the second duration are a combined period selected from about 36 weeks, about 40 weeks, about 48 weeks, about 52 weeks, about 72 weeks, and about 104 weeks. In some embodiments, the first duration and the second duration are a combined period selected from at least about 36 weeks, at least about 40 weeks, at least about 48 weeks, at least about 52 weeks, at least about 72 weeks, and at least about 104 weeks. In some embodiments, the first duration and the second duration are a combined period of about 36 weeks. In some embodiments, the first duration and the second duration are a combined period of at least about 36 weeks. In some embodiments, the first duration and the second duration are a combined period of about 40 weeks. In some embodiments, the first duration and the second duration are a combined period of at least about 40 weeks. In some embodiments, the first duration and the second duration are a combined period of about 48 weeks. In some embodiments, the first duration and the second duration are a combined period of at least about 48 weeks. In some embodiments, the first duration and the second duration are a combined period of about 52 weeks. In some embodiments, the first duration and the second duration are a combined period of at least about 52 weeks. In some embodiments, the first duration and the second duration are a combined period of about 72 weeks. In some embodiments, the first duration and the second duration are a combined period of at least about 72 weeks. In some embodiments, the first duration and the second duration are a combined period of about 104 weeks. In some embodiments, the first duration and the second duration are a combined period of at least about 104 weeks.

[0039] In some embodiments, the method of treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment further comprises orally administering a third therapeutically effective dose level of the GLP-1 receptor NPA compound for a third duration, wherein the third therapeutically effective dose level is greater than the second therapeutically effective dose level.

[0040] In some embodiments, administering the third therapeutically effective dose level for the third duration is sufficient to substantially maintain the therapeutic effect.

[0041] In some embodiments, the third duration is about 2 weeks. In some embodiments, the third duration is at least about 2 weeks. In some embodiments, the third duration is about 4 weeks. In some embodiments, the third duration is at least about 4 weeks. In some embodiments, the third duration is about 26 weeks. In some embodiments, the third duration is at least about 26 weeks. In some embodiments, the third duration is about 48 weeks. In some embodiments, the third duration is at least about 48 weeks. In some embodiments, the third duration is about 52 weeks. In some embodiments, the third duration is at least about 52 weeks.

[0042] In some embodiments, the first duration, the second duration, and third duration are a combined period selected from about 36 weeks, about 40 weeks, about 48 weeks, about 52 weeks, about 72 weeks, and about 104 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period selected from at least about 36 weeks, at least about 40 weeks, at least about 48 weeks, at least about 52 weeks, at least about 72 weeks, and at least about 104 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of about 36 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of at least about 36 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of about 40 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of at least about 40 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of about 48 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of at least about 48 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of about 52 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of at least about 52 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of about 72 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of at least about 72 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of about 104 weeks. In some embodiments, the first duration, the second duration, and third duration are a combined period of at least about 104 weeks.

[0043] In some embodiments, the GLP-1 receptor NPA compound is Compound 1 and the first therapeutically effective dose level of Compound 1 is 12 mg QD. In some embodiments, the GLP-1 receptor NPA compound is Compound 1 and the second therapeutically effective dose level of Compound 1 is 24 mg QD. In some embodiments, the GLP-1 receptor NPA compound is Compound 1 and the third therapeutically effective dose level of Compound 1 is 36 mg QD. In some embodiments, the GLP-1 receptor NPA compound is Compound 1, the first therapeutically effective dose level of Compound 1 is 12 mg QD, the second therapeutically effective dose level of Compound 1 is 24 mg QD, and the third therapeutically effective dose level of Compound 1 is 36 mg QD.

[0044] In some embodiments, each recited dose of Compound 1 (including pharmaceutically acceptable salts thereof, hydrates of Compound 1, and hydrates of the pharmaceutically acceptable salts of Compound 1) is provided on a free acid equivalent amount of Compound 1.

[0045] In some embodiments, the prior GLP-1 RA treatment comprises treatment with a GLP-1 RA peptide. In some embodiments, the prior GLP-1 RA treatment comprises treatment with a GLP-1 RA peptide selected from tirzepatide or semaglutide. In some embodiments, the prior GLP-1 RA treatment comprises treatment with tirzepatide. In some embodiments, the prior GLP-1 RA treatment comprises treatment with semaglutide. In some embodiments, the prior GLP-1 RA treatment comprises treatment with a subcutaneously administered GLP-1 RA peptide.

[0046] In some embodiments, the prior GLP-1 RA treatment was administered in subject having T2DM, obesity, and / or overweight with at least one weight related comorbidity.

[0047] In some embodiments, the subject reached a body weight plateau from the prior GLP-1 RA treatment.

[0048] In some embodiments, the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 5%, or at least 10%, or at least 15%. In some embodiments, the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 5%. In some embodiments, the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 10%. In some embodiments, the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 15%.

[0049] In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to substantially maintain a body weight reduction provided by the prior GLP-1 RA treatment.

[0050] In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain at least 70%, or at least 80%, or at least 90% of a body weight reduction provided by the prior GLP-1 RA treatment. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain at least 70% of a body weight reduction provided by the prior GLP-1 RA treatment. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain at least 80% of a body weight reduction provided by the prior GLP-1 RA treatment. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain at least 90% of a body weight reduction provided by the prior GLP-1 RA treatment.

[0051] In some embodiments, the subject reached a plateau in HbA1c level from the prior GLP- 1 RA treatment.

[0052] In some embodiments, the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 7.5%, or no more than about 7.0%, or no more than about 6.5%. In some embodiments, the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 7.5%. In some embodiments, the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 7.0%. In some embodiments, the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 6.5%.

[0053] In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to substantially maintain an HbA1c level provided by the prior GLP-1 RA treatment.

[0054] In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 15% greater, no more than about 10% greater, or no more than about 5% greater than an HbA1c level provided by the prior GLP-1 RA treatment. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 15% greater than an HbA1c level provided by the prior GLP-1 RAtreatment. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 10% greater than an HbA1c level provided by the prior GLP-1 RA treatment. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 5% greater than an HbA1c level provided by the prior GLP-1 RA treatment.

[0055] In some embodiments, the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 7.5%, or no more than about 7.0%, or no more than about 6.5%. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 7.5%. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 7.0%. In some embodiments, administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 6.5%.

[0056] In some embodiments, orally administering the first therapeutically effective dose level of a GLP-1 receptor NPA compound is started within about the same time period as an administration frequency of the prior GLP-1 RA treatment (e.g., within about 1 week where the administration frequency of the prior GLP-1 RA treatment was once weekly), within about twice the time period of the administration frequency of the prior GLP-1 RA treatment, within about three times the time period of the administration frequency of the prior GLP-1 RA treatment, or within about four times the time period of the administration frequency of the prior GLP-1 RA treatment. In some embodiments, orally administering the first therapeutically effective dose level of a GLP-1 receptor NPA compound is started within about 1 to 4 weeks of discontinuing the prior GLP-1 RA treatment. In some embodiments, orally administering the first therapeutically effective dose level of a GLP-1 receptor NPA compound is started within about 1 to 3 weeks of discontinuing the prior GLP-1 RA treatment. In some embodiments, orally administering the first therapeutically effective dose level of a GLP-1 receptor NPA compound is started within about 1 to 2 weeks of discontinuing the prior GLP-1 RA treatment. In some embodiments, orally administering the first therapeutically effective dose level of a GLP-1receptor NPA compound is started within about 1 week of discontinuing the prior GLP-1 RA treatment.

[0057] In some embodiments, dose levels and dosing frequency of the GLP-1 receptor NPA compound are selected to provide an acceptable adverse event profile.

[0058] If the first therapeutically effective dose level is not administered within the specified time, dose amounts and timing of doses in the methodologies described herein may be adjusted to achieve an acceptable adverse event profile and / or efficacy.

[0059] In some embodiments, administering the GLP-1 receptor NPA compound is used as an adjunct to diet and exercise.

[0060] The disclosure also provides a GLP-1 receptor NPA compound for use in treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, wherein the use comprises starting with orally administering to the subject a first therapeutically effective dose level of the GLP-1 receptor NPA compound for a first duration; and wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.

[0061] The disclosure also provides a use of a GLP-1 receptor NPA compound in the manufacture of a medicament for treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, wherein the use comprises orally administering a first therapeutically effective dose level of a GLP-1 receptor NPA compound for a first duration; and wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. Dosage Forms

[0062] In some embodiments, the GLP-1 receptor NPA compounds of the present disclosure are formulated into a suitable pharmaceutical dosage form. Examples of such pharmaceutical dosage forms include a tablet, a capsule, granules, powders, subtle granules, pills, aqueous or non-aqueous solution or suspension.

[0063] The various pharmaceutical dosage forms may be produced by well-known methods, and in some embodiments include combining a GLP-1 receptor NPA compound of the presentdisclosure with one or more pharmaceutically acceptable additives. Examples of such additives include, for example, an excipient, a lubricant, a binding agent, a disintegrator, a stabilizing agent, correctives, a base, a dispersant, a diluent, a surfactant, and an emulsifying agent, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, Twenty-third edition, Academic Press (2021) discloses various carriers used in formulating pharmaceutically acceptable compositions and known known techniques for preparing such compositions.

[0064] Examples of suitable excipients include starch (including potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.

[0065] Examples of suitable lubricants include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, camauba wax, and paraffin.

[0066] Examples of suitable binding agents include polyvinyl pyrrolidone, macrogol, and similar compounds.

[0067] Examples of suitable disintegrators include chemically modified starch and cellulose, such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and similar compounds.

[0068] Examples of suitable stabilizers include para-oxybenzoates such as methyl paraben, and propyl paraben; benzalkonium chloride; phenols such as phenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0069] Examples of suitable correctives include sweeteners, acidulants, and flavors.

[0070] Examples of suitable bases include fats such as lard; vegetable oil such as olive oil and sesame oil; higher alcohols such as stearyl alcohol, and cetanol; animal oil; lanolin acid; Vaseline; paraffin; bentonite; glycerin; and glycol oil.

[0071] Examples of suitable dispersants include cellulose derivative (Arabic rubber, tragacanth, methyl cellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbate, and sorbitan fatty acid ester.

[0072] Examples of suitable diluents include phenol, chlorocresol, purified water, distilled water, etc.

[0073] Examples of suitable surfactants or emulsifiers include polysorbate polyoxyl 40 stearate and lauromacrogol.

[0074] In some embodiments, a GLP-1 receptor NPA compound of the present disclosure is formulated into capsules. In some embodiments, the capsules contain a solid formulation. In some embodiments, the capsules contain a liquid formulation.

[0075] In some embodiments, a GLP-1 receptor NPA compound of the present disclosure is formulated into tablets. In some embodiments, the tablets are contained in capsules.

[0076] Unless otherwise noted, the doses disclosed herein are based on capsule doses. Exemplary equivalent capsule and tablet doses are provided below. Compound 1a Capsule Dose Equivalent Compound 1a Tablet Dose (mg, free acid equivalent) (mg, free acid equivalent) 1 mg 0.8 mg 3 mg 2.5 mg 6 mg 5.5 mg 12 mg 9 mg 24 mg 14.5 mg 36 mg 17.2 mg

[0077] The equivalent tablet doses to 1 mg, 3 mg, 6 mg, 12 mg, 24 mg and 36 mg Compound 1a capsules were determined in a relative bioavailability assessment as summarized in Example 3b. Definitions

[0078] The present disclosure is further described below without being limited thereby.

[0079] As used herein, the terms “GCG receptor agonist” and “GCG RA” are used interchangeably to refer to a molecule that functions as a glucagon receptor agonist.

[0080] As used herein, the terms “GIP receptor agonist” and “GIP RA” are used interchangeably to refer to a molecule that functions as a glucose-dependent insulinotropic polypeptide receptor agonist.

[0081] As used herein, the terms “GLP-1 receptor agonist” and “GLP-1 RA” are used to refer to a molecule that functions as a glucagon-like peptide-1 receptor agonist. Unless otherwise noted, for example by referring to a “GLP-1-only RA,” such GLP-1 RA molecules may also comprise additional functions, such as a GCG RA function and / or a GIP RA function. In some embodiments, the GLP-1 RA is a dual agonist. In some embodiments, the GLP-1 RA is a dual GLP-1 / GIP RA. In some embodiments, the GLP-1 RA is a dual GLP-1 / GCG RA. In someembodiments, the GLP-1 RA is a GLP-1 / GIP / GCG triagonist. In some embodiments, the GLP-1 RA is selected from semaglutide and tirzepatide.

[0082] As used herein, the term “GLP-1 receptor NPA compound” means glucagon-like peptide-1 non-peptide agonist compound. The term “GLP-1 receptor NPA compound” encompasses the compound per se, as well as various forms of the compound, including pharmaceutically acceptable salts of the compound, solvates of the compound, and solvates of the pharmaceutically acceptable salts of the compound, including hydrates. Tautomers, rotational isomers (i.e., rotamers), diastereomers, and enantiomers are within the scope of the disclosure.

[0083] The disclosure contemplates isotope-substituted compounds in which at least one atom is substituted with an atom having the same atomic number (proton number) and a different mass number (sum of protons and neutrons). Examples of isotopes contemplated by the compound of the present disclosure include substitutions of one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorous atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F, and36Cl. In some embodiments, the isotope is a radioisotope which emits radiation as it decays, such as3H or14C. In some embodiments, the isotopes are stable isotopes that neither decay nor change in their amount, nor have radioactivity, and so the isotopes can be safely administered to a subject. When the atom constituting the compound of the present disclosure is an isotope, it may be transformed according to a common method by replacing a reactant / reagent used in synthesis with a reactant / reagent containing a corresponding isotope.

[0084] As used herein, “Compound 1” refers to the following structure: , pharmaceutically acceptable saltsof the foregoing. Compound 1 can be synthesized according to the methods disclosed in WO 2018 / 056453 and U.S. Patent No. 10,858,356, which are incorporated by reference in their entirety.

[0085] As used herein, “Compound 1a” refers to the following structure: , pharmaceutically acceptable salts any of the foregoing. Compound 1aand methods of making Compound are 2018 / 056453 and U.S. Patent No. 10,858,356, which are incorporated by reference in their entirety.

[0086] As used herein, “OFG” means the free acid form of Compound 1a. “OFG” and “orforglipron” are used interchangeably.

[0087] As used herein, “Compound 2” refers to the following structure: pharmaceutically acceptable saltsany of the foregoing. Compound 2 can be synthesized according to methods disclosed in U.S. Patent No. 11,584,751, which is incorporated by reference in its entirety.

[0088] As used herein, “Compound 3” refers to the following structure: ,pharmaceutically acceptable salts thereof, and solvates of any of the foregoing, wherein: W is -N= or –CRa=; Rais selected from a hydrogen atom and a halogen atom; X is -N= or –CRa=; Rais selected from a hydrogen atom and a halogen atom; Y is selected from -C(=O)- and -CHRa-; R1is selected from a hydrogen atom and C1-6 alkyl; R2is selected from a hydrogen atom and C1-6 alkyl; R3is selected from a hydrogen atom and C1-6alkyl; R4is selected from a hydrogen atom and C1-6alkyl; R5is selected from a hydrogen atom and C1-6 alkyl; R6is selected from a hydrogen atom and C1-6alkyl; R7and R8together with the carbon atom to which they are attached form a C3-15cycloalkane ring, optionally substituted with 1 to 3 C1-6 alkyl; R9is selected from a group represented by Formula (IIa), (IIb), (IIc), and (IId): ;from a hydrogen atom and C1-6alkyl; n1 is an integer of 0 to 3; n2 is an integer of 0 to 5; Q1is C6-10aryl, optionally substituted with 1 to 5 substituents independently selected from a halogen atom and C1-6 alkyl; Q2is a 3 to 12 membered heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from a halogen atom and C1-6alkyl; O ***Z1is a group represented by Formula (IIIa); and Z2is selected from:(a) C6-10 aryl, optionally substituted with 1 to 3 substituents independently selected from: ^ halogen,^ -NRzaRzb, wherein Rzaand Rzbare independently selected from a hydrogen atom and C1-6 alkyl, ^ -C(=O)-NRzaRzb, ^ -S(=O)0-2-Rzc, wherein Rzcis a hydrogen atom, C1-6alkyl, or C3-8cycloalkyl; ^ -S(=O)(=NRzd)-Rze; wherein Rzdis C1-6 alkyl; and Rzeis C1-6 alkyl or C3-8 cycloalkyl; ^ -P(=O)-RzfRzg, wherein Rzfand Rzgare independently selected from C1-6alkyl; and ^ -P(=O)2-Rzh, wherein Rzgis C1-6alkyl; and (b) 5 to 10 membered heteroaryl, optionally substituted with 1 to 5 substituents independently selected from a halogen atom, C1-6 alkyl, and C3-8 cycloalkyl.

[0089] As used herein, “halogen” means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

[0090] As used herein, “alkyl” means a straight chain or branched chain alkyl group. As used herein, “C1-6 alkyl” means a straight chain or branched chain alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1- methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4- methylpentyl, and 2-ethylbutyl.

[0091] As used herein, “cycloalkyl” means a monovalent group derived by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon. As used herein, “C3-15cycloalkyl” means a monovalent group having 3 to 15 carbon atoms derived by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When two groups together form a C3-15 cycloalkane ring, the resulting group is bivalent. Examples include cyclopropane-1, 1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl, and cyclooctane-1,1-diyl.

[0092] When the two groups on two carbon atoms are combined to form a C3-8 carbocyclic ring, the resulting ring forms a condensed ring. Examples include ring structures such that the two carbon atoms are linked by -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-.

[0093] In addition, the cycloalkane ring, the carbocyclic ring, the cyclic hydrocarbon in the cycloalkyl may be a cross-linked ring. Examples of cross-linked rings in the C3-15 cycloalkyl include bicyclo[1.1.0]butane, bicyclo[3.2.l]octane, bicyclo[5.2.0]nonane, bicyclo[4.3.2]undecane, tricyclo[2.2.1.02,6]heptane, tricyclo[4.3.1.12,5]undecane, tricyclo[3.3.1.13,7]decane (adamantane), tricyclo[3.3.l.l3,7]decane-2-ylidene (2- adamantylidene), pentacyclo[4.2.0.02,5.03,8.04,7]octane (cubane), and examples of C3-15 cycloalkyl include bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, bicyclo[4.3.2]undecyl, tricyclo[2.2.1.02,6]heptyl, tricyclo[4.3.1.12,5]undecyl, adamantyl, 2- adamantylidenyl, and cubanyl.

[0094] As used herein, “aryl” means an aromatic carbocyclic group, which may contain a non- aromatic portion in addition to the aromatic portion. As used herein, “C6-10aryl” means an aromatic carbocyclic group having six to ten carbon atoms, which may contain a non-aromatic portion in addition to the aromatic portion.

[0095] As used herein, “heterocyclyl” means a non-aromatic cyclic group comprising one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms, and it may be completely saturated or partly unsaturated. The ring may be a monocyclic ring, a bicyclic ring or a spirocyclic ring of 3 to 12 members. Examples include oxetanyl, azetidinyl, 3,7-dioxa-9- azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6- diazaspiro[3.3]heptyl, 2-thia-6-azaspiro[3.3]heptyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl, indolinyl, isoindolinyl, tetrahydroindolinyl, quinuclidinyl, azepinyl, and tropanyl.

[0096] As used herein, “heteroaryl” means an aromatic 5 to 10 membered cyclic group that comprises, among atoms constituting a ring, one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and it may contain a nonaromatic portion in addition to the aromatic portion. The ring may be monocyclic, or it may be a bicyclic heteroaryl that is condensed with a benzene ring or a monocyclic heteroaryl ring. Examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl , triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzooxazolyl,benzooxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, benzoisoxazolyl, and benzoisothiazolyl.

[0097] As used herein, “Compound 3a” refers to the following structure: , pharmaceutically acceptable salts of the foregoing. Compound 3acan be synthesized according to methods disclosed in U.S. Patent No. 11,492,365, which is incorporated by reference in its entirety.

[0098] As used herein, “Compound 3b” refers to the following structure: , pharmaceutically acceptableof the foregoing. Compound 3b can be synthesized according to methods disclosed in U.S. Patent No. 12,234,236, which is incorporated by reference in its entirety.

[0099] As used herein, “Compound 3c” refers to the following structure: ,pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. Compound 3c can be synthesized according to methods disclosed in U.S. Patent No. 12,234,236, which is incorporated by reference in its entirety.

[0100] As used herein, “Compound 3d” refers to the following structure: , pharmaceutically acceptable of the foregoing. Compound 3dcan be synthesized according to methods disclosed in U.S. Patent No. 12,234,236, which is incorporated by reference in its entirety.

[0101] As used herein, “Compound 3e” refers to the following structure: , pharmaceutically acceptable saltsof the foregoing. Compound 3e can be synthesized according to methods disclosed in U.S. Patent No. 12,291,529, which is incorporated by reference in its entirety.

[0102] As used herein, “Compound 3f” refers to the following structure: ,pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. Compound 3f can be synthesized according to methods disclosed in U.S. Patent No. 12,291,529, which is incorporated by reference in its entirety.

[0103] As used herein, “Compound 3g” refers to the following structure: , pharmaceutically acceptable of the foregoing. Compound 3gcan be synthesized according to methods disclosed in U.S. Patent No. 12,291,529, which is incorporated by reference in its entirety.

[0104] As used herein, “Compound 3h” refers to the following structure: , pharmaceutically acceptableof the foregoing. Compound 3h can be synthesized according to methods disclosed in U.S. Patent No. 12,291,529, which is incorporated by reference in its entirety.

[0105] As used herein, the term “optionally substituted” is used interchangeably with the phrase “unsubstituted or substituted.” The GLP-1 receptor NPA compounds disclosed herein can be optionally substituted with one or more substituents. As disclosed herein, the variables Q2, Z2, and other variables contained in Compound 3 encompass specific optionally substituted groups, such as C6-10aryl. Unless otherwise noted, each of the specific groups for the Q2, Z2, and other variables contained in Compound 3 can be optionally substituted with one or more substituents. Each substituent of a specific group can be further optionally substituted with one to three ofhalogen, cyano, oxo (=O), alkoxy, hydroxy, amino, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. For example, if Z2is 5 to 10 membered heteroaryl, optionally substituted with C1-6 alkyl, the C1-6 alkyl can be optionally substituted with one to three of halogen, cyano, oxo (=O), alkoxy, hydroxy, amino, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0106] As used herein, a “therapeutically effective dose” of a GLP-1 receptor NPA means an amount sufficient to cure, alleviate, or partially arrest the clinical manifestations of a given disease or state and its complications. The effective amount for each purpose may depend on the severity of the disease or condition as well as the weight and general state of the subject. When used in the context of maintaining a treatment effect of a prior treatment, the term “effective amount” means an amount (such as an average daily amount) effective to substantially maintain the prior treatment effect.

[0107] As used herein, a “therapeutic endpoint” means a targeted outcome of a treatment that is used to determine the efficacy of the treatment.

[0108] As used herein, a “treatment effect” is the effect of the treatment on a therapeutic endpoint.

[0109] As used herein, an “acceptable adverse event profile” means that any side effects resulting from a drug or treatment is considered reasonable in relation to potential benefits from the drug or treatment.

[0110] As used herein, the term “maximum tolerated dose” or “MTD” means the highest dose of a drug or treatment that does not cause side effects necessitating termination of the treatment.

[0111] As used herein, the terms “about” and “approximately,” and the symbol “~,” when used in connection with values or ranges of amounts, masses, volumes, lengths,durations, reaction temperatures, doses, weight percentages, etc. refers to values or ranges that are approximate or are close to the recited values or ranges, with an acceptable error for a particular value or range as determined by a person of skill in the art, such that the embodiment may perform as intended. In some embodiments, the terms “about” and “approximately” mean within 20% of a given value or range. When used in the context of milligram doses, the term “about” means ±15%. When used in the context of a period greater than 36 weeks of treatment, the term “about” means ±2 weeks. When used in the context of a period greater than 12 weeks up to and including 36 weeks, the term “about” means ±1 week. When used in the context of a period of 1 week up to and including 12 weeks, the term “about” means ±2 days. When used in the contextof minutes, the term “about” means ±5 minutes. When used in the context of HbA1c level, the term “about” means ±15%. When used in the context of percentage change in HbA1c level, the term “about” means ±0.2%. When used in the context of maintaining a prior treatment effect, the term “approximately” means 15%.

[0112] As used herein, the term “substantially maintain” in the context of a treatment with a GLP-1 receptor NPA compound administered following a prior GLP-1 RA treatment means maintaining at least about 80% of a treatment effect provide by the prior GLP-1 RA treatment. For example, “substantially maintain” includes maintaining about ≥80%, about ≥85%, about ≥90%, and about ≥95% of the treatment effect provided by the prior GLP-1 RA treatment. In the context of weight loss, “substantially maintain” can include maintaining a body weight reduction of about ≥5%, about ≥10%, about ≥15%, or about ≥20% provided by the prior treatment. In the context of an HbA1c level reduced after a prior treatment, “substantially maintain” can include maintaining an HbA1c level of no more than about 7.5%, or no more than about 7.0%, or no more than about 6.5%.

[0113] As used herein, the terms “body weight plateau” and “BW plateau” mean less than 5% body weight change (gain or loss) from baseline prior to the start of GLP-1 receptor NPA treatment. In some embodiments, body weight plateau occurs over a period of 12 weeks, e.g., between week 60 and week 72 of a prior GLP-1 RA treatment.

[0114] As used herein, the term “weight-related comorbidity” means a medical condition that individuals with obesity or overweight are at higher risk of developing due to their weight. In some embodiments, the weight-related comorbidity is selected from hypertension, dyslipidemia, cardiovascular disease, and obstructive sleep apnea.

[0115] As used herein, the term “treatment” or “treating” means the management and care of a subject for the purpose of combating a condition, such as a disease or a disorder. In some embodiments, the term “treatment” or “treating” is intended to include the full spectrum of treatments for a given condition from which the subject is suffering, such as administration of an active GLP-1 receptor NPA to alleviate the symptoms or complications; to delay the progression of a disease, disorder, or condition; or to cure or eliminate the disease, disorder, or condition.

[0116] As used herein, the term “total treatment period” comprises GLP-1 receptor NPA dose escalation and GLP-1 receptor NPA dose maintenance.

[0117] As used herein, the term “received,” when used in the context of prior treatment with a GLP-1 RA, means a subject was administered at least one dose of the GLP-1 RA.

[0118] As used herein, the term “completed,” when used in the context of prior treatment with a GLP-1 RA, means a subject achieved a treatment goal. A subject that has completed a prior treatment also has received a prior treatment. However, a subject that has received a prior treatment may not have completed a prior treatment if a treatment goal was not met.

[0119] As used herein, a “treatment goal” means a subject reached a desired or intended effect (e.g., a body weight plateau or an HbA1c level of no more than 7.0%) after receiving a prior treatment and / or a subject received a prior treatment for a predetermined number of doses and / or for a predetermined duration. The treatment goal may include at least one of a specific reduction in HbA1c, a specific amount of weight loss, or some other therapeutic endpoint.

[0120] As used herein, the term “placebo administration” means administering an equivalent dosage form containing a non-active ingredient.

[0121] As used herein, the terms “dose escalation” and “escalation dose” are used interchangeably with “dose titration” and “titration dose,” respectively. Similarly, dose “escalation” and “titration” are used interchangeably.

[0122] As used herein, the terms “escalating” and “increasing” when referring to changing a dose are used interchangeably.

[0123] As used herein, the term “at the start of the treatment” means the time point of the start of a dose escalation. The weight or HbA1C level of a subject at the start of a treatment is sometimes referred to as the baseline weight or baseline HbA1C level of the subject.

[0124] As used herein, the term “QD” means “once daily.”

[0125] As used herein, the term “QW” means “once a week.”

[0126] As used herein, the term “T2D” means “type 2 diabetes” and “T2DM” means “type 2 diabetes mellitus.”

[0127] As used herein, “weight loss” and “weight reduction” are used interchangeably.

[0128] As used herein, the term “free acid equivalent amount” means an amount of an active ingredient measured as if it were in its free acid (i.e., protonated) form, even if the active ingredient is present in another form, such as a pharmaceutically acceptable salt and / or a solvate or hydrate thereof.Exemplary Embodiments

[0129] Exemplary embodiments of the disclosure include: 1. A method for treating a subject with T2DM, obesity, or overweight with at least one weight related comorbidity in need of such treatment with Compound 1, wherein the subject has completed a tirzepatide or semaglutide treatment prior to an administration of Compound 1, comprising: an oral administration of Compound 1 having the following structure: , or a pharmaceutically acceptableof the compound or the pharmaceutically acceptable salt, to the subject according to the following dosing schedule: starting at a dose of 12 mg QD, and administering at this dose for a minimum of about 2 weeks; escalating to a dose of 24 mg QD, and administering at this dose for a minimum of about 2 weeks; and escalating to a dose of 36 mg QD, and administering at this dose as a maintenance dose for at least 4 weeks; provided that if the maximum tolerated dose (MTD) is reached at 24 mg QD, then no further dose escalation is required and the 24 mg QD MTD dose is administered as a maintenance dose for at least 4 weeks. 2. The method of embodiment 1, comprising: an oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, to the subject according to the following dosing schedule: starting at a dose of 12 mg QD, and administering at this dose for about 4 weeks;escalating to a dose of 24 mg QD, and administering at this dose for about 4 weeks; and escalating to a dose of 36 mg QD, and administering at this dose as a maintenance dose for at least 4 weeks; provided that if the maximum tolerated dose (MTD) is reached at 24 mg QD, then no further dose escalation is required and the 24 mg QD MTD dose is administered as a maintenance dose for at least 4 weeks. 3. The method of any one of embodiments 1-2, wherein Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, is administered to the subject for a minimum total treatment period selected from about 36 weeks, about 40 weeks, about 52 weeks, about 72 weeks, and about 104 weeks; and wherein the total treatment period comprises Compound 1 dose escalations and dose maintenance. 4. The method of any one of embodiments 1-3, wherein 24 mg QD of Compound 1 is the MTD dose and the 24 mg QD MTD dose is administered as a maintenance dose for about 48 weeks. 5. The method of any one of embodiments 1-3, wherein dose escalation during Compound 1 treatment continues to 36 mg QD dose and the 36 mg QD dose is administered as a maintenance dose for about 44 weeks. 6. The method of any one of embodiments 1-5 for treating a patient with obesity or overweight with at least one weight related comorbidity, wherein: the subject has reached a body weight plateau at the end of the tirzepatide treatment; or the subject has reached a body weight plateau at the end of the semaglutide treatment. 7. The method of any one of embodiments 1-6, wherein: the tirzepatide treatment comprises administering at least one escalation dose of tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 2 weeks, and thereafter administering a maintenance dose of tirzepatide, or a pharmaceutically acceptable salt thereof, for at least 4 weeks;wherein the escalation dose is selected from 2.5 mg QW, 5 mg QW, 7.5 mg QW, 10 mg QW, and 12.5 mg QW; and wherein the maintenance dose is selected from 10 mg QW and 15 mg QW; provided that if the maximum tolerated dose (MTD) is reached at 10 mg QW, then no further dose escalation is required and the 10 mg QW MTD dose is administered as a maintenance dose for at least 4 weeks. 8. The method of embodiment 7, wherein the tirzepatide treatment comprises: starting at a dose of 2.5 mg QW of tirzepatide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks; escalating to a dose of 5 mg QW of tirzepatide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks; escalating to a dose of 7.5 mg QW of tirzepatide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks; escalating to a dose of 10 mg QW of tirzepatide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks; escalating to a dose of 12.5 mg QW of tirzepatide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks; and escalating to a dose of 15 mg QW of tirzepatide, or a pharmaceutically acceptable salt thereof, and administering at this dose for at least 4 weeks; provided that if the maximum tolerated dose (MTD) is reached at 10 mg QW, then no further escalation to 12.5 mg QW or 15 mg QW is required and the 10 mg QW MTD dose is administered as a maintenance dose for at least 4 weeks. 9. The method of any one of embodiments 7-8, wherein tirzepatide, or a pharmaceutically acceptable salt thereof, is administered to the subject for a minimum total treatment period selected from about 36 weeks, about 40 weeks, about 52 weeks, about 72 weeks, and about 104 weeks; and wherein the total treatment period comprises tirzepatide dose escalations and dose maintenance.10. The method of any one of embodiments 7-9, wherein dose escalation during the tirzepatide treatment stops at 10 mg QW MTD dose and the 10 mg QW MTD dose is administered as a maintenance dose for about 60 weeks. 11. The method of any one of embodiments 7-9, wherein dose escalation during the tirzepatide treatment continues to 15 mg QW and the 15 mg QW dose is administered as a maintenance dose for about 52 weeks. 12. The method of any one of embodiments 7-11, wherein the subject has reached a body weight plateau at the end of the tirzepatide treatment. 13. The method of any one of embodiments 1-6, wherein: the subject has reached a body weight plateau at the end the semaglutide treatment, wherein: the semaglutide treatment comprises administering at least one escalation dose of semaglutide, or a pharmaceutically acceptable salt thereof, for a minimum of about 2 weeks, and thereafter administering a maintenance dose of semaglutide, or a pharmaceutically acceptable salt thereof, for at least 4 weeks; wherein the escalation dose is selected from 0.25 mg QW, 0.5 mg QW, 1.0 mg QW, and 1.7 mg QW; and wherein the maintenance dose is selected from 1.7 mg QW and 2.4 mg QW; provided that if the maximum tolerated dose (MTD) is reached at 1.7 mg QW, then no further escalation to 2.4 mg QW is required and the 1.7 mg QW MTD dose is administered as a maintenance dose for at least 4 weeks. 14. The method of embodiment 13, wherein the semaglutide treatment comprises: starting at a dose of 0.25 mg QW of semaglutide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks; escalating to a dose of 0.5 mg QW of semaglutide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks;escalating to a dose of 1.0 mg QW of semaglutide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks; escalating to a dose of 1.7 mg QW of semaglutide, or a pharmaceutically acceptable salt thereof, and administering at this dose for about 4 weeks; and escalating to a dose of 2.4 mg QW of semaglutide, or a pharmaceutically acceptable salt thereof, and administering at this dose for at least 4 weeks; provided that if the maximum tolerated dose (MTD) is reached at 1.7 mg QW, then no further escalation to 2.4 mg QW is required and the 1.7 mg QW MTD dose is administered as a maintenance dose for at least 4 weeks. 15. The method of any one of embodiments 13-14, wherein semaglutide, or a pharmaceutically acceptable salt thereof, is administered to the subject for a minimum total treatment period selected from about 36 weeks, about 40 weeks, about 52 weeks, about 72 weeks, and about 104 weeks; and wherein the total treatment period comprises semaglutide dose escalations and dose maintenance. 16. The method of any one of embodiments 13-15, wherein dose escalation during the semaglutide treatment stops at 1.7 mg QW MTD dose and the 1.7 mg QW MTD dose is administered as a maintenance dose for about 60 weeks. 17. The method of any one of embodiments 13-15, wherein dose escalation during the semaglutide treatment continues to 2.4 mg QW and the 2.4 mg QW dose is administered as a maintenance dose for about 56 weeks. 18. The method of any one of embodiments 13-17, wherein the subject has reached a body weight plateau at the end of the semaglutide treatment. 19. The method of any one of embodiments 1-18, wherein the starting dose of 12 mg QD of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound orthe pharmaceutically acceptable salt, is administered to the subject at about 1-2 weeks from the last administered dose of tirzepatide or semaglutide. 20. The method of embodiment 19, wherein the starting dose of 12 mg QD of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, is administered to the subject about 1 week from the last administered dose of tirzepatide or semaglutide. 21. The method of any one of embodiments 1-20, wherein the Compound 1 treatment is superior to a placebo treatment with regard to maintaining the body weight loss of the subject from the end of the tirzepatide treatment or the semaglutide treatment to the end of the Compound 1 or placebo treatment. 22. The method of any one of embodiments 1-21, wherein: the body weight loss of the subject resulting from the tirzepatide treatment is maintained with the treatment using Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt; or the body weight loss of the subject resulting from the semaglutide treatment is maintained with the treatment using Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt. 23. The method of embodiment 22, wherein at least 80% of the body weight reduction resulting from the tirzepatide or semaglutide treatment is maintained at the end of the Compound 1 treatment. 24. The method of embodiment 22, wherein the tirzepatide or semaglutide treatment has resulted in at least 15% of body weight reduction and switching to the Compound 1 treatment maintains this body weight reduction of at least 15%.25. The method of any one of embodiments 1-5, 7-12 and 19-20 for treating a subject with T2DM, wherein the subject has reached an HbA1c level of no more than 7.0% at the end of the tirzepatide treatment or the semaglutide treatment, comprising: an oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, to the subject according to the following dosing schedule: starting at a dose of 12 mg QD, and administering at this dose for about 4 weeks; escalating to a dose of 24 mg QD, and administering at this dose for about 4 weeks; and escalating to a dose of 36 mg QD, and administering at this dose as a maintenance dose for at least 4 weeks; provided that if the maximum tolerated dose (MTD) is reached at 24 mg QD, then no further escalation to 36 mg QD is required and the 24 mg QD MTD dose is administered as a maintenance dose for at least 4 weeks. 26. The method of embodiment 25 for improved glycemic control; wherein the oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, is superior to a placebo treatment with regard to maintaining the subject’s HbA1c level from the end of the the tirzepatide treatment or the semaglutide treatment to the end of the Compound 1 or placebo treatment. 27. The method of any one of embodiments 25-26 for improved glycemic control, wherein: the change of the subject’s HbA1c level is no more than about 1.5% from the end of the tirzepatide treatment or the semaglutide treatment to the end of the Compound 1 treatment. 28. The method of any one of embodiments 25-27 for improved glycemic control, wherein: the change of the subject’s HbA1c level is no more than about 1.0% from the end of the tirzepatide treatment or the semaglutide treatment to the end of the Compound 1 treatment.29. The method of any one of embodiments 25-28 for improved glycemic control, wherein: the subject’s HbA1c level is maintained at a level of no more than about 7.0% at the end of the Compound 1 treatment. 30. The method of any one of embodiments 1-29, wherein each recited dose of Compound 1 is a free acid equivalent amount of Compound 1. 31. The method of any one of embodiments 1-30, wherein Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, is a hemicalcium salt of the following compound or a hydrate of the hemicalcium salt: .32. The method of any one of embodiments 1-31, wherein tirzepatide, semaglutide, or Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, is administered to the subject as an adjunct to diet and exercise. 33. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, for use in the treatment of a subject with T2DM, obesity, or overweight with at least one weight related comorbidity, according to the following dosing schedule: starting at a dose of 12 mg QD, and administering at this dose for about 4 weeks; escalating to a dose of 24 mg QD, and administering at this dose for about 4 weeks; andescalating to a dose of 36 mg QD, and administering at this dose as a maintenance dose for at least 4 weeks; provided that if the maximum tolerated dose (MTD) is reached at 24 mg QD, then no further escalation to 36 mg QD is required and 24 mg QD MTD dose is administered as a maintenance dose for at least 4 weeks; and wherein the subject has completed a tirzepatide treatment or a semaglutide treatment, prior to the administration of Compound 1. 34. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of embodiment 33, is administered to the subject for a minimum total treatment period selected from about 36 weeks, about 40 weeks, about 52 weeks, about 72 weeks, and about 104 weeks; and wherein the total treatment period comprises dose escalation period and dose maintenance period. 35. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of any one of embodiments 33-34, wherein dose escalation during the Compound 1 treatment stops at 24 mg QD MTD dose and the 24 mg QD MTD dose is administered as a maintenance dose for about 48 weeks. 36. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of any one of embodiments 33-34, wherein dose escalation during the Compound 1 treatment continues to 36 mg QD dose and the 36 mg QD dose is administered as a maintenance dose for about 44 weeks. 37. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of any one of embodiments 33-36, for use in treating a subject with obesity or overweight with at least one weight related comorbidity, wherein:the subject has reached a body weight plateau at the end of the tirzepatide treatment and before oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt; or the subject has reached a body weight plateau at the end of the semaglutide treatment and before oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt. 38. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of any one of embodiments 33-37, wherein the starting dose of 12 mg QD of Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt, is administered to the subject about 1-2 weeks from the last administered dose of tirzepatide or semaglutide. 39. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of any one of embodiments 33-37, wherein the Compound 1 treatment is superior to a placebo treatment with regard to maintaining the body weight loss of the subject from the end of the tirzepatide treatment or the semaglutide treatment to the end of the Compound 1 or placebo treatment. 40. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of any one of embodiments 33-39, wherein: the body weight loss of the subject resulting from the tirzepatide treatment is maintained with the treatment using Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt; or the body weight loss of the subject resulting from the semaglutide treatment is maintained with the treatment using Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt. 41. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of any one of embodiments 33-40, wherein atleast 80% of the body weight reduction resulting from the tirzepatide or semaglutide treatment is maintained at the end of the Compound 1 treatment. 42. Compound 1, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the pharmaceutically acceptable salt of embodiment 41, wherein the tirzepatide or semaglutide treatment has resulted in at least 15% of body weight reduction and switching to the Compound 1 treatment maintains this body weight reduction of at least 15%. 43. A method for treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, the method comprising starting with orally administering to the subject a first dose level of a GLP-1 receptor NPA compound for a first duration, wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. 44. The method of claim 43, wherein the subject has completed a prior GLP-1 RA treatment. 45. The method of claim 43, wherein administering the first dose level for the first duration is sufficient to substantially maintain the therapeutic effect. 46. The method of claim 43, wherein the first dose level is an escalation dose level and the method further comprising orally administering a second dose level of the GLP-1 receptor NPA compound for a second duration. 47. The method of claim 46, wherein the second dose level is greater than the first dose level. 48. The method of claim 47, wherein administering the second dose level for the second duration is sufficient to substantially maintain the therapeutic effect.49. The method of claim 46, wherein the second dose level is an escalation dose level and the method further comprising orally administering a third dose level of the GLP-1 receptor NPA compound for a third duration. 50. The method of claim 49, wherein the third dose level is greater than the second dose level. 51. The method of claim 50, wherein administering the third dose level for the third duration is sufficient to substantially maintain the therapeutic effect. 52. The method of any one of claims 43-51, wherein dose levels and dosing frequency of the GLP-1 receptor NPA compound are selected to provide an acceptable adverse event profile. 53. The method of any one of claims 43-52, wherein the first duration is at least about 2 weeks. 54. The method of claim 53, wherein the first duration is about 4 weeks. 55. The method of any one of claims 43-44 and 46-54, wherein the second duration is at least about 2 weeks. 56. The method of claim 55, wherein the second duration is about 4 weeks. 57. The method of claim 56, wherein the first duration and the second duration are a combined period selected from about 36 weeks, about 40 weeks, about 48 weeks, about 52 weeks, about 72 weeks, and about 104 weeks. 58. The method of any one of claims 43-44 and 49-56, wherein the third duration is at least about 4 weeks.59. The method of claim 58, wherein the first duration, the second duration, and the third duration are a combined period selected from about 36 weeks, about 40 weeks, about 48 weeks, about 52 weeks, about 72 weeks, and about 104 weeks. 60. The method of any one of claims 1-59, wherein the prior GLP-1 RA treatment comprises treatment with a GLP-1 RA peptide. 61. The method of claim 60, wherein the prior GLP-1 RA treatment comprises treatment with a GLP-1 RA peptide selected from tirzepatide or semaglutide. 62. The method of any one of claims 60-61, wherein the prior GLP-1 RA treatment comprises treatment with a subcutaneously administered GLP-1 RA peptide. 63. The method of any one of claims 1-62, wherein the GLP-1 receptor NPA compound is Compound 1, or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing. 64. The method of claim 63, wherein the first dose level of the GLP-1 receptor NPA compound is about 12 mg QD. 65. The method of claim 64, wherein when a second dose level of the GLP-1 receptor NPA compound is administered, the second dose level is about 24 mg QD. 66. The method of claim 65, wherein when a third dose level of the GLP-1 receptor NPA compound is administered, the third dose level is about 36 mg QD. 67. The method of any one of claims 63-66, wherein the GLP-1 receptor NPA compound is Compound 1a. 68. The method of any one of claims 63-66, wherein the GLP-1 receptor NPA compound is Compound 1a hemicalcium salt hydrate (Compound 1a 0.5 Ca hydrate).69. The method of any one of claims 63-66, wherein the GLP-1 receptor NPA compound is Compound 1a hemicalcium salt hydrate (Compound 1a 0.5 Ca hydrate). 70. The method of any one of claims 1-69, wherein the prior GLP-1 RA treatment was administered in subject having T2DM, obesity, and / or overweight with at least one weight related comorbidity. 71. The method of any one of claims 1-70, wherein the subject reached a body weight plateau from the prior GLP-1 RA treatment. 72. The method of claim 71, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 5%. 73. The method of claim 71, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 10%. 74. The method of claim 71, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 15%. 75. The method of any one of claims 1-70, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain at least 80% of a body weight reduction provided by the prior GLP-1 RA treatment. 76. The method of claim 75, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain at least 85% of a body weight reduction provided by the prior GLP-1 RA treatment. 77. The method of any one of claims 1-70, wherein the subject reached a plateau in HbA1c level from the prior GLP-1 RA treatment.78. The method of claim 77, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 7.5%. 79. The method of claim 77, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 7.0%. 80. The method of claim 77, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 6.5%. 81. The method of any one of claims 1-70, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to substantially maintain an HbA1c level provided by the prior GLP-1 RA treatment. 82. The method of claim 81, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 15% greater than an HbA1c level provided by the prior GLP-1 RA treatment. 83. The method of claim 81, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 10% greater than an HbA1c level provided by the prior GLP-1 RA treatment. 84. The method of claim 81, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 5% greater than an HbA1c level provided by the prior GLP-1 RA treatment. 85. The method of any one of claims 1-70, wherein administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 7.5%.86. The method of claim 85, wherein administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 7.0%. 87. The method of claim 85, wherein administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 6.5%. 88. The method of any one of claims 1-87, wherein administering the GLP-1 receptor NPA compound is used as an adjunct to diet and exercise. 89. The method of any one of claims 1-88, comprising starting with the orally administering the GLP-1 receptor NPA compound within about 1 to 4 weeks of discontinuing the prior GLP-1 RA treatment. 90. The method of claim 89, comprising starting with the orally administering the GLP-1 receptor NPA compound within about 1 to 3 weeks of discontinuing the prior GLP-1 RA treatment. 91. The method of claim 89, comprising starting with the orally administering the GLP-1 receptor NPA compound within about 1 to 2 weeks of discontinuing the prior GLP-1 RA treatment. 92. The method of claim 89, comprising starting with the orally administering the GLP-1 receptor NPA compound within about 1 week of discontinuing the prior GLP-1 RA treatment. 93. A GLP-1 receptor NPA compound for use in treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, wherein the use comprises starting with orally administering to the subject a first dose level of the GLP-1 receptor NPA compound for a first duration; andwherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. 94. The compound of claim 93, wherein the use comprises orally administering to the subject a second dose level of the GLP-1 receptor NPA compound for a second duration following the administration of the first dose level. 95. The compound of claim 94, wherein the use comprises orally administering to the subject a third dose level of the GLP-1 receptor NPA compound for a third duration following the administration of the second dose level. 96. A unit dose of a GLP-1 receptor NPA compound for administration to a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, wherein the administration comprises starting with orally administering a first dose level of a GLP-1 receptor NPA compound for a first duration; and wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. 97. The unit dose of claim 96, wherein the administration comprises orally administering a second dose level of the GLP-1 receptor NPA compound for a second duration following the administration of the first dose level. 98. The unit dose of claim 97, wherein the administration comprises orally administering to the subject a third dose level of the GLP-1 receptor NPA compound for a third duration following the administration of the second dose level.99. Use of a GLP-1 receptor NPA compound in the manufacture of a medicament for treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, wherein the use comprises starting with orally administering a first dose level of a GLP-1 receptor NPA compound for a first duration; and wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing. 100. The use of claim 99, wherein the use comprises orally administering a second dose level of the GLP-1 receptor NPA compound for a second duration following the administration of the first dose level. 101. The use of claim 100, wherein the use comprises orally administering to the subject a third dose level of the GLP-1 receptor NPA compound for a third duration following the administration of the second dose level. EXAMPLES Compound 1a 0.5 Ca hydrate

[0130] Ethanol (5.60 mL) and 2M sodium hydroxide aqueous solution (0.75 mL) were added to 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4- fluoro-l-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 (Compound 1a, 1120 mg) and the compound was dissolved at room temperature. 1.26 M calcium acetate aqueous solution (0.68 mL), seed crystals of the calcium salt hydrate of Compound 1a and water (0.68 mL) were added to the solution, and the mixture was stirred at room temperature for 3 h. Further, water (1.2 mL) was added and the mixture was stirred at room temperature for 1 h., and then water (2.3 mL) was added and the mixture was stirred at room temperature for 1 h. to obtain calcium salt hydrate crystals (973.0 mg) of Compound 1a as powder crystals. Note that seed crystals were obtained by the following method.

[0131] Compound 1a (69.0 mg) was dissolved in DMSO (0.229 mL), and 1.06M calcium methoxyethoxide (0.147 mL) was added. This solution (0.015 mL) was freeze-dried at -20° C. for 2 days. Water-acetonitrile mixture (3:1, 0.015 mL) was added to the obtained, freeze- dried product, and the mixture was stirred by shaking at room temperature for 7 days to obtain calcium salt hydrate crystals of Compound 1a as powder crystals. Capsule Formulation of Compound 1a 0.5 Ca hydrate

[0132] In some embodiments, Compound 1a is administered to a subject in a capsule. In some embodiments, a capsule comprising Compound 1a can be prepared as described in Examples 1 and 2 below. Example 1 Compound 1a 0.5 Ca hydrate spray-dried dispersion (SDD) preparation

[0133] Compound 1a 0.5 Ca hydrate was dissolved in ethanol, denatured with methanol (5% v / v or w / w). A 20% w / w solids solution was prepared with 30% w / w of the solid fraction composed of the title compound (on a free acid basis) and the balance composed of PVP-VA. This translated to 6% of Compound 1a (on a free acid basis), 14% PVP-VA and 80% of denatured ethanol SDA-3A – all fractions as w / w. After spray drying, the solids that formed were composed of 30% w / w of the solid fraction composed of Compound 1a (on a free acid basis) and the balance composed of PVP-VA. The % values are shown in Table 1 below. Example 1 – Compound 1a SDD Table 1. Compound 1a SDD Compositions Solution Amorphous SDD (mass fractions) (mass fraction) Compound 1a 6% 30.0% PVP-VA 14% 70.0% EtOH SDA-3A 80% EtOH 76% MeOH 4%

[0134] Once solution was prepared, the solution was pumped to a spray dryer where the solution atomizes upon entry. Heated drying gas entered co-current to the atomized liquid at the top of the spray drying chamber at an approximate ratio of 0.044 kg / kg of spray solution to drying gas. The inlet temperature was adjusted to provide an outlet temperature of 35 to 45 °C. The solids formed in the spray dryer were collected from a cyclone as well as a filter housing on the gas stream. The gas was passed over a condenser maintained at -3 °C to remove (to a dewpoint of -3 °C) solvent. The gas was then heated to the inlet temperature and passed back to the spray dryer. Example 2 – Exemplary Capsule Formulation Compound 1a 0.5 Ca hydrate, 1 mg and 15 mg capsule formulation

[0135] The SDD, NaHCO3, microcrystalline cellulose (MCC PH-102), and SiO2were dispensed into separate low-density polyethylene (LDPE) bags. NaHCO3 and MCC PH-102 were passed through a screen (30 mesh) sequentially into separate LDPE bags. ~25% of the sieved NaHCO3 was added to a 10 L mixing bin. Sieve MCC was added to the bag containing the SDD and manually mixed for at least two minutes. Then SiO2 was added to the MCC and SDD blend and manually mixed for at least two more minutes. The blend was sieved through a 30 mesh screen into the bin. The blend LDPE bag was rinsed with the remaining NaHCO3, sieved through a 30 mesh screen into the bin, then blended for 15 minutes at 20 RPM. The blend was sieved through a 30 mesh screen and blended again for 15 min at 20 RPM. The blend was filled into empty 0 capsule shells to the target fill weight using a semi-automated filling machine (e.g. Dott- Bonapace). Table 2. Capsule 1 mg and 15 mg Compositions Ex 3 capsule, 1 mg, Ex 3 capsule, 15 mg, Function mg / capsule mg / capsule Ex. 1a SDD 3.36 50.34 NaHCO3pH modifier 200.0 200.0 MCC PH-102filler / binder 44.14 7.06SiO2, SYLOID 244 FP (1%)glidant 2.5 2.6Total (mg) 250.0 260.0Tablet and Capsule Formulations of Compound 1a 0.5 Ca Hydrate

[0136] In some embodiments, Compound 1a is administered to a subject in a tablet. In some embodiments, exemplary tablets comprising Compound 1a can be prepared as described in the following Examples. Example 3a - Exemplary Tablets and Alternative Capsules Compound 1a SDD Preparation 1

[0137] 30 wt% 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, 0.5 Ca hydrate (8.7 g, 92% potency) and PVP-VA, (also known as copovidone, CAS# 25086-89-9;) (18.7 g) in EtOH (200 mL) at ambient temperature. Following dissolution of the solids the solution was spray dried on a conventional spray dryer with a pressure nozzle. The following parameters in the following Table were used to create the dispersion using a laboratory scale spray drier. Spray drying began when the spray dryer temperature is above 33 ºC. The material was collected and dried under vacuum at 50 ºC overnight to give the title compound (21.99 g, 7.0 g, 92% potency, 80% recovery) and observed via photomicroscopy that the material was microscopically non birefringent particles that were approximately 5-25 µm in diameter. Table 3. SDD Parameters Process Parameter Value Aspirator 100% Nebulization Flow 37 mm (~400 L / hr) Solution flow rate 40% (12.5 mL / min) Chiller Temperature -20 ºC Drying Gas Inlet Temperature 120 ºC Spray Dryer Outlet Temperature (°C) 75 ºCCompound 1a Preparation 2 SDD

[0138] Compound 1a 0.5 Ca hydrate was dissolved in EtOH, denatured with MeOH (5% v / v or w / w). A 20% w / w solids solution was prepared with 30% w / w of the solid fraction composed of the title compound; (on a free acid basis) and the balance composed of PVP-VA. This translated to 6% of the title compound (on a free acid basis), 14% PVP-VA and 80% of denatured EtOH SDA-3A – all fractions as w / w. After spray drying, the solids that form were composed of 30% w / w of the solid fraction composed of the title compound (on a free acid basis) and the balance composed of PVP-VA. The % values are shown in the Table below. Table 4. Composition of Preparation 2 SDD Solution Amorphous SDD (mass fractions) (mass fraction) Compound 1a 6% 30.0% PVP-VA 14% 70.0% EtOH SDA-3A 80% EtOH 76% MeOH 4%

[0139] Once the solution was prepared, the solution was pumped to a spray dryer where the solution atomized upon entry. Heated drying gas entered co-current to the atomized liquid at the top of the spray drying chamber at an approximate ratio of 0.044 kg / kg of spray solution to drying gas. The inlet temperature was adjusted to provide an outlet temperature of 35 to 45 °C. The solids formed in the spray dryer were collected from a cyclone as well as a filter housing on the gas stream. The gas was passed over a condenser maintained at -3 °C, to remove (to a dewpoint of -3 °C) solvent. The gas was then heated to the inlet temperature and passed back to the spray dryer. Compound 1a Preparation 3 SDD

[0140] Compound 1a 0.5 Ca hydrate is dissolved in EtOH, and denatured with MeOH (5% v / v or w / w). A 20% w / w solids solution is prepared with 30% w / w of the solid fraction composed of the title compound; (on a free acid basis) and the balance composed of PVP-VA. This translatesto 6% of the title compound (on a free acid basis), 14% PVP-VA and 80% of denatured EtOH SDA-3A – all fractions as w / w. After spray drying, the solids that form are composed of 30% w / w of the solid fraction composed of the title compound (on a free acid basis) and the balance composed of PVP-VA. The % values are shown in Table 2 below. Table 4a. Composition of Preparation 3 SDD Solution (mass fractions) Amorphous SDD (mass fraction) Compound 1a 6% 30.0% PVP-VA 14% 70.0% EtOH SDA-3A 80% EtOH 76% MeOH 4%

[0141] Once the solution is prepared, the solution is pumped to a spray dryer where the solution atomizes upon entry. Heated drying gas enters co-current to the atomized liquid at the top of the spray drying chamber at an approximate ratio of 0.044 kg / kg of spray solution to drying gas. The inlet temperature is adjusted to provide an outlet temperature of 35 to 45 °C. The solids formed in the spray dryer are collected from a cyclone as well as a filter housing on the gas stream. The gas is passed over a condenser maintained at -3 °C to remove (to a dewpoint of -3 °C) solvent. The gas is then heated to the inlet temperature and passed back to the spray dryer. Compound 1a Capsule Preparation

[0142] Capsules were prepared by first adding NaHCO3(600 mg) to a size 0 hypromellose capsule followed by adding Preparation 3 SDD (54 mg). Table 5. Quantitative Capsule Composition, Preparation 3 Capsule Wt% mg / tablet Preparation 3 SDD 8.26 54 NaHCO3 (anhydrous) 91.74 600 Total 100 654Compound 1a Tablet Formulation Core Tablet Composition Preparation

[0143] To prepare core tablets, Compound 1a (13.33 % w / w) SDD and excipients, (as set forth below), except magnesium stearate, were screened through a 600 µm sieve before use. The materials were added to a vessel (1000 mL) and mixed with a mixer at 32 rpm for about 10 min. The mixture blend was passed through sieve (600 µm) and mixed with mixer a 2nd time at 32 rpm for about 10 min. Magnesium stearate was added and the mixture was mixed at 32 rpm for about 3 min. The mixture blend was compressed using a 14.10 x 7.75 mm oval tablet tooling on a single station tablet press to produce tablets (400.0 mg) with a hardness of 30 kP.

[0144] Tablet compositions were prepared substantially as described herein above, using parameters of the following Tables to prepare corresponding Examples (Compositions T1, T2, A, B, C, D, and E). Each example included an IR coating substantially as described herein and additionally included an enteric coating. A tablet of Composition E of Table 12 included only an IR coating. Table 6. Tablet composition T1 Composition T1 Component Function % w / w mg / tablet Quantity / 300 g batch (g) 53.33 39.48 Prep 2 SDD (30 wt%) Drug 13.33 *(16.00) (39.99) Microcrystalline 170.52 Filler 56.67 226.67 cellulose (170.01) Na2CO3 anhydrous pH modifier 10.00 40.00 30.00 Crospovidone XL-10 disintegrant 17.50 70.00 52.50 Silicon dioxide Glidant 2.00 8.00 6.00 Magnesium stearate Lubricant 0.50 2.00 1.50 Total 100.00 400.00 300.00 Table 7. Tablet Composition T2 Composition T2 Component Function Quantity / % w / w mg / tablet 300 g batch (g) 53.33 Prep 2 SDD (30 wt%) Drug 13.33 39.99 (16.00)Microcrystalline cellulose Filler 72.17 288.67 216.51 Na2CO3anhydrous pH modifier 10.00 40.00 30.00 Crospovidone XL-10 disintegrant 2.00 8.00 6.00 Silicon dioxide Glidant 2.00 8.00 6.00 Magnesium stearate lubricant 0.50 2.00 1.50 Total 100.00 400.00 300.00 Table 8. Tablet Composition A Composition A Component Function % w / w mg / tablet Quantity / 300 g batch (g) 53.33 Prep 2 SDD (30 wt%) Drug 13.33 38.86 (16.00) Microcrystalline cellulose Filler 61.67 246.67 186.14 Na2CO3anhydrous pH modifier 5.00 20.00 15.00 Crospovidone XL-10 disintegrant 17.50 70.00 52.50 Silicon dioxide Glidant 2.00 8.00 6.00 Magnesium stearate lubricant 0.50 2.00 1.50 Total 100.00 400.00 300.00 Table 9. Tablet Composition B Composition B Component Function % w / w mg / tablet Quantity / 300 g batch (g) 53.33 Prep 2 SDD (30 wt%) Drug 13.33 38.86 (16.00) Microcrystalline cellulose Filler 51.67 206.67 156.14 Na2CO3 anhydrous pH modifier 15.00 60.00 45.00 Crospovidone XL-10 disintegrant 17.50 70.00 52.50 Silicon dioxide Glidant 2.00 8.00 6.00 Magnesium stearate Lubricant 0.50 2.00 1.50 Total 100.00 400.00 300.00 Table 10. Tablet Composition C Composition C Component Function Quantity / % w / w mg / tablet 300 g batch (g)53.33 Prep 2 SDD (30 wt%) Drug 13.33 38.86 (16.00) Microcrystalline cellulose Filler 69.17 276.67 208.64 Na2CO3anhydrous pH modifier 15.00 60.00 45.00 Silicon dioxide Glidant 2.00 8.00 6.00 Magnesium stearate Lubricant 0.50 2.00 1.50 Total 100.00 400.00 300.00 Table 11. Tablet Composition D Composition D Component Function Quantity / % w / w mg / tablet 300 g batch (g) 53.33 Prep 2 SDD (30 wt%) Drug 13.33 39.98 (16.00) Microcrystalline cellulose Filler 79.17 316.67 20.00 Na2CO3anhydrous pH modifier 5.00 20.00 8.00 Silicon dioxide Glidant 2.00 8.00 2.00 Magnesium stearate Lubricant 0.50 2.00 400.00 Total 100.00 400.00 300.00 Table 12. Tablet Composition E Composition E Component Function Quantity / % w / w mg / tablet 300 g batch (g) 53.33 Prep 2 SDD (30 wt%) Drug 13.33 38.86 (16.00) Microcrystalline cellulose Filler 56.67 226.67 171.14 Na2CO3 anhydrous pH modifier 10.00 40.00 30.00 Crospovidone XL-10 Disintegrant 17.50 70.00 52.50 Silicon dioxide Glidant 2.00 8.00 6.00 Magnesium stearate Lubricant 0.50 2.00 1.50 Total 100.00 400.00 300.00 Example 3b – Relative Bioavailability Assessment for Exemplary Equivalent Capsule and Tablet Doses

[0145] Relative bioavailability assessments were conducted using three tablet doses evaluated against one reference capsule dose. Subjects were administered the tablets and, after one tabletdosing interval, AUC and Cmaxvalues were determined for each tablet. The resulting tablet GLSM values were compared to the capsule GLSM. Equivalence was estimated by calculating the ratio of GLSMs and selecting the value closest to 1.0.

[0146] Statistical Analysis of Pharmacokinetic Parameters (Relative Bioavailability Assessment) for Study J2A-MC-GZPI (Pharmacokinetic Population) – Exploratory Analysis (Part A) Abbreviations: AUC(0τ),ss area under the concentration versus time curve during one dosing interval at steady state (τ is 24 hours for QD dosing) CI confidence Cmax,ssmaximum observed drug concentration during a dosing interval at steady state CV coefficient of variation (%) GLSM geometric least squares mean ln natural log LSM least square mean n number of participants with valid observations QD once daily Model: ln(parameter)= treatment sequence + period + treatment + participant(treatment sequence)+ random error, with participant(treatment sequence) fitted as a random effect. The GLSMs, ratios of GLSMs, and corresponding CIs were obtained by taking the exponential of the LSMs, differences in LSMs, and corresponding CIs on the ln scale. Matrix: Plasma; Analyte: Orforglipron (OFG); Profile Day: 7 Table 12a. Capsule Dose Level: 1 mg Parameter Treatment n GLSM Ratio of GLSMs (90% CI) AUC(0-τ),ss 1 mg OFG Capsule QD (Reference) 52 91.0 (ng.h / mL) 0.8 mg OFG Tablet QD (Test) 52 88.9 0.976 (0.9288, 1.0265) Cmax,ss(ng / mL) 1 mg OFG Capsule QD (Reference) 52 6.18 0.8 mg OFG Tablet QD (Test) 52 5.88 0.951 (0.9001, 1.0039)Table 12b. Capsule Dose Level: 3 mg Parameter Treatment n GLSM Ratio of GLSMs (90% CI) AUC(0-τ),ss 3 mg OFG Capsule QD (Reference) 47 270 (ng.h / mL) 2.5 mg OFG Tablet QD (Test) 47 269 0.994 (0.9466, 1.0447) Cmax,ss(ng / mL) 3 mg OFG Capsule QD (Reference) 47 18.0 2.5 mg OFG Tablet QD (Test) 47 18.4 1.021 (0.9572, 1.0881) Table 12c. Capsule Dose Level: 6 mg Parameter Treatment n GLSM Ratio of GLSMs (90% CI) AUC(0-τ),ss 6 mg OFG Capsule QD (Reference) 44 572 (ng.h / mL) 5.5 mg OFG Tablet QD (Test) 45 571 0.999 (0.9327, 1.0691) Cmax,ss(ng / mL) 6 mg OFG Capsule QD (Reference) 44 39.4 5.5 mg OFG Tablet QD (Test) 45 39.3 0.998 (0.9178, 1.0861) Table 12d. Capsule Dose Level: 12 mg Parameter Treatment n GLSM Ratio of GLSMs (90% CI) AUC(0-τ),ss 12 mg OFG Capsule QD (Reference) 50 903 (ng.h / mL) 9 mg OFG Tablet QD (Test) 49 866 0.959 (0.9095, 1.0102) Cmax,ss(ng / mL) 12 mg OFG Capsule QD (Reference) 50 57.5 9 mg OFG Tablet QD (Test) 49 58.3 1.015 (0.9442, 1.0908) Table 12e. Capsule Dose Level: 24 mg Parameter Treatment n GLSM Ratio of GLSMs (90% CI) AUC(0-τ),ss 24 mg OFG Capsule QD (Reference) 49 1408 (ng.h / mL) 14.5 mg OFG Tablet QD (Test) 45 1412 1.003 (0.9441, 1.0652) Cmax,ss(ng / mL) 24 mg OFG Capsule QD (Reference) 49 88.5 14.5 mg OFG Tablet QD (Test) 45 96.6 1.092 (1.0037, 1.1888)Table 12f. Capsule Dose Level: 36 mg Parameter Treatment n GLSM Ratio of GLSMs (90% CI) AUC(0-τ),ss 36 mg OFG Capsule QD (Reference) 43 1799 (ng.h / mL) 17.2 mg OFG Tablet QD (Test) 44 1735 0.965 (0.8929, 1.0424) Cmax,ss(ng / mL) 36 mg OFG Capsule QD (Reference) 43 117 17.2 mg OFG Tablet QD (Test) 44 119 1.018 (0.9259, 1.1183) Example 4 – Clinical Data

[0147] The clinical pharmacology, PK, and PD of Compound 1a were studied in 2 completed Phase 1 studies in healthy volunteers and in participants with T2D. Results from these studies demonstrated a PK profile appropriate for once daily oral dosing that can be administered without limitations pertaining to food or water intake or time of day. The PK of Compound 1a plasma concentration increase was approximately proportional to the increase of dose across the 9 mg QD to 45 mg QD dose range.

[0148] In these Phase 1 studies, GI AEs of nausea, vomiting, and constipation were the most reported AEs. PD results from one study showed clinically relevant improvements in HbA1c of up to -1.4%, and weight loss of up to -5.8 kg after 12 weeks of treatment with 9 mg of Compound 1a QD to 45 mg QD in people with T2D.

[0149] Two Phase 2 studies have evaluated the safety and efficacy of Compound 1a for the treatment of T2D and another for treatment of obesity or overweight with at least one weight related comorbidity. In one study, Compound 1a treatment for 26 weeks at doses of 3 mg to 45 mg QD resulted in mean changes from baseline in HbA1c up to -2.1% (treatment difference of - 1.7% vs placebo) and mean weight loss of up to 10 kg (treatment difference of 8 kg vs placebo).

[0150] In another Phase 2 study in people with obesity or overweight with at least one weight related comorbidity, mean percent weight loss of up to 13% from baseline (11% compared to placebo) was observed with Compound 1a treatment at the primary 26-week endpoint. Most common TEAEs were GI related (nausea, vomiting, diarrhea and constipation).

[0151] The detailed results of these two Phase 2 studies are provided in more detail in Examples 4A and 4B below.Example 4A – Phase 2 Clinical Data

[0152] In a randomized, double-blind Phase 2 clinical trial, 272 adults were enrolled with obesity or overweight with at least one weight related comorbidity, excluding diabetes, to examine the weight reduction efficacy and safety of 4 dose levels (12 mg, 24 mg, 36 mg and 45 mg OFG) of Compound 1a hemicalcium salt hydrate compared with once daily administered placebo for 36 weeks. The primary endpoint was the percentage change in body weight from baseline to week 26, with a secondary 36-week endpoint. Trial Design

[0153] A 36-week Phase^2, multicenter, randomized, double-blind, parallel, placebo-controlled study was designed to examine the efficacy and safety of 4^dose levels of once daily administered Compound 1a, compared with once daily administered placebo in participants 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 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) treatment groups. The 36 and 45 mg cohorts were subdivided in a 36 mg-1 and 36 mg-2 as well as 45 mg-1 and 45 mg-2 respectively, as different starting doses, dose escalations and dose escalation steps were investigated in these subgroup cohorts (Fig. 2). The different dose escalations were performed to assess the maintenance dose and titration steps for future trials. Participants

[0154] Eligible male or female participants were ≥18 years of age with a HbA1c <6.5% (48 mmol / mol) and a BMI of ≥30 kg / m2or ≥27 kg / m2and <30 kg / m2with at least 1 of the following weight-related comorbidities: hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea. Participants had a stable body weight (< 5% body weight gain and / or loss) for the 3 months prior to randomization. Procedures

[0155] The study period included a 2-week screening / lead in period, a 36-week treatment period followed by a 2 week off-drug safety follow-up period. During the treatment period, doses wereescalated for all treatment groups. The dose escalation period ranged from 0 to 16 weeks depending on dose group. The initial dose was 2 or 3^mg followed by additional escalation steps depending on assigned cohort (Fig. 2). Compound 1a or matching placebo was administered daily by oral capsule. All participants were provided healthy eating and exercise education by study personnel throughout the trial. Endpoint

[0156] 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 percentage of study participants who achieved ≥5% body weight (kg) reduction, and ≥10% body weight (kg) reduction, at week 26 and week 36. Key safety endpoints included adverse events, blood pressure, heart rate, safety laboratory measures, PK parameters, and patient-reported outcomes. Statistical Analyses

[0157] A sample size of 270 participants was calculated to provide at least 90% power for testing superiority of Compound 1a versus placebo in the primary endpoint. The estimand used for efficacy analyses was an “efficacy estimand,” representing the average treatment effect for the randomized population if the treatment was administered as intended, thus including data from all randomized participants who received at least one dose of study drug and excluding data after permanent discontinuation of study drug. All tests of treatment effects were conducted at a 2-sided alpha level of 0.05 without adjustment for multiple comparisons, and 2-sided 95% CIs were calculated. To test efficacy of Compound 1a with adequate statistical power, for 36 mg and 45 mg the evaluation of the primary endpoint was made by pooling 2 dose escalation regimens (combining 36 mg-1 and 36 mg-2, for 36 mg, and combining 45 mg-1 and 45 mg-2, for 45 mg).

[0158] Safety analyses were conducted by comparing safety of Compound 1a with placebo irrespective of adherence to study drug. The safety analyses were conducted using the safety analysis set, which includes all randomized participants who received at least one dose of study drug. The results were presented in summary statistics, point estimates, and 95% confidence intervals along with p-values for treatment comparisons. Results

[0159] At baseline the mean body weight was 108.7 kg and the mean BMI was 37.9kg / m2. The mean percentage change in body weight from baseline ranged from -8.6% to -12.6% at week 26, in a dose dependent manner, and -9.4% to -14.7% at week 36, compared with -2.0% and -2.3% with placebo respectively (Fig. 3). The percentage of patients who had weight reduction of 10% or more at 36 weeks ranged from 47% to 75%, versus 9% with placebo. At the highest Compound 1a dose (45 mg), 48% of patients had a weight reduction of 15% or more at 36 weeks 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 are consistent with the GLP-1 RA class.

[0160] Across all treatment groups there was a statistically significant, dose dependent, continuous decrease in placebo corrected body weight from baseline to 26- and 36-weeks, in all treatment groups, ranging from -6.9 kg to -11.2 kg (all p<0.001) at 26-weeks and -7.4 kg to -13.0 kg (all p<0.001) at 36-weeks (Fig. 3). Additional Treatment Outcomes

[0161] There was a mean reduction in systolic blood pressure (SBP) from baseline to week 26 (ranging from -4.8 to -10.5 mmHg) and from baseline to week 36 (ranging from -6.7 to -10.5 mmHg) in the Compound 1a groups, compared with -3.6 and -1.8 for placebo respectively. SBP tended to decrease in all Compound 1a groups relative to placebo during the study. No differences were noted in diastolic blood pressure (DBP) when compared to placebo. Benefits with Compound 1a were noted with respect to changes in the fasting lipids (triglycerides, total cholesterol, non-HDL cholesterol, LDL and VLDL) while there was no significant change in HDL cholesterol versus placebo at week 36. Participants who received Compound 1a treatment reported greater improvements in health-related quality of life and physical activity readouts versus placebo.

[0162] Changes to systolic or diastolic blood pressure and mean pulse rate compared with placebo were consistent with the results found in the Phase 2 study described in Example 4B. Prevalence, incidence, and onset of nausea, vomiting, diarrhea, and constipation observed in this study are also generally consistent with the results found in Example 4B.Tolerability and Safety

[0163] Nausea, constipation, vomiting, diarrhea, and eructation were the most common events reported with Compound 1a and were more frequent on Compound 1a vs. placebo. Most gastrointestinal events were mild-to-moderate in severity, occurred mainly during initial titrations and were transient, and resolved without permanent discontinuation of the treatment. Overall, the percentage of patients who reported AEs was slightly higher in the Compound 1a groups (86% to 90.2%) vs placebo (76.0%). The most frequent GI reactions did not increase in a dose-dependent manner with Compound 1a dose above 3 mg. The starting dose of 3 mg had higher GI AE events throughout the trial versus the 2 mg starting dose. There was a superior tolerability if dose was escalated every 3 weeks compared to every 1-2 weeks. Overall, after the titration phase, Compound 1a was well tolerated across all arms. Liver function tests were not significantly increased in participants receiving Compound 1a compared with placebo. Example 4B – Phase 2 Clinical Data Trial Design

[0164] A 26-week Phase^2, multicenter, randomized, double-blind, parallel, placebo-controlled study was designed to examine the efficacy and safety of 5^dose levels of once daily administered OFG, compared with once daily administered placebo and once weekly administered dulaglutide. The patients were randomized 5:5:5:5:5:3:3:3:3 to once daily placebo, once weekly dulaglutide + oral placebo or OFG maintenance doses of 3 mg, 12 mg, 24 mg, 36 mg (36-1, 36-2) or 45 mg (45-1, 45-2) treatment groups. The 36 and 45 mg cohorts were subdivided in a 36 mg-1 and 36 mg-2 as well as 45 mg-1 and 45 mg-2 respectively, as different starting doses, dose escalations and dose escalation steps were investigated in these subgroup cohorts (Fig. 4). Participants

[0165] Eligible male or female participants were >18 years of age with T2D with a HbA1c 7.0 % to 10.5% and a body mass index (BMI) of ≥23^kg / m2, treated with diet and exercise alone or with a stable dose of metformin and with a stable body weight (≤5% body weight gain and / or loss) for at least 3 months prior to screening / Visit 1.Procedures

[0166] The study period included a 2-week screening / lead in period and a 26-week treatment period. During the treatment period, doses were escalated for all treatment groups. The dose escalation period ranged from 4 to 12 weeks depending on dose group. The initial dose was 2 or 3^mg followed by additional escalation steps depending on assigned cohort (Fig. 4). All participants took one capsule orally each day (OFG or matching placebo) and one subcutaneous injection each week (dulaglutide 1.5 mg or matching placebo). All participants were provided healthy eating and exercise education by study personnel throughout the trial. Endpoint

[0167] The primary endpoint was change in HbA1c from baseline at week 26, comparing OFG doses versus placebo. Secondary endpoints included percentage of participants with HbA1c ≤6.5% and of <7.0% at week 26, change from baseline in fasting blood 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, rate and incidence of hypoglycaemia 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 change in safety laboratory parameters, electrocardiogram, and vital signs. Statistical Analysis

[0168] A sample size of 370 participants was calculated to provide at least 90% power for testing superiority of OFG versus placebo in the primary endpoint. The estimand used for efficacy analyses was an “efficacy estimand,” representing the average treatment effect for the randomized population if the treatment was administered as intended, thus including data from all randomized participants who received at least one dose of study drug and excluding data after permanent discontinuation of study drug. All tests of treatment effects were conducted at a 2- sided alpha level of 0.05 without adjustment for multiple comparisons, and 2-sided 95% CIs were calculated. To test efficacy of OFG with adequate statistical power, for 36 mg and 45 mg the evaluation of the primary endpoint was made by pooling 2 dose escalation regimens (combining 36 mg-1 and 36 mg-2, for 36 mg, and combining 45 mg-1 and 45 mg-2, for 45 mg).

[0169] Safety analyses were conducted by comparing safety of OFG with placebo and with dulaglutide irrespective of adherence to study drug. The safety analyses were conducted using the safety analysis set, which includes all randomized participants who received at least one dose of study drug. The results were presented in summary statistics, point estimates, and 95% confidence intervals along with p-values for treatment comparisons. Result

[0170] 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% with placebo and -1.1% with dulaglutide 1.5 mg, respectively. The percentage of patients who attained an HbA1c of 7% or less at 26 weeks ranged from 65.2% to 95.8%, versus 24.3% with placebo and 64.1% with dulaglutide 1.5 mg. Treatment with OFG resulted in significant improvements versus placebo in fasting glucose. The most common adverse events with OFG were gastrointestinal, mild to moderate in severity, and occurred primarily during dose escalation. The HbA1c results are shown in Fig. 5.

[0171] At baseline, the mean body weight was 100.3 kg (standard deviation 21.5). At week 26, mean changes from baseline in body weight for participants who received OFG were -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 versus -3.9^kg (0.76) for dulaglutide and -2.2^kg (0.74) for placebo (Fig. 6). OFG was superior to placebo (ETD -4.3^kg [95% CI -6.4 to -2.2] with 12^mg, 7.6^kg [-9.8 to -5.3] with 24^mg, -7.4^kg [-9.4 to -5.3] with 36^mg, -7.9^kg [-9.9 to -5.9] with 45^mg, p<0.0001 OFG 12^mg or greater and superior to dulaglutide (ETD -2.6^kg [-4.7 to -0.5] with 12^mg, -5.9^kg [-8.1 to -3.6] with 24^mg, -5.7^kg [-7.8 to -3.6] with 36^mg, -6.2^kg [-8.3 to -4.2] with 45^mg; p=0.0153 for OFG 12 mg, p<0.0001 for OFG 24^mg, 36^mg, and 45^mg) in decreasing body weight.

[0172] The percentages of participants achieving HbA1c and weight loss targets in the various groups are shown in Fig. 7. Additional Treatment Outcomes

[0173] At week 26, no statistically significant differences were noted in systolic or diastolic blood pressure compared with dulaglutide or placebo. An increase in mean pulse rate wasreported in all OFG treatment arms, with the maximal change occurring around Week 12. At Week 26, participants who received OFG had changes from baseline of +3.0 to +6.1 beats per minute (bpm) compared to +2.3 and -1.6 bpm with dulaglutide and placebo, respectively. More detailed vital sign parameters are provided in the following table. Table 13. Summary and Analysis of Changes from Baseline in Vital Sign Parameters (Blood Pressure and Pulse Rate) at Baseline and Week 26 Baseline Week 26 Treatment N Actual N Actual CFB Within Value Value LSM treatment LSM (SE) LSM (SE) (SE)cgroup p- value Systolic blood pressure (mm Hg) 135.2 128.9 -5.5 .001 Placebo 55 51 (1.76) (1.65) (1.65) 132.5 126.2 -8.2 <.001 OFG 3 mg 51 47 (1.83) (1.72) (1.72) 134.8 126.7 -7.6 <.001 OFG 12 mg 54 50 (1.78) (1.66) (1.66) 129.7 127.7 -6.7 <.001 OFG 24 mg 47 43 (1.90) (1.80) (1.80) a 133.0 127.1 -7.3 <.001 OFG 36 mg 60 56 (1.70) (1.58) (1.58) a 136.7 125.7 -8.7 <.001 OFG 45 mg 63 60 (1.64) (1.53) (1.53) 135.7 - OFG 1.5 mg 50 49 (1.84) Diastolic blood pressure (mm Hg)81.5 (1.11) 78.5 (0.98) -1.8 .073 Placebo 55 51 (0.98)Baseline Week 26 Treatment N Actual N Actual CFB Within Value Value LSM treatment LSM (SE) LSM (SE) (SE)cgroup p- value 81.2 (1.16) 77.8 (1.01) -2.5 .016 Dula 1.5 mg 50 49 (1.01) Pulse Rate (bpm)Placebo 72.4 (1.37) 72.0 (1.19) - .184 55 51 1.6 (1.19) OFG 3 mg 73.6 (1.43) 76.6 (1.24) 3.0 (1.24) .016 OFG 12 mg72.4 (1.39)79.7 (1.20) 6.1 (1.20) <.001 OFG 24 mg 47 72.2 (1.49) 43 77.4 (1.29) 3.8 (1.29) .004 OFG 36 mgb60 75.6 (1.33) 56 79.7 (1.14) 6.1 (1.14) <.001 OFG 45 mgb63 76.1 (1.28) 60 79.2 (1.10) 5.6 (1.10) <.001 Dula 1.5 mg 50 72.1 (1.44) 49 75.9 (1.22) 2.3 (1.22) .055 Abbreviations: CFB = change from baseline; Dula = dulaglutide; HbA1c = hemoglobin A1c; LSM = least squares mean; MMRM = mixed model repeated measures; N = number of participants in the specified category; SE = standard error.aSafety analysis – all data available are included for safety analyses, including those from both the treatment period and safety follow-up.bOFG 36 mg-1 and OFG 36 mg-2 were combined for OFG 36 mg; OFG 45 mg-1 and OFG 45 mg-2 were combined for OFG 45 mg.cMMRM model for postbaseline measures: log (Actual Measurement / Baseline) = log (Baseline) + Country + Baseline HbA1c Group (≤8.0%, >8.0%) + Treatment + Time + Treatment × Time (Type III sum of squares). Variance-Covariance structure (Actual Measurement) = Unstructured. Note 1: Only participants with nonmissing baseline value and at least 1 nonmissing postbaseline value of the response variable were included in analysis. Note 2: Model estimates for pooled treatments are estimated via a linear contrast that averages estimates from individual treatment groups. Summary statistics for pooled treatments are calculated based on observed data without linear contrasts. Tolerability and Safety

[0174] Gastrointestinal adverse events occurred more frequently with participants receiving high initial doses or rapid dose escalation, for example in the OFG 36^mg treatment group, 70.4% of participants in the 36^mg-1 treatment group experienced a gastrointestinal adverse event, versus 44.1% in the 36^mg-2 treatment group. Table 14. Summary of Prevalence, Incidence, and Onset of Nausea, Vomiting, Diarrhea, and Constipation by Time Interval by Treatment Group over Time Safety Analysis SetTime pointPlaceboOFG OFG OFG OFG OFG OFG OFG Dula N = 55 3 mg 12 mg 24 mg 36 mg-136 mg-2 45 mg-145 mg-21.5 mg N = 51 N = 56 N = 47 N = 27 N = 34 N = 31 N = 32 N = 50 Nausea Prevalence (%) After the 1st dose 5.5 23.5 37.5 34.0 37.0 26.5 29.0 25.0 18.0 0 ≤ Weeks ≤ 12 5.5 23.5 37.5 34.0 37.0 23.5 29.0 25.0 18.0 12 < Weeks ≤ 16 0 6.0 5.8 13.3 15.4 11.8 10.0 9.4 4.0 16 < Weeks ≤ 20 0 4.2 3.8 6.7 15.4 8.8 6.7 6.5 4.1 20 < Weeks ≤ 26 0 6.4 3.8 4.4 15.4 9.1 6.7 6.5 4.1 26 < Weeks ≤ End of treatment 0 2.9 0 2.6 9.1 11.5 9.1 8.7 2.3 period Incidence (%) After the 1st dose 5.5 23.5 37.5 34.0 37.0 26.5 29.0 25.0 18.0 0 ≤ Weeks ≤ 12 5.5 23.5 37.5 34.0 37.0 23.5 29.0 25.0 18.0 12 < Weeks ≤ 16 0 0 0 2.2 3.8 8.8 6.7 0 0 16 < Weeks ≤ 20 0 0 0 0 3.8 0 3.3 0 0 20 < Weeks ≤ 26 0 2.1 0 0 0 0 0 0 0 26 < Weeks ≤ End of treatment 0 0 0 0 0 0 0 0 0 period Onset (%) After the 1st dose 5.5 23.5 37.5 34.0 37.0 26.5 29.0 25.0 18.0 0 ≤ Weeks ≤ 12 5.5 23.5 37.5 34.0 37.0 23.5 29.0 25.0 18.0 12 < Weeks ≤ 16 0 0 0 0 0 2.9 0 0 0 16 < Weeks ≤ 20 0 0 0 0 0 0 0 0 0 20 < Weeks ≤ 26 0 0 0 0 0 0 0 0 0 26 < Weeks ≤ 0 0 0 0 0 0 0 0 0 End of periodTime pointPlaceboOFG OFG OFG OFG OFG OFG OFG Dula N = 55 3 mg 12 mg 24 mg 36 mg-136 mg-2 45 mg-145 mg-21.5 mg N = 51 N = 56 N = 47 N = 27 N = 34 N = 31 N = 32 N = 50 Vomiting Prevalence (%) After the 1st dose 1.8 5.9 21.4 27.7 33.3 20.6 35.5 21.9 8.0 0 ≤ Weeks ≤ 12 0 5.9 19.6 25.5 33.3 17.6 35.5 21.9 6.0 12 < Weeks ≤ 16 0 0 1.9 6.7 7.7 5.9 0 3.1 0 16 < Weeks ≤ 20 1.9 0 1.9 2.2 7.7 0 0 0 0 20 < Weeks ≤ 26 0 0 1.9 0 7.7 0 3.3 0 2.0 26 < Weeks ≤ End of treatment 0 0 5.6 0 4.5 0 0 0 0 period Incidence (%) After the 1st dose 1.8 5.9 21.4 27.7 33.3 20.6 35.5 21.9 8.0 0 ≤ Weeks ≤ 12 0 5.9 19.6 25.5 33.3 17.6 35.5 21.9 6.0 12 < Weeks ≤ 16 0 0 0 4.4 3.8 5.9 0 3.1 0 16 < Weeks ≤ 20 1.9 0 0 0 3.8 0 0 0 0 20 < Weeks ≤ 26 0 0 0 0 3.8 0 3.3 0 2.0 26 < Weeks ≤ End of treatment 0 0 2.8 0 0 0 0 0 0 period Onset (%) After the 1st dose 1.8 5.9 21.4 27.7 33.3 20.6 35.5 21.9 8.0 0 ≤ Weeks ≤ 12 0 5.9 19.6 25.5 33.3 17.6 35.5 21.9 6.0 12 < Weeks ≤ 16 0 0 0 2.2 0 2.9 0 0 0 16 < Weeks ≤ 20 1.9 0 0 0 0 0 0 0 0 20 < Weeks ≤ 26 0 0 0 0 0 0 0 0 2.0Time pointPlaceboOFG OFG OFG OFG OFG OFG OFG Dula N = 55 3 mg 12 mg 24 mg 36 mg-136 mg-2 45 mg-145 mg-21.5 mg N = 51 N = 56 N = 47 N = 27 N = 34 N = 31 N = 32 N = 50 26 < Weeks ≤ End of treatment 0 0 2.8 0 0 0 0 0 0 period Diarrhea Prevalence (%) After the 1st dose 7.3 21.6 16.1 14.9 25.9 5.9 29.0 28.1 12.0 0 ≤ Weeks ≤ 12 5.5 19.6 14.3 12.8 18.5 2.9 29.0 25.0 8.0 12 < Weeks ≤ 16 1.9 4.0 3.8 4.4 11.5 2.9 3.3 9.4 6.0 16 < Weeks ≤ 20 1.9 4.2 1.9 2.2 3.8 0 3.3 3.2 6.1 20 < Weeks ≤ 26 0 4.3 1.9 0 7.7 0 3.3 3.2 4.1 26 < Weeks ≤ End of treatment 0 0 5.6 0 4.5 0 4.5 4.3 4.7 period Incidence (%) After the 1st dose 7.3 21.6 16.1 14.9 25.9 5.9 29.0 28.1 12.0 0 ≤ Weeks ≤ 12 5.5 19.6 14.3 12.8 18.5 2.9 29.0 25.0 8.0 12 < Weeks ≤ 16 0 2.0 0 2.2 7.7 2.9 0 6.3 4.0 16 < Weeks ≤ 20 1.9 2.1 0 2.2 0 0 0 0 2.0 20 < Weeks ≤ 26 0 0 0 0 3.8 0 0 0 0 26 < Weeks ≤ End of treatment 0 0 2.8 0 0 0 0 0 0 period Onset (%) After the 1st dose 7.3 21.6 16.1 14.9 25.9 5.9 29.0 28.1 12.0 0 ≤ Weeks ≤ 12 5.5 19.6 14.3 12.8 18.5 2.9 29.0 25.0 8.0 12 < Weeks ≤ 16 0 2.0 0 0 3.8 2.9 0 3.1 2.0 16 < Weeks ≤ 20 1.9 0 0 2.2 0 0 0 0 2.0Time pointPlaceboOFG OFG OFG OFG OFG OFG OFG Dula N = 55 3 mg 12 mg 24 mg 36 mg-136 mg-2 45 mg-145 mg-21.5 mg N = 51 N = 56 N = 47 N = 27 N = 34 N = 31 N = 32 N = 50 20 < Weeks ≤ 26 0 0 0 0 3.8 0 0 0 0 26 < Weeks ≤ End of treatment 0 0 2.8 0 0 0 0 0 0 period Constipation Prevalence (%) After the 1st dose 1.8 13.7 12.5 12.8 22.2 2.9 3.2 12.5 0 0 ≤ Weeks ≤ 12 1.8 11.8 10.7 12.8 18.5 2.9 0 12.5 0 12 < Weeks ≤ 16 0 8.0 3.8 0 11.5 2.9 0 3.1 0 16 < Weeks ≤ 20 0 2.1 1.9 2.2 11.5 2.9 0 3.2 0 20 < Weeks ≤ 26 0 2.1 3.8 0 7.7 3.0 3.3 3.2 0 26 < Weeks ≤ End of treatment 0 2.9 5.6 0 0 3.8 4.5 0 0 period Incidence (%) After the 1st dose 1.8 13.7 12.5 12.8 22.2 2.9 3.2 12.5 0 0 ≤ Weeks ≤ 12 1.8 11.8 10.7 12.8 18.5 2.9 0 12.5 0 12 < Weeks ≤ 16 0 2.0 1.9 0 0 0 0 0 0 16 < Weeks ≤ 20 0 0 0 2.2 3.8 0 0 0 0 20 < Weeks ≤ 26 0 0 1.9 0 0 0 3.3 3.2 0 26 < Weeks ≤ End of treatment 0 0 0 0 0 0 0 0 0 period Onset (%) After the 1st dose 1.8 13.7 12.5 12.8 22.2 2.9 3.2 12.5 0 0 ≤ Weeks ≤ 12 1.8 11.8 10.7 12.8 18.5 2.9 0 12.5 0 12 < Weeks ≤ 16 0 2.0 0 0 0 0 0 0 0Time pointPlaceboOFG OFG OFG OFG OFG OFG OFG Dula N = 55 3 mg 12 mg 24 mg 36 mg-136 mg-2 45 mg-145 mg-21.5 mg N = 51 N = 56 N = 47 N = 27 N = 34 N = 31 N = 32 N = 50 16 < Weeks ≤ 20 0 0 0 0 3.8 0 0 0 0 20 < Weeks ≤ 26 0 0 1.9 0 0 0 3.3 0 0 26 < Weeks ≤ End of treatment 0 0 0 0 0 0 0 0 0 period Abbreviations: Dula = dulaglutide; N = number of participants in a specified treatment group.

[0175] Note: Prevalence refers to the proportion of participants who have an event during a time interval. Incidence refers to the proportion of participants who have a new event during a time interval. Onset refers to the time interval where participants who have an event were first present. After the 1st dose refers to the interval from Week 0 to end of treatment period. Example 5 – Phase 3 Clinical Study

[0176] In a randomized, double-blind Phase 3 clinical trial, 559 adults were enrolled with type 2 diabetes and inadequate glycemic control with diet and exercise alone to examine the efficacy and safety of 3 dose levels (3 mg, 12 mg, and 36 mg) of OFG compared with once-daily administered placebo for 40 weeks. The primary endpoint was A1C reduction from baseline of 8.0% compared to placebo at 40 weeks using the efficacy estimand. Key secondary endpoints included percent weight reduction from baseline of 90.2 kg and weight reduction from baseline of 90.2 kg. Trial Design

[0177] A 40-week Phase^3, randomized, double-blind, placebo-controlled study was designed to examine the efficacy and safety of 3 dose levels (3 mg, 12 mg, and 36 mg) of once-daily administered OFG, compared with once-daily administered placebo in participants with type 2 diabetes and inadequate glycemic control with diet and exercise alone. A total of 559 patients across the U.S., China, India, Japan, and Mexico were randomized 1:1:1:1 to receive either 3 mg, 12 mg, or 36 mg OFG or placebo. All participants in the OFG treatment arms started the study at a dose of OFG 1 mg once-daily and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 3 mg (via a 1 mg step), 12 mg (via steps at 1 mg, 3 mg, and 6 mg), or 36 mg (via steps at 1 mg, 3 mg, 6 mg, 12 mg, and 24 mg). Flexible dosing was not permitted. Participants

[0178] Eligible male or female participants were ≥18 years of age with an HbA1c level between ≥7.0% and ≤9.5% and a BMI of ≥23 kg / m2. Procedures

[0179] In this phase 3, randomized, double-blind, placebo-controlled trial, 559 participants with type 2 diabetes and inadequate glycemic control with diet and exercise alone were enrolled. The participants were naïve to insulin use, had not been treated with any antihyperglycemic medication during the 90 days preceding Visit 1, and had a baseline HbA1c level between ≥7.0% and ≤9.5% and a BMI of ≥23 kg / m2. Participants were randomly assigned in a 1:1:1:1 ratio to receive 3 mg OFG, 12 mg OFG, 36 mg of OFG or placebo, respectively, once daily for 40 weeks.

[0180] The trial consisted of 3 periods: (1) a screening and lead-in period of up to 4 weeks; (2) a treatment period of 40 weeks including dose escalation and maintenance dose; and (3) a safety follow-up period of 2 weeks. The change from baseline in HbA1c level was assessed at the end of the study period of 40 weeks. Change and percentage change from baseline in body weight were also assessed at week 40. Additionally, treatment related adverse events were further assessed at the end of the trial (week 40). Endpoint

[0181] The primary endpoint was A1C reduction from baseline of 8.0% compared to placebo at 40 weeks using the efficacy estimand. Key secondary endpoints included percent weight reduction from baseline of 90.2 kg and weight reduction from baseline of 90.2 kg. Statistical Analyses

[0182] A sample size of 559 participants was calculated to provide at least 90% power for testing superiority of OFG (3 mg, 12 mg, and 36 mg, each tested in parallel) versus placebo at a2-sided significance level of 0.0167, relative to the primary endpoint (mean change in HbA1c from baseline to 40 weeks). The estimand used for efficacy analyses was an “efficacy estimand,” representing efficacy had all participants remained on study intervention (with possible dose interruptions) for 40 weeks without initiating additional antihyperglycemic medications (>14 days of use). Results

[0183] OFG met the primary endpoint of superior A1C reduction compared to placebo at 40 weeks, lowering A1C by an average of 1.3% to 1.6% from a baseline of 8.0%, using the efficacy estimand. In a key secondary endpoint, more than 65% of participants taking the highest dose of OFG achieved an A1C less than or equal to 6.5%, which is below the American Diabetes Association’s defined threshold for diabetes. In an additional key secondary endpoint, participants taking OFG lost an average of 16.0 lb (7.9%) at the highest dose. Given that participants had not yet reached a body weight plateau at the time the study ended, it appears that full weight reduction was not yet attained.

[0184] For the treatment-regimen estimand, each dose of OFG led to statistically significant A1C reductions. In the key secondary endpoint for body weight, 12 mg and 36 mg doses led to statistically significant reductions. Treatment-Regimen Estimand OFG 3 mg OFG 12 mg OFG 36 mg Placebo Primary Endpoint A1C reduction from baseline of 8.0% 1.2% 1.5% 1.5% 0.4%Key Secondary Endpoints Percent weight reduction from baseline 4.5% 5.8% 7.6% 1.7% of 90.2 kg (198.9 lb) Weight reduction from baseline of 4.2 kg 5.2 kg 7.2 kg 1.5 kg 90.2 kg (198.9 lb) (9.3 lb) (11.5 lb) (15.8 lb) (3.4 lb)

[0185] The overall safety and tolerability profile of OFG in ACHIEVE-1 was consistent with injectable GLP-1 class therapies. The most commonly reported adverse effects were gastrointestinal-related and generally mild to moderate in severity. No hepatic safety signal was observed. Example 6 – Phase 3 Clinical Study

[0186] In this phase 3 clinical study, OFG is administered to a subject per the Clinical Study Protocol as described herein to compare the effect of OFG with insulin glargine on the incidence of MACE-4 in individuals with T2D, obesity or overweight with at least one weight related comorbidity who are at increased risk for cardiovascular (CV) events. A brief summary of this study is provided in the following table. Ex. No. Description Primary Primary and Total Treatments / Objective Key Secondary number of maintenance Study ID Endpoints participants dose Ex. 5 A phase 3, To MACE-4: Event2620OFG 36open-label demonstrate • MI driven mg or ACHIEVE study of once that OFG is • Stroke (~122 MTD -4 (GZGS) daily OFG non- inferior • Hospitalizatio MACE compared to insulin n for UA -4) Insulin with insulin glargine • CV death Glargine glargine in (with a NIM 100 U / mL adult of 1.8) in participants occurrence with T2D and of MACE-4 obesity or overweight at increased cardiovascular risk

[0187] A detailed description of this study is provided below. Table 15. Objectives, Endpoints, and Estimands: Endpoints Objectives Primary To demonstrate that OFG is non-inferior to Time to first occurrence of any MACE-4 event insulin glargine (with a non-inferiority • MI margin of 1.8) in occurrence of MACE-4 • stroke events • hospitalization for unstable angina, or • CV death Table 16. Intervention Groups and Duration: This table lists the OFG Insulin glargine interventions used in this clinical study. Intervention Name Dosage Level(s) 1 mg, 3 mg, 6 mg, prefilled pen containing 300 units (3 12 mg, 24 mg, and mL), individualized dosing to achieve a 36 mg capsules fasting blood glucose (FBG) target of ≤100 mg / dl (≤5.6 mmol / L) Route of Administration Oral QD Subcutaneous injection QD

[0188] A schema showing patient visits and treatment schedules including time, durations and doses is shown in Fig. 1.

[0189] The abbreviations and footnotes used in Fig. 1 are provided below. FTV = final treatment visit; MACE = major adverse cardiovascular events; QD = once daily. a) All participants will be on stable treatment of at least 1 and no more than 3 oral antihyperglycemic drugs (metformin, sodium-glucose co-transporter 2-inhibitors (SGLT- 2 inhibitors), or sulfonylurea). b) The starting dose of insulin glargine will be 10 IU / day, titrated to a FBG ≤100 mg / dL (≤5.6 mmol / L) following an insulin dosing schedule. Participants will titrate insulin glargine dose in a weekly manner and will make the dose decision with the investigator for the first 8 weeks (phone or clinic visit). From Week 8 to Week 16participants will continue weekly titration and will have phone or clinic visit every other week checking the accurate dose decision based on the algorithm. c) Participants will be on study intervention for at least 12 months and will continue until study completion criteria are met. d) Participants reaching 104 weeks of treatment prior to study closure will continue repeating visits every 12 weeks until study completion criteria are met. Study Population - Inclusion Criteria

[0190] Type of participant and disease characteristics 1. Have a clinical diagnosis of T2D based on the World Health Organization classification or other locally applicable diagnostic standards. 2. Have HbA1c value at screening Visit 1 a. between ≥7.0% (53 mmol / mol) and ≤10.5% (91 mmol / mol) if background diabetes medication does not include a sulfonylurea, or b. between ≥7.5% (58 mmol / mol) and ≤10.5% (91 mmol / mol) if background diabetes medication includes a sulfonylurea. 3. Are on stable treatment of at least 1 and no more than 3 oral antihyperglycemic drugs for at least 90 days before screening Visit 1. Allowed antihyperglycemic drugs • metformin (required dose ≥1500 mg / day unless lower dose required per country- specific labeling based on eGFR or other renal function measure), • SGLT-2 inhibitors, or • sulfonylurea. 4. Have increased risk of CV events Study Intervention(s) and Concomitant Therapy

[0191] This table lists the interventions used in this clinical study. Table 17. Intervention Name OFG Insulin glargineDosage Level(s) 1 mg, 3 mg, 6 mg, prefilled pen containing 300 units (3 mL), 12 mg, 24 mg, and individualized dosing to achieve a FBG 36 mg capsules target of ≤100 mg / dl (≤5.6 mmol / L) Route of Administration Oral QD Subcutaneous injection QD Participants randomized to OFG

[0192] The starting dose of OFG will be 1 mg QD for 4 weeks, followed by increases in dose every 4 weeks up to 36 mg QD as outlined in this table. Table 18. OFG Dose Escalation Visit (Week) Weekly Dose Additional dosing instruction Visit 3 (Week 0) 1 mg QDDose increases occur every 4 weeksVisit 7 (Week 4) 3 mg QD until the 36 mg dose, or maximum Visit 11 (Week 8) 6 mg QD Visit 13 (Week 12) 12 mg QD tolerated dose (MTD) is reached. Visit 15 (Week 16) 24 mg QD Visit 16 (Week 20) 36 mg QD OFG is administered orally once daily. Participants randomized to insulin glargine

[0193] The starting dose of insulin glargine will be 10 IU / day, participants should administer their daily doses at the time of day agreed upon between the participant and the investigator, typically before bedtime. Insulin glargine will be titrated to a FBG ≤100 mg / dL (≤5.6 mmol / L) following the insulin titration schedule in the Treat-to-Target trial (adapted from Riddle et al. 2003). Table 19. Insulin Dose Schedule Median FBGaDose Adjustment of Insulin Glarginemg / dL mmol / L(units / day)<70 <3.9Decrease by 2 to 4 unitsb,c70 to 99 3.9 to 5.5 No adjustment 100 to 119 5.6 to 6.6 Increase by 2 units 120 to 139 6.7 to 7.7 Increase by 4 units 140 to 179 7.8 to 9.9 Increase by 6 units ≥180 ≥10.0 Increase by 8 unitsaBased on the last 3 fasting self-monitored body glucose (SMBG) values. b Dose should also be decreased by 2 to 4 units in the following situations • If multiple episodes of non-severe hypoglycemia were recorded during the assessment period at any time during the day; and / or • If at least 1 episode that met the criteria for severe hypoglycemia (events requiring assistance to administer therapy) or was associated with SMBG value <54 mg / dL (<3.0 mmol / L) was recorded during the assessment period. c If only 1 hypoglycemic episode with SMBG value ≥54 mg / dL (≥3.0 mmol / L) and <70 mg / dL (<3.9 mmol / L) was recorded, insulin dose should not be changed. Efficacy Assessments Assessments for the Primary Objective

[0194] The primary objective of the study is to demonstrate that OFG is non-inferior to insulin glargine with a non-inferiority margin of 1.8 in occurrence of MACE-4 events. The endpoints include circulating endothelial cells (CEC)-confirmed MI, stroke, hospitalization for unstable angina and CV death. Example 7 – Phase 1 Clinical Data

[0195] In randomized, open-label, crossover Phase 1 clinical studies A and B, the effect of food on OFG concentration in healthy adults after a single 3 mg dose (study A) and after a 16 mg daily dose (study B), which was reached by weekly dose escalation starting with 2 mg, was evaluated.

[0196] Based on statistical analysis, Cmax was 23% (study A) and 21% (study B) lower in the fed state. AUC(0-∞), and AUC(0-24) were 24% (study A) and 18% (study B) lower when administered with food. Tmax and T1 / 2 were similar with or without food. In study A and Study B, treatment emergent adverse events (TEAEs) were mild. In study B, TEAEs occurred most often with 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%).

[0197] Overall mean exposure to OFG based on Cmax and AUC was numerically lower when administered with food and had little effect on Tmax and T1 / 2. These PK differences between fed and fasted administrations were not expected to result in clinically meaningful differences in OFG safety and efficacy based on exposure response relationship.Table 20 STUDY A – 3 mg STUDY B –16 mg (with titration) N 12 34 Age (years)a45.0 (10.9) 42.8 (10.2) Weight (kg)a82.3 (9.8) 73.1 (10.4) Fasted Fed Fasted Fed Cmax (ng / mL)b13.4 (44%) 10.1 (44%) 80.5 (64%) 67.5 (40%) AUC (ng∙h / ml)b362 (33%)c260 (43%)c1200 (58%)d1050 (40%)dTmax (h)e8.0 (4.0-24.0) 8.0 (4.0-12.0) 8.0 (4.0-16.0) 8.0 (4.0-24.0) T1 / 2 (h)f29.5 (19.6-50.6) 27.9 (19.9-37.9) 26.0 (8.0-73.4) 24.6 (8.7-87.1)amean (SD),bgeometric LS mean (geometric CV%),cAUC(0-∞),dAUC(0-24),emedian (range),fgeometric mean (range) Examples 8-12 – Additional Phase 3 Clinical Studies

[0198] Examples 8-12 describe additional phase 3 clinical studies which are summarized in Table 21 below. OFG is administered to a subject per the respective Clinical Study Protocols, the contents of which are incorporated herein by reference, to study the effect of OFG for treating individuals with T2D, obesity, or overweight with at least one weight related comorbidity. Table 21. Summary of Additional Phase 3 Clinical Trials Ex. No. Description Primary Primary Treatment Total Treatments / Objective and Key duration number of Maintenance Study ID Secondary for primary participants Doses Endpoints objective Type 2 Diabetes (T2D) Ex. 8 A phase 3, To • HbA1c 40 weeks 888 OFG 3 mg randomized, demonstrate • % open-label that OFG 3 participants OFG 12 mg study to mg, 12 mg attainingACHIEVE investigate and / or 36 mg HbA1c <7% OFG 36 mg -2 the efficacy are and ≤6.5% (GZGV) and safety of noninferior • Fasting Dapagliflozin once daily to glucose 10 mg oral OFG dapagliflozin • Body compared in glycemic weight with control, • nonHDL dapagliflozin using an and in adult NIM of triglycerides participants 0.3% • Systolic with type 2 blood diabetes and pressure inadequate glycemic control with metformin Ex. 9 A phase 3, To • HbA1c 52 weeks 1576 OFG 12 mg randomized, demonstrate • % ACHIEVE open-label that participants OFG 36 mg -3 study to (i) OFG 36 attaining (GZGU) investigate mg is HbA1c <7% Oral the efficacy noninferior and ≤6.5% semaglutide and safety of to • Fasting 7 mg once daily semaglutide glucose oral OFG 14 mg in • Body Oral compared glycemic weight semaglutide with oral control 14 mg semaglutide and / or in adult (ii) OFG 12 participants mg is with type 2 noninferior diabetes and to inadequate semaglutide glycemic 7 mg in control with glycemic metformin controlEx. 10 A phase 3, To • HbA1c 40 weeks 520 OFG 3 mg randomized, demonstrate • % ACHIEVE- double-blind that OFG 12 participants Note: OFG 12 mg 5 (GZGW) study to mg and / or attaining During the investigate 36 mg is HbA1c <7% study, all OFG 36 mg the efficacy superior to and ≤6.5% participants and safety of placebo in • Fasting will be on Placebo once daily glycemic glucose background oral OFG control • Body treatment compared weight with insulin with placebo • nonHDL glargine in adult and alone; or a participants triglycerides combination with type 2 • Systolic of insulin diabetes and blood glargine inadequate pressure with (i) glycemic metformin, control with or (ii) insulin SGLT-2 glargine, with inhibitor, or or without (iii) both metformin metformin and / or SGLT- and SGLT-2 2 inhibitor inhibitor. Chronic Weight Management Ex. 11 A Phase 3, To • Body 72 weeks 3000 OFG 6 mg randomized, demonstrate weight ATTAIN-1 double-blind that OFG 6 • % of OFG 12 mg (GZGP) study to mg, 12 mg, participants investigate and / or 36 who achieve OFG 36 mg the efficacy mg QD is a body and safety of superior to weight Placebo once-daily placebo for reduction of: oral OFG body weight • ≥5%, ≥10%, compared ≥15%, or with placebo ≥20% in adult • Waist participants circumferen with obesity ce or overweight • nonHDL with weight- and related triglycerides comorbidities• Systolic blood pressure Ex. 12 A Phase 3, To • Body 72 weeks 1500 OFG 6 mg randomized, demonstrate weight ATTAIN-2 double-blind that OFG 6 • % of OFG 12 mg (GZGQ) study to mg, 12 mg participants investigate and / or 36 who achieve OFG 36 mg the efficacy mg is a body and safety of superior to weight Placebo once-daily placebo in reduction of: oral OFG change from • ≥5%, ≥10%, compared baseline for ≥15% with placebo body weight • Waist in adult circumferen participants ce with obesity • HbA1c and or overweight other and type 2 glycemic diabetes control measures • nonHDL and triglycerides • Systolic blood pressure Example 13 – Additional Phase 3 Clinical Study

[0199] Overall Design: this GZPN study is a Phase 3b, multicenter, randomized, parallel-arm, double-blind, placebo-controlled study.

[0200] Study participants will be randomly assigned in a 3:2 ratio (OFG 36 mg or MTD (24 mg or 36 mg) and placebo).

[0201] This study will consist of 3 periods: • a screening and lead-in period: up to 2 weeks • a treatment period: 52 weeks, including dose escalation and maintenance dose, and • a safety follow-up period: 2 weeks.

[0202] Brief Summary:

[0203] The purpose of this study is to measure efficacy and safety of OFG compared with placebo, in achieving maintenance of body weight reduction from the 72 weeks of tirzepatide or semaglutide treatment in participants who have obesity or overweight with weight-related comorbidities and previously participated in Study SURMOUNT-5.

[0204] Study details include: • The study duration will be up to 56 weeks. • The treatment duration will be up to 52 weeks. • The visit frequency will be every 4 weeks.

[0205] Study Population:

[0206] In general, an individual may take part in this study if they • Had received treatment in Study SURMOUNT 5, and completed Visits 2, 17, and 20 (Weeks 0, 60, 72 respectively) of Study SURMOUNT 5 • Have lost ≥5% of BW during 72-week treatment with tirzepatide or semaglutide • Are reliable, and willing to make themselves available and follow study procedures for the duration of the study. • Are assigned male at birth / assigned female at birth, and their use of contraception should be in accordance with the local regulations for participation in clinical trials. • Are capable of giving signed informed consent.

[0207] Number of Participants:

[0208] Approximately 320 participants will be randomly assigned in a 3:2 ratio to receive OFG 36 or MTD (24 mg or 36 mg), or placebo, respectively.

[0209] Intervention Groups and Duration:

[0210] This table lists the interventions to be used in this clinical study. Intervention Name OFG Placebo Dosage Level(s) 1 mg, 3 mg, 6 mg, 12 mg, 24 mg, Capsule of OFG placebo to and 36 mg capsules matchRoute of Oral QD Oral QD Administration Abbreviation: QD = once daily All participants will initiate treatment with a 12 mg QD dose of OFG or matching placebo and increase dose every 4 weeks until the randomized maintenance dose of 36 mg or MTD (24 mg or 36 mg) is reached.

[0211] A schema showing patient visits and treatment schedules including time, durations and doses is shown in Fig. 8.

[0212] A summary of this clinical study is provided in the following table. Table 22. Ex. 13 A Phase 3b, To To 52 weeks 320 OFG 12 mg randomized, investigate demonstrate ATTAIN- double-Blind, whether that OFG 36 MTD of MAITAIN placebo- switching mg or MTD, OFG 24 mg (GZPN) controlled from once- (24 mg or 36 & study to weekly mg) is OFG 36 mg evaluate the injectable superior to efficacy and tirzepatide or placebo at safety of semaglutide week 52 for switching to (maximum the mean OFG once tolerated percent daily 36 mg dose) to maintenance or maximum daily oral of body tolerated dose OFG 36 mg weight (24 mg or 36 or MTD (24 reduction mg) versus mg or 36 achieved with placebo for mg) in 72 weeks of maintenance participants treatment of body with obesity with weight or tirzepatide reduction in overweight 15mg or participants with MTD (10 mg who have comorbiditie or 15 mg) in obesity or s (without randomized overweight T2D) can participants with weight- lead to who achieved related superior a body weight long-term plateau.comorbidities maintenance . of body weight reduction compared to switching to placebo.

[0213] The objectives, endpoints, and estimands are provided below. Participants treated with tirzepatide in SURMOUNT-5 Objectives Endpoints Primary To demonstrate that OFG 36 mg or MTD, (24 Percent maintenance of BW reduction mg or 36 mg) is superior to placebo at week achieved during the 72 weeks of tirzepatide 52 for the mean percent maintenance of BW treatment reduction achieved with 72 weeks of treatment with tirzepatide 15mg or MTD (10 mg or 15 mg) in randomized participants who achieved a BW plateaua. Secondary To demonstrate that OFG 36 mg or MTD (24 • Assessment (yes / no) of mg or 36 mg) is superior to placebo at Week • maintaining ≥80% of the BW reduction 52 for maintenance of BW reduction achieved achieved during 72 weeks of tirzepatide with 72 weeks treatment of tirzepatide 15mg treatment or MTD (10 mg or 15 mg) in randomized participants who have reached a BW plateaua• maintaining ≥ 15% BW reduction for participants who have already lost ≥15% BW after 72-week of tirzepatide treatment To demonstrate that OFG 36 mg or MTD (24 Percent change in body weight from baseline mg or 36 mg) is superior to placebo at week prior to the initiation of tirzepatide treatment 52 for the mean percent change in body weight from baseline in all randomized participants Abbreviations: BW = body weight; MTD = maximum tolerated dose a BW plateau is defined as <5% BW change between visit 17 (week 60) and Visit 20 (Week 72) of Study GPHJ.Participants treated with semaglutide in SURMOUNT-5 Objectives Endpoints Primary To demonstrate that OFG 36 mg or MTD (24 Percent maintenance of BW reduction mg or 36 mg) is superior to placebo at Week achieved during the 72 weeks of semaglutide 52 for the mean percent maintenance of BW treatment reduction achieved with 72 weeks of treatment with semaglutide 2.4 mg or MTD (1.7 mg or 2.4 mg) in randomized participants who achieved a BW plateaua. Secondary To demonstrate that OFG 36 mg or MTD (24 • Assessment (yes / no) of mg or 36 mg) is superior to placebo at Week • maintaining ≥80% of the BW 52 for maintenance of BW reduction achieved reduction achieved during 72 weeks of with 72 weeks treatment of semaglutide 2.4 semaglutide treatment. mg or MTD (1.7 mg or 2.4 mg) in randomized participants who have reached a • maintaining ≥ 15% BW reduction for BW plateauaparticipants who have already lost ≥15% BW after 72 weeks of semaglutide treatment To demonstrate that OFG 36 mg or MTD (24 Percent change in BW from SURMOUNT-5 mg or 36 mg) is superior to placebo at Week baseline prior to the initiation of semaglutide 52 for the mean percent change in BW from treatment SURMOUNT-5 baseline in all randomized participants Abbreviations: BW = body weight; MTD = maximum tolerated dose a BW plateau is defined as <5% BW change between visit 17 (week 60) and Visit 20 (Week 72) of Study GPHJ. Primary estimand

[0214] The primary estimand evaluated in this study is the efficacy estimand and the secondary estimand is the modified treatment-regimen estimand. Efficacy estimand

[0215] The clinical question of interest is: What is the treatment difference at Week 52 for OFG versus placebo in mean percent maintenance of body weight (BW) reduction achieved with 72-week treatment with tirzepatide or semaglutide, as an adjunct to a reduced-calorie diet and increased physical activity in participants with obesity or overweight with at least 1 weight-related comorbid condition,assuming that participants had stayed on treatment, had not taken other AOMs, GLP-1 RAs, GIP / GLP-1 RAs, or DPP-4 inhibitors, had not had bariatric surgery or other weight management procedures, and assuming that participants who took rescue OFG would not have received any additional improvement from their randomized study treatment? Example 14

[0216] A patient with and in need of treatment for at least one of T2DM, obesity, and overweight with at least one weight related comorbidity is treated via subcutaneous administration with a peptide that agonizes at least one of the GLP-1 receptor, the GIP receptor, and the Glucagon receptor. The treatment continues until the identified treatment goal is reached.

[0217] The treatment goal may be at least one of a specific reduction in HbA1c, a specific amount of weight loss, or some other therapeutic endpoint. The treatment goal may be a lack of further therapeutic response (i.e., a treatment plateau), such as no further reduction in HbA1c, no further weight loss, or some other therapeutic endpoint, with continued treatment. The treatment goal may be a medically appropriate treatment duration, such as 56 or 72 weeks. It is understood that where such treatment is discontinued, the patient can be expected to lose some or all of the therapeutic benefits of the subcutaneous peptide treatment, which may manifest, for example, as an increase in HbA1c and / or body weight.

[0218] The patient is then treated via oral administration with a non-peptide drug that agonizes at least one of the GLP-1 receptor, the GIP receptor, and the Glucagon receptor. The non-peptide drug may be Compound 1, Compound 2, Compound 3, or combination thereof. Alternatively, the orally administered drug may be other oral non-peptide treatments described herein.

[0219] The oral non-peptide drug is first administered within about the same treatment interval as used for the subcutaneous peptide treatment. Where the subcutaneous peptide treatment interval was once daily, the oral non-peptide drug is administered within about one day of stopping the subcutaneous peptide treatment. Where the subcutaneous peptide treatment interval was once weekly, the oral non-peptide drug is administered within about one week of stopping the subcutaneous peptide treatment. Where the subcutaneous peptide treatment interval was once bi-weekly, the oral non-peptide drug is administered within about two weeks of stopping the subcutaneous peptide treatment. Where the subcutaneous peptide treatment interval was oncemonthly, the oral non-peptide drug is administered within about four weeks or one month of stopping the subcutaneous peptide treatment.

[0220] The oral non-peptide drug is administered at a dose, frequency, and duration sufficient to substantially maintain treatment effect provided by the subcutaneous peptide treatment. The treatment effect to be maintained may be a specific reduction in at least one of HbA1c, a specific level of weight loss, or some other therapeutic endpoint. For instance, where the subcutaneous peptide treatment provided a 15% weight loss, an oral non-peptide dose effective to provide a similar weight loss will be used. For instance, the dose first administered may be therapeutically effective and its continued administration may be sufficient to substantially maintain treatment effect provided by the subcutaneous peptide treatment. For instance, continued administration of the first dose may not be sufficient to substantially maintain treatment effect provided by the subcutaneous peptide treatment and a second higher therapeutically effective dose level is then administered. For instance, the second dose administered may be therapeutically effective and its continued administration may be sufficient to substantially maintain treatment effect provided by the subcutaneous peptide treatment. For instance, continued administration of the second dose may not be sufficient to substantially maintain treatment effect provided by the subcutaneous peptide treatment and a third higher therapeutically effective dose is then administered. For instance, the third dose administered is therapeutically effective and its continued administration is sufficient to substantially maintain treatment effect provided by the subcutaneous peptide treatment.

[0221] To substantially maintain the treatment effect, the oral non-peptide treatment will be first administered at a dose known to be therapeutically effective for providing a treatment effect. Where the oral non-peptide treatment is Compound 1a as described in Example 2, it will be administered at a dose of at least 12 mg without the use of lower starting doses.

[0222] In the treatment methods described herein, the oral treatment will not result in intolerable side effects, such as gastrointestinal side effects like nausea, vomiting, and diarrhea even without starting the oral treatment at a sub-efficacious titration dose. This makes it possible to start with a higher, therapeutically effective dose of the oral treatment. Where the oral non-peptide treatment is Compound 1a as described in Example 2, it will be administered at a starting dose of at least 12 mg once daily without the prior administration of lower doses, such any one or more of 1 mg, 2 mg, 3 mg, 6 mg daily starting or escalation doses.

[0223] To substantially maintain the treatment effect provided by the subcutaneous peptide treatment and / or to increase the treatment effect provided by oral non-peptide treatment, the dose and / or treatment frequency of the oral non-peptide treatment may be increased to a second higher therapeutically effective level. Where the oral non-peptide treatment is Compound 1a as described in Example 2, the second higher dose may be 24 mg once daily.

[0224] To substantially maintain the treatment effect provided by the subcutaneous peptide treatment and / or to increase the treatment effect provided by oral non-peptide treatment, the dose and / or treatment frequency of the oral non-peptide treatment may be increased to a third higher therapeutically effective level. Where the oral non-peptide treatment is Compound 1a as described in Example 2, the third higher dose may be 36 mg once daily.

Claims

CLAIMS 1. A method for treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, the method comprising starting with orally administering to the subject a first therapeutically effective dose level of a GLP-1 receptor NPA compound for a first duration, wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.

2. The method of claim 1, wherein the subject has completed a prior GLP-1 RA treatment.

3. The method of claim 1, wherein administering the first therapeutically effective dose level for the first duration is sufficient to substantially maintain the therapeutic effect.

4. The method of claim 1, wherein administering the first therapeutically effective dose level for the first duration is insufficient to substantially maintain the therapeutic effect.

5. The method of any one of claims 1-4, further comprising orally administering a second therapeutically effective dose level of the GLP-1 receptor NPA compound for a second duration, wherein the second therapeutically effective dose level is greater than the first therapeutically effective dose level.

6. The method of claim 5, wherein administering the second therapeutically effective dose level for the second duration is sufficient to substantially maintain the therapeutic effect.

7. The method of claim 5, wherein administering the second therapeutically effective dose level for the second duration is insufficient to substantially maintain the therapeutic effect.

8. The method of any one of claims 1-7, further comprising orally administering a third therapeutically effective dose level of the GLP-1 receptor NPA compound for a third duration, wherein the third therapeutically effective dose level is greater than the second therapeutically effective dose level.

9. The method of claim 8, wherein administering the third therapeutically effective dose level for the third duration is sufficient to substantially maintain the therapeutic effect.

10. The method of any one of claims claim 1-9, wherein dose levels and dosing frequency of the GLP-1 receptor NPA compound are selected to provide an acceptable adverse event profile.

11. The method of any one of claims 1-10, wherein the first duration is about 2 weeks.

12. The method of any one of claims 1-10, wherein the first duration is at least about 2 weeks.

13. The method of any one of claims 1-10, wherein the first duration is about 4 weeks.

14. The method of any one of claims 1-10, wherein the first duration is at least about 4 weeks.

15. The method of any one of claims 1-10, wherein the first duration is about 26 weeks.

16. The method of any one of claims 1-10, wherein the first duration is at least about 26 weeks.

17. The method of any one of claims 1-10, wherein the first duration is about 48 weeks.

18. The method of any one of claims 1-10, wherein the first duration is at least about 48 weeks.

19. The method of any one of claims 1-10, wherein the first duration is about 52 weeks.

20. The method of any one of claims 1-10, wherein the first duration is at least about 52 weeks.

21. The method of any one of claims 1-20, wherein the second duration is about 2 weeks.

22. The method of any one of claims 1-20, wherein the second duration is at least about 2 weeks.

23. The method of any one of claims 1-20, wherein the second duration is about 4 weeks.

24. The method of any one of claims 1-20, wherein the second duration is at least about 4 weeks.

25. The method of any one of claims 1-20, wherein the second duration is about 26 weeks.

26. The method of any one of claims 1-20, wherein the second duration is at least about 26 weeks.

27. The method of any one of claims 1-20, wherein the second duration is about 48 weeks.

28. The method of any one of claims 1-20, wherein the second duration is at least about 48 weeks.

29. The method of any one of claims 1-20, wherein the second duration is about 52 weeks.

30. The method of any one of claims 1-20, wherein the second duration is at least about 52 weeks.

31. The method of any one of claims 1-20, wherein the first duration and the second duration are a combined period selected from about 36 weeks, about 40 weeks, about 48 weeks, about 52 weeks, about 72 weeks, and about 104 weeks.

32. The method of any one of claims 1-20, wherein the first duration and the second duration are a combined period selected from at least about 36 weeks, at least about 40 weeks, at least about 48 weeks, at least about 52 weeks, at least about 72 weeks, and at least about 104 weeks 33. The method of any one of claims 1-32, wherein the third duration is about 2 weeks.

34. The method of any one of claims 1-32, wherein the third duration is at least about 2 weeks.

35. The method of any one of claims 1-32, wherein the third duration is about 4 weeks.

36. The method of any one of claims 1-32, wherein the third duration is at least about 4 weeks.

37. The method of any one of claims 1-32, wherein the third duration is about 26 weeks.

38. The method of any one of claims 1-32, wherein the third duration is at least about 26 weeks.

39. The method of any one of claims 1-32, wherein the third duration is about 48 weeks.

40. The method of any one of claims 1-32, wherein the third duration is at least about 48 weeks.

41. The method of any one of claims 1-32, wherein the third duration is about 52 weeks.

42. The method of any one of claims 1-32, wherein the third duration is at least about 52 weeks.

43. The method of any one of claims 1-42, wherein the first duration and the second duration and the third duration are a combined period selected from about 36 weeks, about 40 weeks, about 48 weeks, about 52 weeks, about 72 weeks, and about 104 weeks.

44. The method of any one of claims 1-42, wherein the first duration and the second duration and the third duration are a combined period selected from at least about 36 weeks, at least about 40 weeks, at least about 48 weeks, at least about 52 weeks, at least about 72 weeks, and at least about 104 weeks 45. The method of any one of claims 1-44, wherein the prior GLP-1 RA treatment comprises treatment with a GLP-1 RA peptide.

46. The method of any one of claims 1-44, wherein the prior GLP-1 RA treatment comprises treatment with a GLP-1 RA peptide selected from tirzepatide or semaglutide.

47. The method of any one of claims 1-44, wherein the prior GLP-1 RA treatment comprises treatment with a subcutaneously administered GLP-1 RA peptide.

48. The method of any one of claims 1-47, wherein the GLP-1 receptor NPA compound is Compound 1.

49. The method of any one of claims 1-48, wherein the GLP-1 receptor NPA compound is Compound 1 and the first therapeutically effective dose level of the GLP-1 receptor NPA compound is about 12 mg QD.

50. The method of any one of claims 1-49, wherein the GLP-1 receptor NPA compound is Compound 1 and the second therapeutically effective dose level of the GLP-1 receptor NPA compound is about 24 mg QD.

51. The method of any one of claims 1-50, wherein the GLP-1 receptor NPA compound is Compound 1 and the third therapeutically effective dose level of the GLP-1 receptor NPA compound about 36 mg QD.

52. The method of any one of claims 1-47, wherein the GLP-1 receptor NPA compound is Compound 1a.

53. The method of any one of claims 1-47, wherein the GLP-1 receptor NPA compound is Compound 1a hemicalcium salt hydrate (Compound 1a 0.5 Ca hydrate).

54. The method of any one of claims 1-53, wherein the prior GLP-1 RA treatment was administered in subject having T2DM, obesity, and / or overweight with at least one weight related comorbidity.

55. The method of any one of claims 1-54, wherein the subject reached a body weight plateau from the prior GLP-1 RA treatment.

56. The method of any one of claims 1-55, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 5%.

57. The method of any one of claims 1-55, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 10%.

58. The method of any one of claims 1-55, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is a body weight reduction of at least 15%.

59. The method of any one of the claims 1-58, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to substantially maintain a body weight reduction provided by the prior GLP-1 RA treatment.

60. The method of any one of the claims 1-59, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain at least 80% of a body weight reduction provided by the prior GLP-1 RA treatment.

61. The method of any one of the claims 1-60, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain at least 90% of a body weight reduction provided by the prior GLP-1 RA treatment.

62. The method of any one of claims 1-61, wherein the subject reached a plateau in HbA1c level from the prior GLP-1 RA treatment.

63. The method of any one of claims 1-62, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 7.5%.

64. The method of any one of claims 1-62, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 7.0%.

65. The method of any one of claims 1-62, wherein the therapeutic effect provided by the prior GLP-1 RA treatment is an HbA1c level of no more than about 6.5%.

66. The method of any one of claims 1-65, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to substantially maintain an HbA1c level provided by the prior GLP-1 RA treatment.

67. The method of any one of claims 1-66, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 15% greater than an HbA1c level provided by the prior GLP-1 RA treatment.

68. The method of any one of claims 1-67, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 10% greater than an HbA1c level provided by the prior GLP-1 RA treatment.

69. The method of any one of claims 1-68, wherein administering the GLP-1 receptor NPA compound continues at a dose level and duration sufficient to maintain an HbA1c level no more than about 5% greater than an HbA1c level provided by the prior GLP-1 RA treatment.

70. The method any one of claims 1-69, wherein administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 7.5%.

71. The method any one of claims 1-69, wherein administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 7.0%.

72. The method any one of claims 1-69, wherein administering the GLP-1 receptor NPA compound continues at a dose and duration sufficient to maintain an HbA1c level of no more than about 6.5%.

73. The method of any one of claims 1-72, wherein administering the GLP-1 receptor NPA compound is used as an adjunct to diet and exercise.

74. The method of any one of claims 1-73, comprising starting with the orally administering the GLP-1 receptor NPA compound within about 1 to 4 weeks of discontinuing the prior GLP-1 RA treatment.

75. The method of any one of claims 1-73, comprising starting with the orally administering the GLP-1 receptor NPA compound within about 1 to 3 weeks of discontinuing the prior GLP-1 RA treatment.

76. The method of any one of claims 1-73, comprising starting with the orally administering the GLP-1 receptor NPA compound within about 1 to 2 weeks of discontinuing the prior GLP-1 RA treatment.

77. The method of any one of claims 1-73, comprising starting with the orally administering the GLP-1 receptor NPA compound within about 1 week of discontinuing the prior GLP-1 RA treatment.

78. A GLP-1 receptor NPA compound for use in treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, wherein the use comprises starting with orally administering to the subject a first therapeutically effective dose level of the GLP-1 receptor NPA compound for a first duration; and wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.

79. A unit dose of a GLP-1 receptor NPA compound for administration to a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, wherein the administration comprises starting with orally administering a first therapeutically effective dose of a GLP-1 receptor NPA compound for a first duration; and wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.

80. Use of a GLP-1 receptor NPA compound in the manufacture of a medicament for treating a subject who has received a prior GLP-1 RA treatment and achieved a therapeutic effect provided by the prior GLP-1 RA treatment, wherein the use comprises starting with orally administering a first therapeutically effective dose level of a GLP-1 receptor NPA compound for a first duration; and wherein the GLP-1 receptor NPA compound is selected from Compound 1, Compound 1a, Compound 2, Compound 3, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing.

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